About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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July 29, 2015

Sanofi Pays to Get Back Into Oncology

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Posted by Derek

You may recall that Sanofi basically threw its hands up in the air some time back about its entire oncology R&D efforts. Or, since they're so relentlessly French over there, perhaps it was the Gallic Shrug instead. Either one would fit - the company just wasn't seeming to get anywhere. So when that happens, what you do is you pay someone else to do it for you, and in this case, that would be Regeneron. The two companies announced a deal in immuno-oncology this week, and they are indeed paying:

Sanofi is committed to pay at least $1.8 billion in the rich deal, including a $640 million upfront, $750 million of the first $1 billion in costs to reach proof-of-concept data, half of the $650 million tab for developing the PD-1 drug REGN2810, with another $75 million being reallocated to this deal from another pact. The partnership also includes a special $325 million bonus milestone if they hit a high sales target.

There are two ways to look at this, and (at this point) a case can be made for either one. With all the money and effort being thrown around in this area, it's quite possible that Sanofi is late to the party here. On the other hand, it's a wide field, and there are surely surprises left in it, so this may be one of the "end of the beginning" situations instead. I lean a little more towards the latter, since I always have immunology filed away in my mind under "hideously complex with many key aspects unknown". But in that case, it's still true that Sanofi is, to some extent, hoping to get lucky in order to be a strong player in this area, and that's never a good thing to have as an explicit step in a business plan.

And while they would have been even further behind if they'd tried to catch up on their own, this deal does emphasize how much the company felt that their internal R&D had come up short. They let a lot of people go, took a lot of loss on the whole effort, and now they're reaching in for at least another billion dollars more. . .

Comments (8) + TrackBacks (0) | Category: Business and Markets | Cancer

July 28, 2015

An Irresponsible Statement About Curing Cancer

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Posted by Derek

OK, let's stop doing this. Here's the head of the Fred Hutchinson Cancer Institute, telling people that "It is actually plausible that in 10 years we will have cures and therapies for most, if not all, human cancers". I object, on several grounds.

(1) Most, if not all? Although some great progress has been made in the last few years, we still face a number of all-too-common cancers for which a diagnosis is very bad news. Glioblastoma, renal cell carcinoma, hepatocellular carcinoma, the various pancreatic cancers - what do we have to offer? And although immunotherapy is great stuff, these aren't all good candidates, or not yet (and it's not like people haven't been looking at them in view of the latest techniques, either).

(2) Ten years is not a very long time, at least when you're talking about drug discovery and development. It would be best, to meet that timeline, if someone had something in hand right now. Maybe they get another year or so to find it, but that requires everything downstream to go pretty much perfectly. My guess is that Gary Gilliland, the Hutch president, is not sitting on a handful of potential cures that were found last week.

(3) This statement (as reported, anyway) leaves out the diagnostic angle. There has been progress here (a potential early diagnostic for pancreatic cancer was reported recently in Nature, for example), but a lot more is needed. Look at the case of Oliver Sacks: here is an extremely competent and acute physician, but the first diagnosis he had of liver cancer was when it was already metastatic. Not much we can do about that. Without better diagnostics, it's hard to see how we're going to achieve really impressive cure rates.

(4) Finally. . .no. You don't go around telling people that you're going to cure cancer, or Alzheimer's, or what have you. Cures are hard to find, and hard to prove, and most of the things that look like they're going to work actually don't. It is irresponsible to talk as if we're going to solve all these problems in such a way. Sure, tell people that we're making a lot of progress, tell them that we've opened up whole new avenues of therapy in the last few years and that we're excited about what could happen as we explore them, tell them that there's more potential than there's ever been. All true! But telling people that "most, if not all, cancers" are going to be cured in ten years? Over the line.

Comments (79) + TrackBacks (0) | Category: Cancer

July 7, 2015

Another Longevity Target

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Posted by Derek

Add another potential target to the longevity list: this paper in Cell (open access, actually) provides evidence that the well-known Ras-ERK-ETS pathway is also involved in lifespan. This is work in Drosophila, which is one of the usual places to look for this sort of thing.

Figure 6 in the paper proposes a way to tie several longevity targets together - insulin signaling, PI3K/AKT, these current Ras/ERK results, and Aop-Foxo. Do any of these apply to mammals? The authors think they may well:

. . .This role of cAMP/PKA in aging may be conserved in mammals, as disruption of adenylyl cyclase 50 and PKA function extend murine lifespan (Enns et al., 2009; Yan et al., 2007). However, cAMP/PKA are not generally considered mediators of Ras function in metazoa. Instead, our data suggest that signaling through Erk and the ETS TFs mediates the longevity response to Ras. Interestingly, fibroblasts isolated from long-lived mutant strains of mice and long-lived species of mammals and birds show altered dynamics of Erk phosphorylation in response to stress (Elbourkadi et al., 2014; Sun et al., 2009), further suggesting a link between Erk activity and longevity. Importantly, the ETS TFs are conserved mediators of Ras-Erk signaling in mammals (Sharrocks, 2001). Investigation of the effects of Ras inhibition on mammalian lifespan and the role of the mammalian Aop ortholog Etv6 are now warranted.

This work in fruit flies relied on trametinib, an MEK inhibitor used in oncology, and you would have to wonder what its effects would be in humans who don't have metastatic melanoma. It would seem certain that no one in that position has ever taken it since its Phase I trials (and those must not have been for very long). The authors strongly suggest taking a look at this, and it's going to be interesting to see if someone takes them up on it.

Comments (9) + TrackBacks (0) | Category: Aging and Lifespan | Cancer

June 2, 2015

Bristol-Myers Squibb Sues a Former VP

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Posted by Derek

You don't often see noncompete agreements invoked in the biopharma industry, but here's one. According to Pharmalot, Bristol-Myers Squibb is suing a former executive (David Berman) for taking a job with AstraZeneca. Berman was highly placed in BMS's immuno-oncology area, and this is such a competitive environment that they feel that his departure (for a competitor) could be damaging.

The lawsuit says that Berman was under an agreement not to do anything like that for a year should he leave BMS. He'd been promoted into his present job at the end of last year, and at the end of March, accepted a stock incentive plan that included the noncompete agreement. He resigned, though, on May 26, which must have been unwelcome news, and BMS got this one into the courts pretty quickly. (The request for an injunction (link at the Pharmalot article) is dated May 28. This should be interesting to watch. . .

Comments (24) + TrackBacks (0) | Category: Business and Markets | Cancer

May 29, 2015

Two Types of Risk

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Posted by Derek

It's the time for the ASCO meeting again, so everyone who follows oncology drug development will be busy catching up on the news. Bruce Booth has a good overview of things here, based on look at the abstracts submitted for the meeting. An analysis of the words mentioned in them shows some interesting features: the number one term is "HER2", and the number two is "PD1". These rise to the top by two rather different routes.

If you combine HER2 with other related targets (EGFR, HER3, etc.), that group is number one by a good margin, which is something to think about, considering how much work has already been done in this area. Something to think about, next time you see stories in the popular press about how this or that key to this or that cancer has been "figured out". Booth himself was struck by how much there apparently is left to do in this area, and by how many different people and organizations are doing it. I am, too - most everyone I know, if they went to their own oncology folks and said "Hey, I've got this idea for something in EGFR", would be given puzzled looks and asked if they didn't have any new ideas. (Keep in mind, though, that the "C" in ASCO is for "clinical", so this is all work that's well downstream of discovery).

Meanwhile, PD1 is part of the hot, hip, happening immuno-oncology world. I'm not making fun of it, either - it's hot and happening for a lot of very good reasons, like clinical trials that get stopped because of efficacy (not exactly something that oncologists are used to seeing). It's no surprise that everyone with a lab coat is piling into this area.

But that brings up the other point in Booth's post: what this means is that the risks in these popular areas are starting to flip over - less from the science, which has more and more backing, and more from the overcrowding. How do you differentiate your tyrosine kinase approach, or immuno-oncology approach, from everyone else's? That's a particularly fraught question in oncology, where the animal models are so nonpredictive and questions like this get settled in the clinic. If yours were the only organization developing one of these things, you could just blast away in a series of Phase IIa trials to find the best places to land, and you'd surely find some. But that's what everyone else is doing, too. What if several of you try to land on the same spot at the same time?

So that's why any proposal for a new oncology program has (or better have) an emphasis on how this one is going to be off the paths that everyone else is taking. If you're already in the clinic, you're going to be cranking away at the differentiation problem as best you can, with an eye on all the competition. But back in the early research stage, you have the chance to take care of that question early, and you'd better take it. That doesn't always work - there's competition in the early research stages, too, and some of those now-crowded areas were entered by people who didn't plan on them being quite so popular. But you do the best you can.

One classic way to go has been to target things that have little or no existing therapies - glioblastoma, pancreatic cancer, things like that. Anything that works half-decently against any of those will immediately set itself apart from the crowd, because the crowd has nothing. But going this route means that you've minimized your commercial risk at the cost of maximizing your scientific risk, because these diseases are underserved for a lot of really good reasons, and a lot of ideas just as plausible as yours have already bounced off of them with no effect at all.

So there's a bit of a conservation law at work here - if you dial down the risk on one side, you've probably dialed it up in the other. I supposed that there is a worst-of-both possibility: a long-shot attempt at doing something that well-known agents already do. That quadrant is lightly populated, or had better be. But the other remaining quadrant, the one where you have a really good shot at working against something that no one else is even trying, that's where the unicorns play. You don't get to visit that territory very often - and even when you think you are, you might find that you have company.

Comments (13) + TrackBacks (0) | Category: Business and Markets | Cancer | Clinical Trials | Drug Development

May 18, 2015

The Nativis Voyager Appears

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Posted by Derek

To my surprise, there has apparently been a sighting of the "Natavis Voyager" device in the wild. Nativis, as long-time readers will recall, is the company that claims to be able to record "RF signatures" of drugs in solution, which can then be played back at other solutions or organisms to generate the effect of the original drug. No, I'm not making that up, that's pretty much what they're saying. And no, I can't see any way that can possibly work or even make sense, either.

When last heard from, the company had apparently moved on from veterinary applications and was preparing for some sort of clinical trial in glioblastoma. And thanks to an alert reader, here is a news report of the first patient who is trying the thing:

This time, in order to help hope, Doug decided to try a new piece of technology. It is a device he would have to wear on his head more than 20 hours a day: A thin blue headband called the Nativus Voyager. (sic)

The coach was the first human to try the device, which is designed to block cancer cells from multiplying.

"What is does is tells the cancer cells not to divide, not to grow," he said. "It's a frequency that disrupts everything."

The experiment has led to one stable MRI after another so far.

"I feel like, at times, I can feel it working," he said.

I certainly hope that Coach Doug Corta survives glioblastoma multiforma. It's an awful disease, and those afflicted with it need all the help that they can get. There's a very tough call to make in these situations, though, about offering hope. You want to be able to help patients, and you want to be able to offer then something. But I have never been able to understand how the Nativis device can be more than an interesting-looking placebo. As a chemist, their rationales for it and the technology behind it have never made sense to me.

I'm aware that there is an RF device (from NovoCure) that has been used in glioblastoma multiforma patients. I'm not the biggest fan of that one, either - the rationale behind it is apparently membrane disruption of the dividing tumor cells. The NovoCure device was tried in GBM patients with recurrent disease, and is "intended as an alternative to standard medical therapy for recurrent GBM after surgical and radiation options have been exhausted". The prognosis for recurrent GBM is very poor indeed, and the fact that the NovoTTF/Optune device was similar to standard-of-care in these patients probably tells you more about the standard of care than it does about NovoCure's technology, which remains the subject of much disagreement.

But Novocure's supposed mechanism of action still looks more plausible to me than the Nativis Voyager's. But that's on a relative scale. On the absolute scale, in case you're wondering, I rank the former as "unlikely to be real", and the latter as "don't see any possible way it can be real". Interestingly, Nativis appears to be going for the same market. Their page says that "This feasibility study will assess the effects of the Nativis Voyager therapy in patients with recurrent GBM who have either failed standard of care or are intolerant to therapy". The inclusion criteria are that patients have failed (or are intolerant to) radiation therapy and temozolomide, which are really the only things that can be offered to GBM patients. That news article I linked to, though, makes it sound as if Coach Corta is receiving some sort of chemotherapy (up near the beginning of the piece), although that doesn't sound like a temozolamide dosing schedule, either. So I'm not sure what's going on. All I can say is that the Swedish Neuroscience Institute in Seattle (and three other research centers - see that clinical trial link) are involved in some very unusual treatment options indeed.

Comments (40) + TrackBacks (0) | Category: Cancer | Clinical Trials

May 14, 2015

Puma Update: The Roller Coaster Heads Down

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Posted by Derek

There's more news on Puma Biotechnology and their drug, neratinib. It's been quite a story over the last couple of years, and it's not getting any less convoluted.

The initial results in breast cancer looked promising, and Puma's stock jumped tremendously. Then (as that link above details) things got murkier. Now (last night) new clinical results were released for the upcoming ASCO meeting, and the survival benefit is down to 2.3 months, which is not what people had been hoping for. Pumas's stock went down 25% in after-hours trading, and will not have a good day today.

Here's Matthew Herper's email exchange with the company's CEO. (As the headline mentions, he himself saw a good deal of personal wealth vanish last night). There are possible mitigations in the data, but not nearly enough (I think) to take the drug back to the status it used to have.

Comments (4) + TrackBacks (0) | Category: Cancer | Clinical Trials

May 1, 2015

Aileron and p53

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Posted by Derek

In the long-running saga of getting a stapled peptide to work as a drug, Aileron Therapeutics was last heard from raising money for their p53 candidate. Now comes word that the company is basically going all-in with that one, raising yet more cash and gearing up for some definitive human trials.

I wish them luck. p53 is one of those great targets that no one's ever been able to make anything out of, so a completely new approach (like a stapled peptide) is a reasonable thing to try. And the whole stabilized-helical-structure approach that the stapled compounds represent needs to be given a real-world test, too. From one perspective, you might say that such a different technique should be tried out on a well-validated target, so you at least cut the risk down that way. But that's not how things go. Exotic techniques get used on the problems that other methods have failed on. But on the other hand, p53 is (biologically) about as well-validated as you can get, total lack of clinical success aside.

This will be exciting to watch, although I can't help but wonder if it's a death-or-glory move for Aileron. They've raised a fair amount of money over the last few years, and you can't go back and fill that bucket too many times. Good luck to them!

Comments (14) + TrackBacks (0) | Category: Cancer | Chemical Biology | Clinical Trials

April 20, 2015

PD-1 Charted

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Posted by Derek

Via AndyBiotech on Twitter, here's a chart from the ongoing AACR meeting on what sorts of tumors are responding best to the PD-1 antibodies that are creating such excitement. You can look at this two ways - what parts of oncology practice are on their way to being transformed, and/or what parts still have a big need for small molecules (!) Here's more from Matthew Herper.

Comments (21) + TrackBacks (0) | Category: Cancer | Clinical Trials

April 17, 2015

Stopped For Efficacy - Again

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Posted by Derek

Well, just weeks after Merck halted a trial of their anti PD-1 antibody Keytruda (pembrolizumab) due to efficacy, Bristol-Myers Squibb has announced that a trial of their own PD-1 antibody, Opdivo (nivolumab) against non-squamous non-small-cell lung cancer has been halted for the same reason: it's working so well that it's unethical to continue. Nivolumab has already shown activity like this before in another lung cancer trial, so there's no doubt that the PD-1 excitement is justified. Oncology is really going through a big change, and we can hope that this is just the start.

Comments (21) + TrackBacks (0) | Category: Cancer | Clinical Trials

April 6, 2015

China's First Homegrown Pharma

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Posted by Derek

The Wall Street Journal had an article on a new HDAC inhibitor from Shenzhen Chipscreen (full text here from The Australian). It's worth highlighting. Epidaza (chidamide) appears to be the first homegrown drug discovery and development effort to reach regulatory approval in China.

Their founder, Xian-Ping Lu, was working at Galderma before he went back to China in the early 2000s to start his own company. Chidamide is a start-to-finish compound for Chipscreen, and that puts China on a rather short list of countries that have demonstrated the ability to do that in small molecule drug development. You see claims for this sort of thing that don't quite hold up, but this certainly appears to be the real thing, and congratulations to them.

Some thoughts: first off, this would be the fourth (I think) histone deacetylase inhibitor to get regulatory approval somewhere. That class of compounds was a hot topic for development ten or twelve years ago (I was working on some then, not to any great effect). It's the first class of pharmacological agents deliberately targeting epigenetic signaling, and the complexities of that field have made things run slower than people were hoping. As this article in Nature Reviews Drug Discovery put it:

Oncology drug developers have long been interested in the role of HDACs, which can repress gene transcription by modulating chromatin structure, because altered expression of HDAC enzymes is often seen in tumours. HDAC inhibitors, the researchers hoped, could drive the re-expression of silenced genes, including those that encode tumour-suppressing proteins. However, the failure of multiple HDAC inhibitors to show activity in most cancer types, especially in solid tumours, has over the years led to an outbreak of 'HDAC inhibitor fatigue' in the research community — distinct from the physical fatigue many patients experience as a common side-effect of the drugs. “The wave of excitement surrounding this early class of epigenetic drugs has waned and been replaced by a wave of scepticism,” says Jean-Pierre Issa of Temple University in Philadelphia, Pennsylvania, USA, who researches epigenetic mechanisms in cancer.

As these mechanisms get more worked out, the hope is that the HDAC compounds can get on a more sound footing, but for now, they're minor players in the oncology world. (I have no feel for how well chidamide compares to the other marketed compounds).

The second thought is whether Chipscreen plans to seek approval to market the drug anywhere outside China. I hope so - it would be good for Chipscreen and good for the global reputation of the Chinese drug industry. What would be good is if China becomes another market like the US, EU and Japan, where companies from each region get drugs approved in the others. There are (or can be) some slightly different requirements in each, and sometimes regulatory authorities will let something through in one that doesn't fly in the others, but the serious drugs end up in all of them and other markets (Canada, South America, Australia, Israel and so on) besides. (I'm excluding some of the no-efficacy-just-safety compounds from Japan from that category). What China does not need is to become a sort of regulatory backwater. The sheer size of the market there argues against that happening, but if the drug industry there continues to develop, the government could conceivably start tipping the scales towards China-discovered compounds. Getting chidamide out into the rest of the world would help to get things off to a good start.

The last thought comes from the statement in the article that the drug cost about $70 million to develop. That is indeed cheap, as little as ten per cent of what it would cost to do that in the US or the EU. And why is that? One's first thought is cost of labor, but although it can be cheaper to outsource some parts of drug research to China, it does not save you 90% by any means. Most of the money spent in a drug project is spent in the clinic, so my guess is that Chipscreen was able to get their clinical trials done for much less money than it would cost over here. Just how and where those savings came in, though, I couldn't tell you. If that's a real effect, though, and if those are real figures, then the Chinese companies would appear to have a huge cost advantage on the rest of their worldwide competition, which makes you wonder why it's taken until 2015 for the first locally-produced small molecule to show up. I should note as well that the other big multinational drug companies have not swarmed into the Chinese clinical trial space, not to the degree you'd expect if there were really 90% savings to be realized by doing so. This part will remain an open question for now.

But all of that aside, I'm glad to see Chipscreen make it through with their own compound. I'm glad to see any small company do that, Chinese or not, but their position as the first to do it in China is something that no one can take away from them. People have been waiting for it to happen, and here it is.

Comments (25) + TrackBacks (0) | Category: Business and Markets | Cancer | Drug Development

March 24, 2015

The Best Way to Halt a Clinical Trial

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Posted by Derek

These are words that you really like to hear: "stopped for efficacy". That's Merck's situation with their anti-PD-1 antibody Keytruda (pembrolizumab), which was in a clinical trial in advanced melanoma patients versus Yervoy (ipilimumab), which targets CTLA-4. Couple this with the kinds of data that Bristol-Myers Squibb and others are generating, and PD-1 looks like it's justifying its hype (which has been significant).

This antibody came from Organon, which was bought by Schering-Plough, which was bought by Merck, so it may be the main thing that Merck gets out of the whole deal. The cancer immunotherapy wave is showing no signs of breaking.

Comments (11) + TrackBacks (0) | Category: Cancer | Clinical Trials

March 5, 2015

Twenty-One Billion Dollars. Really.

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Posted by Derek

Ibrutinib seems to be worth even more than everyone thought! As of this morning, AbbVie has won what was apparently a lively bidding war for Pharmacyclics, paying $21 billion for the company. Now that is a lot of money, and I'm not sure that I can made those numbers add up, but presumably there are people at AbbVie who are paid more than I am to figure such things out. (Adam Feuerstein sounds a bit stunned, too). Many news organizations had stories yesterday about how J&J was about to buy them, but if you're willing to pay enough money, you can horn in on any deal you like.

I would assume that the company is going to aggressively move the compound into clinical trials for as many plausible indications/combinations as possible - that's the main way I can see this working out. But as I said last week, this is what keeps people investing in biopharma: back in 2009, you could have had Pharmacyclics for $1 per share or less. Last night's offer was $261.25. David Shayvitz has a good history of ibrutinib here, and it's quite a story. Personally, I think that a lot of Pharmacyclics people are probably just relieved that they're not going to have to attend any more sessions to learn how to become geniuses.

Comments (42) + TrackBacks (0) | Category: Business and Markets | Cancer | Drug Development

March 2, 2015

Of Proteasome Inhibitors and PAINs

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Posted by Derek

Amgen is out with some new data that might well justify their purchase of Onyx a year and a half ago. A big driver for that deal was the proteasome inhibitor Kyprolis (carfilzomib), and the company just reported results in a head-to-head trial in multiple myeloma versus the Takeda/Millennium competition, Velcade.

Kyprolis comes out looking pretty good:

In the "ENDEAVOR" study announced Sunday night, patients with multiple myeloma still progressing despite one to three prior therapies were randomized to receive Kyprolis plus a steroid or Velcade plus the same steroid. Following an interim analysis, patients in the Kyprolis arm had a 47% reduction in the risk of disease worsening or death compared to Velcade. At the median, Kyprolis patients went 18.7 months before their disease progressed compared to 9.4 months for Velcade patients. The benefit favoring Kyprolis was statistically significant.

The study is continuing to see what the overall survival benefit might be, but I'm sure that Amgen is hopeful that those numbers will translate into something robust. Velcade itself will be off patent in a couple of years, so Amgen is going to need data to make the case that people should get their drug rather than the generic competition.

It's worth taking a look at the structures of those two drugs again. Velcade is, of course, a boronic acid, the first to get approved as a human therapy. "Boron is for morons" went the joke for many years, as boron-containing enzyme inhibitors ran into trouble on their way to the clinic. But that particular moronic compound brought in over two billion dollars in sales last year, which a lot of us smart people who've avoided boron have never been able to ring out with anything we've made. And Kyprolis is rather funny-looking, too. It came out of some natural products work in Craig Crews' lab at Yale, and it's a modified tetrapeptide with an epoxide hanging off it. This is another structure that would get the fisheye from a lot of people, for both those reasons, but there it is, out there in the clinic working well.

Now, I take the point that targeting the proteasome is not exactly like coming up with a new diabetes drug. You're going to be treating some very sick patients, many of whom are (otherwise) going to die quickly. The sorts of structures that a project is willing to look at do need to be calibrated a bit for these things. But a lot of us - including me, a few years ago - would have calibrated these two drug structures right off the side of the page, and that clearly would have been a bad decision. Yet another reminded for us to loosen up a bit.

"Right", I can hear some readers saying. "Here's one of those guys who's death on PAINs and makes fun of people's screening compounds, telling us to loosen up on funny structures". A fair point, but here's where I get off saying this. The big rap on boronic acids and peptidic drugs is that they have poor PK, and that's something that can be checked out. You'll note that morpholine hanging off the end of carfilzomib, and I suspect that's on there for just those PK reasons. Epoxides, for their part, are actually a lot less reactive and nonspecific than their reputation has it.

PAINs, though, are not looked at with distaste becuase of their phamacokinetics or how they've tended to perform in the clinic. They're trouble because they tend to give false screening results and/or hit in way too many assays to be good candidates for further development. So when they show up in a paper as great new screening hits, and the authors show no sign of realizing their problematic nature in just the sorts of assays that they've been running, then yes, it's a problem. Anyone developing a boronic acid, a tetrapeptide, or an epoxide should know that they have a lot of PK and tox assays waiting for them, and that no one will believe in these compounds until they start passing them. For PAINs, this disbelief kicks in very early, as is should. The very first step in the whole process, activity in the screening assay, may well be bogus.

And in the same way that there are PK and tox assays to sort out odd-looking structures that have been known to have trouble in these areas, there are screening-level assays that need to be run for suspicious-looking hits. They need to be shown not to be redox cyclers, not to hit all sorts of other targets, not to decompose to reactive species under the assay conditions, not to soak up thiol nucleophiles nonspecifically, not to hit because of fluorescent interference, and so on, and so on. Peptides and boronic acids have a reputation for not clearing the later hurdles in drug development, so if you're working on them, be prepared and let the data guide you. They'll work, or they won't, and you'll get a clear answer. False positives are not a big problem in most PK assays.

But PAINs are the compounds that tend to not even clear the first hurdles, while looking like they have. Let the data guide you there, too, but that means getting the correct data with those follow-up assays after your initial screen, not declaring them wonderful new leads and pushing on regardless.

Comments (6) + TrackBacks (0) | Category: Cancer | Clinical Trials | Drug Assays | Drug Development

February 26, 2015

Ibrutinib's Rise

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Posted by Derek

Pharmacyclics and their reactive kinase inhibitor Imbruvica (ibrutinib) have come up a few times around here in the past. (And someone who was involved in its earlier development at Celera shows up here in the comments from time to time). Here's a piece at Bloomberg that spells out just what a massive return buying that compound has turned out to have. Pharmacyclics picked it up in 2006 for a few million, and it's expected to have sales of up to 4 billion a year. This is why people keep investing in small pharma and biotech: because neither we, nor they, nor anyone else can predict when this sort of thing will happen next.

Comments (15) + TrackBacks (0) | Category: Cancer | Drug Development

February 19, 2015

Experience Phase III Failure, Twice

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Posted by Derek

I'm going to use a short phrase that should make everyone who's ever been involved with clinical research shiver a little bit: post-hoc subgroup analysis. This comes up again and again in drug research (and has been the subject of several posts here over the years), because when a drug comes up short in the clinic, the natural impulse is to see if there are some groups that just responded better than others. New hope! New trial!

But you're walking into a very dangerous landscape when you do this sort of thing. The first big factor is how the trial itself was set up: did you define these subgroups before you started, and thus (presumably) took care to see that they were all populated with enough patients to have a chance of being meaningful? And just how many subgroups are we talking about, here? As everyone should be aware, the more of these you look at, the greater the risk you have of a seemingly interesting effect being nothing more than chance. Given the uncertainties of most clinical readouts, if you can look at enough subgroups in a large data enough data set, you can jack things up to the point where at least one of them will have to look significant. Getting excited about this is not recommended.

I bring this up because we've had yet another example of a company pushing onwards in the clinic after a subgroup analysis and getting scorched. Takeda and Amgen took an anti-VEGF (among other things) compound, motesanib, into the clinic against non-small-cell lung cancer a few years ago. Phase II looked encouraging enough to go on, but the Phase III trial (adding it to existing chemotherapy) struck out pretty thoroughly.

Not all that surprising in small-molecule oncology, that sort of result. And adding hydra-headed tyrosine kinase inhibitors into the NSCLC mix was an idea that had failed before with other compounds. I think that it was at this point that Amgen exited the picture, but Takeda dug into the data and believed that Asian patients actually showed some response to the drug. That's not a crazy idea, of course, but that doesn't mean it's real, either.

They went on to do another Phase III, with patients recruited from various East Asian countries. And two days ago, they announced the results: the primary endpoint (progression-free survival) was missed completely. And so the saga of motesanib comes to an end - well, in non-small-cell lung cancer, anyway. I believe the compound is still being looked at in thyroid cancer, and Takeda is probably trying to think of some other uses even now.

But in general, when your big Phase III trial flops, you'd better be ready for it to flop again if you still want to press on. I'm trying to think of any examples where this resuscitation strategy has worked. Even one is enough to give a person (or a company) hope, given the amount of money at stake, but given the odds, just how much hope is appropriate? How much was appropriate here?

Comments (22) + TrackBacks (0) | Category: Cancer | Clinical Trials

February 16, 2015

Targeting a Transcription Factor

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Posted by Derek

Here's a paper in Science on inhibition of the transcription factor CBFbeta-SMMHC. That's a messed-up version of CBFbeta itself, which has been found to drive many forms of acute myeloid leukemia (AML) though its interactions with another transcription factor, RUNX1. So tying this one up with some sort of small-molecule therapy is an attractive idea, the only problem being that getting small molecules to work on transcription factor pathways has been very difficult indeed.

Transcription.jpg This group set up a FRET assay and screened the National Cancer Institute's diversity set of compounds to see what they could come up with, and 2-(2-pyridyl)-5-methoxybenzimidazole same out as a micromolar hit. (Without the methoxy, it lost at least 10x potency). Since the transcription factor itself is dimeric, they then tried stitching two of these together, with the results shown. All of these are in the 300/400 nM range. There's a good deal of downstream biological data suggesting that these compounds are hitting this pathway.

So, what does a medicinal chemist think about these compounds? For starters, 2-pyridylbenzimidazole is going to be a very good metal chelator, and I would wonder if some of the effects might not be due to an off-target mechanism of that sort. The paper itself does not mention any possibility of metal chelation, as far as I can see. The 5-methoxybenzimidazole itself isn't objectionable per se (that's the left-hand side of omeprazole), but I have seen assay hits with that sort of chelating group in them, and in my own experience they've been difficult to prosecute. (I'd be glad to hear some other opinions).

Now, as far as the dimer idea, since the target itself is a dimer, it's hard to object to the idea. But for whatever reason, this strategy doesn't seem to have paid off a lot in drug discovery. Perhaps it's the added molecular weight and PK properties that you pick up when you do this that make them harder to advance. On top of this, medicinal chemists have a sort of instinctive distaste for completely symmetric molecules like these - and I do, too - but I've never been quite sure why. I think that we feel that there are more reasons for something like this not to be real than for it to be acting as advertised, but that's not a very quantitative look at things.

I would feel better about this latest paper if the chemical matter had been given more of a going-over than appears to have been done. I don't see any mention of selectivity assays or the like, and I really would like to run something like this across some sort of broad panel just to make sure that it doesn't set off too many other things. On the other hand, though, the authors do have a lot of cell data that points toward this particular transcription factor being the target, and I'm really to applaud anyone who gets the small-molecule transcription factor thing to work. I'll look forward to seeing what comes of this, for sure.

Comments (21) + TrackBacks (0) | Category: Cancer | Drug Assays

January 15, 2015

A Kinase Inhibitor Overview

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Posted by Derek

Here's a very worthwhile review of kinase inhibitors by Oliver Hantschel, specifically focusing on the things that you might not otherwise notice. There are plenty of kinase inhibitors available in the catalogs as research tools, and they're listed as "Inhibitor of XYZ Kinase", as if that's all that they do. But what's really going on?

Quite a bit, in some cases. Making a truly selective kinase inhibitor has never been easy, especially in some parts of the kinase landscape. Hantschel makes a point that is worth thinking about - that it was perhaps fortunate that Gleevec (imatinib) was the first approved drug in this class. This is one of the more selective compounds, and its side-effect profile is quite manageable. If some of the later compounds had instead come first, the field might have developed differently. (Keep in mind that for some time kinases were considered basically undruggable, since the binding sites were considered too similar and the likelihood of trouble too high. The only kinase inhibitors known tended to have funky structures and poor selectivity, which was a self-reinforcing situation. I think, though, that people were still surprised that some of the broader-spectrum inhibitors were tolerated, well after the field was an accepted area for drug discovery).

The paper goes over the modern techniques for profiling kinase selectivity, which now can run to assays using hundreds of kinases. At this level of detail, most of the marketed kinase inhibitors still inhibit a dozen different enzymes or so, which is worth thinking about when such compounds are used as research tools - plenty of wrong assignments have been proposed over the years, and plenty more are surely waiting to be made. Modeling can tell you about which kinases have the most similar binding sites to the main target, which is a good start. But there are several compounds that are known to strongly inhibit different kinases by binding in completely different fashions, and throwing open a computational search to pick up changes of that size is problematic. Better to do the actual screening, when possible, while remembering that in vitro ranking may not completely translate to what's actually going on the cells.

As experiences in the clinic have demonstrated, there are an awful lot of kinase mechanisms in vivo that we don't yet understand. Dosing these inhibitors in animals and humans has helped to uncover a lot of new biology, but people should keep in mind that this is what they're probably going to be doing with each new compound. Hantschel goes into a couple of good examples of this (RAF and JAK2) where the initial rationale for the inhibitors as drugs turned out to be only part of some much larger and more complicated stories.

So there's plenty to think about just inside the kinase universe. The review goes on, though, to detail the many and various off-target effects that have been seen. A variety of non-kinase proteins can be picked up, including bromodomains, nucleotide-processing enzymes, oxidoreductases, and more. Some of these could be relevant to the cellular phenotypes that could otherwise be ascribed to kinase inhibition. It's important to keep in mind that kinase inhibitors are, in many cases, targeting binding motifs that have been re-used a number of times in living systems. The worries from thirty years ago about the whole field being untouchable were overblown, but it doesn't mean that there aren't plenty of surprises waiting.

From a drug development standpoint, those surprises are a bug. From a basic research standpoint, though, they're a feature. There's really no way that we could have learned so much about all these pathways other than by developing all these compounds and trying to untangle the results they've produced, and the untangling is going to continue for quite some time to come.

Comments (6) + TrackBacks (0) | Category: Cancer | Drug Assays | Drug Industry History

January 14, 2015

The Duke/Potti Scandal, From the Inside

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Posted by Derek

You may remember Anil Potti, the cancer researcher at Duke whose biomarker-driven therapies turned out to be so poorly designed as to be useless. (Or you might recall the bizarrely clumsy firm that he hired to try to burnish his online reputation).

But what you probably don't know (I certainly didn't) was that someone in Potti's own research group, a third-year med student named Bradford Perez, had figured out that things were going wrong and had reported his concerns to the university. We wouldn't know that, because Duke has stated that they received no such whistleblower reports. The Cancer Letter, however, has the memos and e-mails, which flatly contradict the university's statements. This has come to light via a lawsuit from the families of some of the affected patients, and will no doubt make interesting reading at the upcoming trial.

Whatever its legal significance, the memo and the flurry of emails it touched off provide new insight into Duke’s handling of the Potti controversy:

• The memo shows that, by ignoring the content of the Perez memo, Duke’s deans allowed Nevins to investigate his protégé himself.

• Responding to Perez’ memo, Nevins and Potti promised to conduct a review of the data in April 2008. A thorough, unbiased review of this sort would have produced evidence of fraud, statisticians say.

• Emails demonstrate, step-by-step, how Duke officials convinced Perez to present his principled stance as a difference of opinion between him and two senior scientists.

Perez started to realize the situation he was in during the review of a paper he was publishing with Potti in the Journal of Clinical Oncology. Reviewers had noted the questions raised by Keith Baggerly and colleagues about early work in the Potti group, and were asking for more details about the statistics in this manuscript. And when he started digging into that, he found (as he put it in an e-mail to a third party) that the lab's techniques for validating its methods amounted to "erasing the samples that don’t fit the cross validation from the figure and then reporting the cross validation as meaningful and justification for a good predictor".

Perez, after several months of trouble, ended up writing a detailed memo on all this to a director at the medical school, Joseph Nevins. He laid out exactly what had been going wrong, in detail, and went on to say:

At this point, I believe the situation is serious enough that all further analysis should be stopped to evaluate what is known about each predictor and it should be reconsidered which are appropriate to continue using and under what circumstances.

“By continuing to work in this manner, we are going a great disservice to ourselves, to the field of genomic medicine and to our patients. I would argue that at this point nothing should be taken for granted. All claims of predictor validations should be independently and blindly performed. Unfortunately, since validation databases on the supplementary website have been shown to be misrepresented in multiple situations, those datasets should be obtained from their respective sources through channels that bypass the researchers.”

As things turned out, he was completely correct. What was the reaction from Nevins and from Duke? To ask him not to bring these complaints forward to anyone else, and to promise an internal investigation. But this is still two years before all the trouble came to light, and before another round of suspect trials had even started. Despite promises that all the data would be re-evaluated. Perez left the Potti lab (understandably), but the university presented this situation to the Howard Hughes Medical Institute (the source of funding) as a "difference of opinion" between a student and a professor, and stated that "It is important to note that there have been no allegations of scientific misconduct". But that wasn't the case. As the various emails show, the phrase "research fraud" had already come up, and not for the last time, either.

Bradford Perez's part in exposing all these problems has been unknown until now - well, unknown to everyone, apparently, except a long list of a higher-ups at Duke. I'm glad to see him getting his due. The article quotes Donald Berry of MD Anderson, a guy who knows his clinical research statistics, saying:

"Brad Perez is a hero. . .(but) there is more to this story than the heroic and principled actions of an erudite young man and the shame that has befallen a great university in blindly and selfishly defending its own. It is indicative of a lack of understanding of the scientific method among many scientists.

“The Duke scandal is extreme, to be sure. But irreproducibility in academic research is common. And the reward structure and complacency of universities is to blame. . ."

Quite so. (And yes, it's not like there are no problems with the reward system in industrial research, either). But Duke did this to themselves, and let Anil Potti do it to them, despite (as is now clear) numerous opportunities to have caught things earlier. (They only really got into gear once Potti's CV turned out to have been enhanced with things like a nonexistent Rhodes Scholarship). The Potti scandal was and is disgraceful, and so was the university's handling of it. But faculty and administrators at other universities shouldn't kid themselves into thinking that this was just a Duke problem. Things like this can happen all over the place - the opportunities and the incentives are there. There is a constant supply of people like Anil Potti, and a constant supply of administrators who don't want to hear about their conduct, and who are willing to stall and obfuscate in the hopes that such problems will just go away quietly. I'm not so sure if there's such a constant supply of people like Brad Perez, but we can hope.

Comments (32) + TrackBacks (0) | Category: Cancer | Clinical Trials | The Dark Side

January 12, 2015

Unstoppable Nivolumab

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Posted by Derek

The J. P. Morgan Healthcare Conference is going on right now, so there's a lot of information coming out from the companies attending. One thing I noticed this morning was another blast of successful data for nivolumab from Bristol-Myers Squibb. A trial of this anti-PD-1 antibody was stopped early due to efficacy (not something that most of us get to experience very often!), and this follow up on encouraging data reported last fall. From all indications, both cancer patients and BMS are going to do very well indeed with this compound - the number of clinical trials and combinations being studied with it must be hard to keep track of by now.

Comments (5) + TrackBacks (0) | Category: Cancer | Clinical Trials

January 7, 2015

More Odd Compounds

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Posted by Derek

When you look into the literature on small-molecule agents for really tricky targets, something stands out to medicinal chemists immediately: the structures start to get strange. Examples of this sort of thing are beyond counting, but this recent paper will serve as well as any. It's from a large multicenter academic team, and proposes several compounds as ligands for Bax, a protein of the Bcl family that's involved in apoptosis and is a potential target for a range of lung cancers. There's a particular serine residue whose phosphorylation has been shown to alter Bax function significantly, and the present paper notes that there may well be a small-molecule-sized pocket nearby.

The work starts off by computationally docking a large collection of molecules from the NCI database to a model of this pocket. 36 out of 300,000 were found to score well, so the team exposed Bax-expressing cells to all 36 of them and looked for effects. Three of the compounds showed apoptotic effects, which were less marked in lung cancer cell lines that expressed less Bax. The compounds were able to compete with a fluorescent protein that also binds to Bax, and this assay gave affinities of around 50 nanomolar. Update: see the comments. These compounds give weirdly similar data.

These results sound promising. But let's look at the structures of the compounds. SMBA1 is not very attractive, for sure. You'd want to make sure that any fluorescence assay involving it doesn't suffer from some sort of interference, because it sure looks like a compound that would make its presence known in the UV/Vis spectrum. I have no experience with these sorts of fluorenylidene phenols, but some stability and reactivity checks would not be out of place.
The problem is, SMBA2 and SMBA3 make that first compound look like ibuprofen. I know that the NCI compound collection has a lot of wooly stuff in it, but come on. These are formaldehyde/amine condensation products. In aqueous solution, they exist in various equilibria depending on pH, and such structures are known to be reactive reagents in organic chemistry. (See the Delépine reaction, among others). SMBA3, in fact, is an intermediate structure from that very reaction, as if someone were trying to synthesis allylamine. I would be very worried about exposing such compounds to cells - there are no guarantees that they're going to remain the way that they're drawn, and the species that form can be quite reactive. Figuring out what's really going on with them would be quite a job.

I can see no indication from the paper that any of this bothered anyone. The only characterization that seems to have been done with these compounds was some DLS, dynamic light scattering, to look for aggregation. Nothing wrong with checking that, but there's no other chemical characterization or purity assessment of the compounds at all, or at least none that I can see. I mean, they're probably what they say on the label, but who can tell? And even if they're pure, how do they behave under the assay conditions?

The problems don't end there. SMBA2 is said to have 57 nM affinity to Bax. But that's an extraordinary value for a compound with a molecular weight of 168 - that kind of ligand efficiency should make a person suspect covalency. Covalent compounds are not necessarily bad, but you do want to examine them closely to see if they're working on the target you think they're hitting. I don't think the paper has any tests for that, such as checking for time-dependent inhibition or looking at the isolated Bax protein from the assay by mass spec. Meanwhile, SMBA3 has 54 nM affinity, and is shown as having a molecular weight of 308. But that includes the iodide counterion, and that doesn't count: this thing is not floating around in cells, nor binding to its putative target, with its iodide partner. Its real molecular weight is about 181, and that also represents a wildly high ligand efficiency. (There's also the question of how a charged quaternary compound like this gets into the cells so easily, but that's another issue).

The docked structures of these three compounds with Bax are shown in the paper. The two formaldehyde/amine compounds are shown interacting with two Asp residues, and there had certainly better be some strong interactions if you're going to pull out potencies like these. But the positively charged nitrogen in SMBA3 would surely seek out a negatively charged Asp if this were the case, a classic salt bridge, but that's not what the docking shows. Meanwhile, SMBA1, the fluorenyl compound, is shown just sort of floating there in space, not doing anything with the Asp residues, and not showing any strong interactions that I can see from the figure at all. Even the phenol doesn't seem to be doing anything, unless that's a pi-stack with Phe176. These dockings structures do not, unfortunately, inspire confidence.

So in light of all these objections and complications, let me get back to the point from the first paragraph of this post. When you get weird-looking structures out of a screen for a difficult target, you can explain them two ways. One possibility is that such targets, and such binding sites, are not evolutionarily optimized to bind any particular small molecules, and that regular "drug-like" chemical matter should not then be expected to hit them any more than anything else. Odd sites, in this view, will generate odd molecules. The other possibility, though, is that these things are false positives. The ways in which compounds can fool you are legion - in this case, I've mentioned some of the possibilities already, but there are more where those came from.

One thing that's for sure about targets like this one is that their intrinsic screening hit rates are very low. So that means, necessarily, that if the false positive rate is at any realistic level, then the bulk of what you get out of a screen will be just that: false positives. The challenge in screening these things is to dig through the garbage heap in search of the few hits that might be real. It's not a lot of fun, in some cases, because the list can be long and playing endless whack-a-mole with the compounds on it can be wearying. But you have to give all your hits the same tough love, or you run a significant risk of wasting your time.

So yes, I think that the odds are good that the compounds reported in this paper are false positives. They clearly seem to have cellular effects, and these may well be mediated by the Bax pathway. But it's a big leap, at least for me, to believe that everything lines up the way it's supposed to here. Odds are that anything reported for this Bax binding site is a false positive, and (although I hate to say it) this paper hasn't convinced me that its authors have given this problem sufficient attention.

Comments (28) + TrackBacks (0) | Category: Academia (vs. Industry) | Cancer | Chemical Biology | Drug Assays

December 8, 2014

Amazing, Up to a Point

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Posted by Derek

A friend of mine in the drug discovery business asked me this morning on the train if I'd seen "60 Minutes" last night. I hadn't, but he went on to tell me about a report they'd done on Patrick Soon-Shiong, an entrepreneur who's trying to change cancer diagnosis and therapy. What struck my colleague was that pretty much all the points made during the piece seemed to him, as an experienced drug discovery scientist, to be pretty common knowledge, but that the program treated them as a series of amazing breakthroughs.

Matthew Herper has more here, based on a longer report he wrote back in September. Overall, he has a favorable impression of Soon-Shiong, but not a universally favorable one. Well worth a read.

Comments (16) + TrackBacks (0) | Category: Cancer

December 3, 2014

Puma and Neratinib Take Longer Than Expected

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Posted by Derek

When I last wrote about Puma Biotechnology and their irreversible kinase inhibitor neratinib, things were going great. The company had reported good Phase III data, taking investors by surprise, and the stock had shot up. An FDA filing was planned for just after the first of the year, and the future was bright.

The story has become complicated since then, as a lot of stories in our line of work have a tendency to do. Neratinib recently failed to beat Herceptin in a head-to-head trial (one Puma had downplayed, at least for that primary endpoint). And now comes more bad news: the company has been talking about changing its target patient population, and a recent meeting with the FDA looks to delay their regulatory filing for at least a year. (They need to address some preclinical carcinogenicity data).

So this is not exactly a home run just yet. Neratinib may well make it through fine after the delay. But if you bought the stock when it jumped back in the summer, you're flat now, and probably wondering if you're ready to be a long-term investor or not. . .

Comments (5) + TrackBacks (0) | Category: Business and Markets | Cancer | Regulatory Affairs

November 20, 2014

Bind's Attempts To Remake Chemotherapy

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Posted by Derek

There's a lot of effort (and a lot of money) going into targeted nanoparticle drug delivery. And that's completely understandable, because the way we dose things now, with any luck, will eventually come to seem primitive. So you used to just have people eat the compound, did you, or just poke it into their bloodstream with a sharp stick, and let it float around wherever it would and hope that it made it to the target without doing too much else? Quaint.

The nanoparticle idea, on the other hand, is to encapsulate the drug somehow in the layers of these tiny particles which will release it only under the right conditions. The outermost layers, meanwhile, are meant to be coated in ways (recognition peptides, usually) that send the payload to only the right cell types. Imagine a drug for lung cancer where all of the dose goes to the lungs, and all of it hits only the cancerous cells. You could put in the roughest, toughest chemotherapy agents available, because you wouldn't be stuck with poisoning the rest of the patient's body at a slightly slower rate than the cancer, which is how it works too much of the time now.

But that level of control is yet to come. We just got another read on this in the clinical results from Bind Therapeutics, one of the leading companies in this field. Bind is another Bob Langer-derived company - when other parts of the US (or other countries) talk about wanting to have humming biotech hubs of their own, they'd be happy just to have Bob Langer. Bind, under CEO Scott Minick, has deals with an impressive list of big pharma companies to try to apply their nanoparticle delivery systems to existing drugs, although Amgen pulled out of an arrangement with them over the summer.

That didn't help the stock, and neither did the latest news. This was a Phase II study in non-small-cell lung cancer patients with docetaxel, a widely used chemotherapy drug that could certainly use some targeted delivery. The results were mixed. Investors were clearly hoping for something better, but it could have been much worse. As that FierceBiotech link above details, the company saw some responders when the new formulation was dosed every three weeks, but not when it was dosed every week, an interesting result that's going to take some thinking about. Inside the every-three-weeks group, the patients with two particular tumor varieties (KRAS or squamous cell carcinoma) seemed to show relatively good responses. But the sample sizes there are small.

The company is planning another round of Phase II, concentrating on those subtypes and dropping the once-a-week dose. That's exactly what you do in Phase II: the drug has hit the real world with real patients in it, and you do whatever seems to work. It would have been great if they'd seen a bigger across-the-board response, but these are the early days of targeted nanoparticles. There's a vast amount we don't know about these things; the odds are huge that no one is going to be hitting any balls over any fences for a while yet. Bind's next trial should tell them, though, if their current docetaxel particle idea is worthwhile for NSCLC.

That could go either way. The current trial may turn out to have lit up just the sorts of patients who will go on to show impressive benefits, or those effects could just flatten out and slide back into the statistical swamp. Here it is, the absolute essence of drug discovery: there is no way to know in advance. The only way to find out is to round up some more patients, round up some more drug, and round up some more money and try it. Good luck to them!

Comments (10) + TrackBacks (0) | Category: Cancer | Clinical Trials | Pharmacokinetics | Toxicology

November 13, 2014

The Drug Worked, Unfortunately

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Posted by Derek

There's an old story of a guy who lost three cars by betting on inside straights in poker games. He lost the first two when he drew and didn't fill the hand - and he lost the third one when he did. In other words, you need to be sure that even if things work the way you want them to that they'll be enough, and that brings us to a company called Oxigene.

They've been working on fosbretabulin for ovarian cancer. That's a phosphate prodrug of the known chemotherapy agent combretastatin A-4, and there's nothing wrong with that - prodrugs can dramatically change compound distribution and efficacy. The company has just reported Phase II results in a tough group of patients to treat, recurrent ovarian cancer, and they have positive data. Progression-free survival was increased in the combo of fosbretabulin and Avastin compared to Avastin alone, and a post-hoc look at a smaller group whose cancer was resistant to platinum-containing agents seemed to show an even bigger effect. So far, so good.

But is it good enough? That's what Adam Feuerstein asked at One big problem is that, interestingly, Avastin is not approved for this indication. So Oxigene's trial was not conducted versus the official standard of care. The company chose this, though, because Roche is running trials of its own to try to get approval in this area. And their numbers on Avastin plus standard chemotherapy look somewhat better than Oxigene's combination data, and in a larger trial at that. Put another way, if both the Roche and Oxigene data are solid, then Oxigene may have just proven its combo's inferiority.

As Feuerstein goes on to say, and he's absolutely right, Oxigene now faces some tough decisions in Phase III. Later this month, Roche may well get approval for that Avastin+chemo treatment in these patients, so that now becomes the obvious standard-of-care comparison for Oxigene. And if the Avastin combo doesn't get approved, then Oxigene is really up the creek, because all their clinical data will then have been generated with a drug that the FDA hasn't approved for the indication at all. Feuerstein has some advice for them (see his article), but it'll be a bold step. Update: the approval has come through.

Bold steps may be the only ones Oxigene has left, though. If the Roche trials had worked enough for approval, and Oxigene's own trial data had been superior to that in turn, they'd be in great shape. That didn't happen, and the quicker the company comes to terms with that situation, the better off they'll be.

Comments (1) + TrackBacks (0) | Category: Cancer | Clinical Trials

October 30, 2014

Nivolumab Racks Up Another Success

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Posted by Derek

I'm always happy to highlight impressive clinical data, and this is impressive. Bristol-Myers Squibb's nivolumab (which has been doing very well in clinical trials so far) apparently has very significant effects in refractory squamous cell lung cancer as well. 41% of the patients on the drug in the latest study are alive at the one-year mark, and expected survival is maybe 15% at best. That's a very tough patient population to treat, and this is very good news.

The entire PD-1 therapeutic area looks to change the oncology landscape, because we're just barely getting into what's possible with different approaches and drug combinations. And that's just part of the immunotherapy efforts. Small molecules are going to be a part of this, but they're not going to be in the lead, unless any of you know of reliable small-molecule ways to modulate the appropriate immune pathways, which is no small challenge.

Comments (13) + TrackBacks (0) | Category: Cancer | Clinical Trials

October 29, 2014

Aileron Heads Toward the Clinic

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Posted by Derek

Aileron, the stapled-peptide company, has had its ups and downs over the past few years. They went through the typical cut-back-hard phase not too long ago, but have been rounding up more money to try out their p53-targeted idea (blogged on here).

I'm glad to hear it. I would really like to see how some good stapled-peptide candidates performs in the clinic, and the p53 pathway is just the sort of hard-to-drug place you'd go with one. Aileron has one in Phase I in the growth-hormone pathway, but there's been very little news of it, from what I can see. I hope there's enough money to do a good job with these things.

Comments (8) + TrackBacks (0) | Category: Cancer | Clinical Trials

October 28, 2014

An Open-Source Cancer Pitch, Deconstructed

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Posted by Derek

I'm confused. Read this and see if you end up the same way. TechCrunch has the story of Isaac Yonemoto, who's crowdsourcing a project around a potential oncology compound. It's a derivative of sibiromycin, a compound I hadn't come across, but it seems that it was first studied in Russia, and then at Maryland. Yonemoto's own work on the compound is in this paper from 2012, which looks reasonable. (Here's more). And the crowdfunding pitch is also reasonable, in lay-audience terms:

The drug candidate 9DS was developed at the University of Maryland. The last work done on the drug showed that it had activity against cancer competitive with leading cancer drugs such as taxol. Moreover, 9DS is also likely to have lower side effects than most chemotherapies, since a related compound, SJG-136, seems to have low side effects in early clinical trials.

Project Marilyn involves: production of more 9DS, and submitting 9DS to a xenograft study ('curing cancer in mice'). This is the next step in drug development and an important one on the way to doing clinical (human) studies. The process we're seeking to fund should take approximately 6 months. If we recieve more funding, we will add stretch goals, such as further preclinical experiments on 9DS, development 9DS analogs, or other exciting anti-cancer ideas.

But here's where things begin to swerve off into different territory. Yonemoto isn't just talking about some preclinical spadework on yet another oncology compound (which is what the project actually is, as far as I can tell). He's pitching it in broader terms:

. . .Some drugs can cost upwards of $100,000 a year, bankrupting patients. This level of expense is simply unacceptable, especially since 1/3 of people will get cancer in their lifetime.

One solution to this problem is to develop unpatented drugs - pharmaceutical companies will have to sell them at a reasonable price. To those who believe that drugs cannot be made without patents we remind them:

When Salk and Sabin cured polio, they didn't patent the vaccine. It's time to develop a patent-free anticancer drug for the 21st century.

The software industry and the open-source movement have shown that patenting is not necessary for innovation. Releasing without a patent means the drugs will be cheaper and it will be easier to build on the work to make improved drugs or drug combinations. Releasing without a patent means expanded access to drugs in countries that can't afford extensive licensing and export agreements.

OK, let's take this one apart, piece by piece, in good old classic blogging style. Yes, some oncology drugs are indeed very expensive. This is more of a problem for insurance companies and governments, since they're paying nearly all of these costs, but the topic of drug prices in oncology has come up around here many times, and will do so again. It's especially worrisome for me that companies are already up close to the what-the-market-will-possibly-bear price with things that are not exactly transformative therapies (what pricing structure will those have?)

But are unpatented drugs the solution? It seems to me that pharmaceutical companies will not "have to sell them at a reasonable price". Rather, unpatented compounds will simply not become drugs. Yonemoto, like so many others who have not actually done drug development, is skipping over the longest, most difficult, and most expensive parts of the process. Readers of the crowdsourcing proposal might be forgiven if they don't pick up on this, but getting a compound to work in some mouse xenograft models does not turn it into a drug. Preparing a compound to go into human trials takes a lot more than that: a reliable scale-up route to the compound itself, toxicology studies, more detailed pharmacokinetic studies, formulation studies. This can't be done by a handful of people: a handful of people don't have the resources and expertise. And that's just setting the stage for the real thing: clinical trials in humans. That crowdsourcing proposal skates over it, big-time, but the truth is that the great majority of money in drug development is spent in the clinic. The amount of money Yonemoto is raising, which is appropriate for the studies he's planning, is a roundoff error in the calculations for a decent clinical campaign.

So who's going to do all that? A drug company. Are they going to take that on with an unpatented compound that they do not own? They are not. Another thing that a lay reader won't get from reading Yonemoto's proposal is that the failure rate for new oncology compounds in the clinic is at least 90%, and probably more like 95. If you are going to spend all that money developing compounds that don't make it, you will need to make some money when one of them finally does. If a compound has no chance of ever doing that, no one's even going to go down that road to start with.

Now we get to the Salk/Sabin patent example. There are plenty of persistent myths about the polio vaccine story (this book review at Technology Review is a good intro to the subject). Jonas Salk created one of the most enduring myths when he famously told Edward R. Murrow in an interview that "There is no patent. Would you patent the sun?". But the idea of patenting his injected, killed-virus vaccine had already been looked into, and lawyers had determined that any application would be invalidated by prior art. (Salk himself, in his late work on a possible HIV vaccine, did indeed file patent applications).

Sabin's oral attenuated-virus vaccine, on the other hand, was indeed deliberately never patented. But this does not shed much light on the patenting of drugs for cancer. The Sabin polio vaccine protected all comers after a single dose. The public health implications of a polio vaccine were obvious and immediate: polio was everywhere, and anyone could get it. But Yonemoto's 9SDS is not in that category: cancer is not a single disease like polio, and is not open to a single cure. Even if a sibiromycin derivative makes it to market (and they've been the subject of research for quite a while now), it will do what almost every other cancer drug does: help some people, to a degree, for a while. The exceptions are rare: patients who have a tumor type that is completely dependent on a particular mechanism, and that doesn't mutate away from that phenotype quickly enough. Most cancer patients aren't that fortunate.

So here's the rough part of cancer drug discovery: cancer, broadly speaking, is indeed a big public health issue. But we're not going to wipe it out the way the polio and smallpox vaccines wiped out their homogeneous diseases. Cancer isn't caused by a human-specific infectious agent that we can eliminate from the world. It crops up over and over again as our cells divide, in thousands of forms, and fighting it is going to take tremendous diagnostic skill and an array of hundreds of different therapies, most of which we haven't discovered yet. And money. Lots of money.

So when Yonemoto says that "The software industry and the open-source movement have shown that patenting is not necessary for innovation", he's comparing apples and iguanas. Drug discovery is not like coding, unfortunately: you're not going to have one person from San Jose pop up and add a chlorine atom to the molecule while another guy pulls an all-nighter in St. Louis and figures out the i.v. formulation for the rat tox experiments. The pitch on, which is really about doing some preliminary experiments, makes it sound like the opening trumpet of a drug discovery revolution and that it's going to lead to "releasing" a drug. That's disingenuous, to say the least. I wish Yonemoto luck, actually, but I think he's going to be running into some very high-density reality pretty soon.

Update: Yonemoto has added this to the comments section, and I appreciate him coming by:

"Thanks Derek! You've basically crystallized all of my insecurities about the future of open-source drugs. But that's okay. I think there are business models wherein you can get this to work, even under the relatively onerous contemporary FDA burden. To answer a few questions. I think sibiromycin is not a bad candidate for several reasons: 1. (I'm not sure I buy this one but) it's a NP derived and NP derived tends to do well. 2. A molecule with a similar mechanism has made it into phase III and phase I/II show only mild hepatotoxicity and water retention, which are prophylactically treatable with common drugs. 3. There is reportedly no bone marrow suppression in these compounds, and importantly it appears to be immune-neutral, which would make PBDs excellent therapies to run alongside immune-recruitment drugs."

Comments (58) + TrackBacks (0) | Category: Cancer | Clinical Trials | Drug Development | Drug Industry History | Infectious Diseases | Patents and IP

September 29, 2014

The Case of Northwest Biotherapeutics

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Posted by Derek

There have been a lot of strong words exchanged about Northwest Biotherapeutics (NWBO), a small Maryland-based company developing a brain cancer vaccine. Over at Fierce Biotech, they're wondering why this program was picked by the UK authorities as their first official "Promising Innovative Medicine", given the scarcity of data (and the dismal track record of dendritic vaccines in the field).

Adam Feuerstein has said a bunch of similar things, vigorously, at over the last few months as well. He's been especially skeptical of the company's own vigorous PR efforts, and in general tends to be unenthusiastic about small go-it-alone oncology programs. The Feuerstein-Ratain rule, that small-cap cancer trials fail, has been hard to refute.

Well, just the other day Washington Post columnist Steven Pearlstein waded into this story with a piece about how evil short-sellers are hurting promising little biotech companies. That's pretty much the tone of the whole thing, and he uses Feuerstein and NWBO as his prime example, with not-quite-stated allegations of collusion with short-sellers.

My belief is that this is a load of crap, from someone who doesn't understand very much about how the stock market works. Small companies that have been unable to interest anyone else in their technologies have a difficult time of it, to be sure. But we don't need to go to conspiracy theories to explain this. There are indeed short-selling investors who are trying to drive stocks down, but they are absolutely overwhelmed in number by the number of people who are trying to drive stocks up. That's what a stock market is: differences of opinion, held strongly enough for money to be put down on them.

If you look at Feuerstein's most recent column on NWBO, you find that only one other company has even applied for the "Promising Innovative Medicine" designation (and that application is in process). So this is not some incredible milestone. And you also find a lot of useful information on the company's debt structure, the exact sort of thing that an investor in the company should be interested in. Will you get these details by reading press releases from Northwest Biotherapeutics? You will not. You will get them from people who are willing to scrutinize a company, its operations, and its pipeline in detail.

Does Steven Pearlstein think that these details about NWBO's debt deal are false? He should say so. But he also talks about short-sellers crippling Dendreon, which ignores completely the fact that what's crippled Dendreon is that their vaccine doesn't work very well. Wonderful drugs don't get buried by short-sellers. Drugs get buried by data.

Update: is now seeking a retraction from Pearlstein. One of the key sentences is "Mr. Pearlstein -- who said he knew nothing about biotech or medicine . . ." Pretty much had that part figured out already. The letter to the Post goes on to claim a number of other serious deficiencies with Pearlstein's reporting. It's going to be interesting to see where this leads. . .

Comments (42) + TrackBacks (0) | Category: Business and Markets | Cancer | Clinical Trials

September 2, 2014

Exelixis Against the Wall

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Posted by Derek

Exelixis is a company with a very interesting history, but that's in the sense of "much rather read about it than experience it", like the interesting parts in a history book. At one point they had a really outsized pipeline of kinase inhibitors, to the point where it could be hard to keep track of everything, but these projects have largely blown up over the last few years. Big collaboration deals have been wound down, compounds have been returned to them, and so on.

Most recently, the company has been developing cabozantinib for prostate cancer. Along the way (2011) they had a dispute with the FDA about clinical trial design - the company had a much speedier surrogate endpoint in mind, but the agency wasn't having it. At this point, there are enough options in that area to make overall survival the real endpoint that matters, and the FDA told them to go out and get that data instead of messing around with surrogates. So the company plowed ahead, and yesterday announced Phase III results. They weren't good. The compound showed some effects in progression-free survival (PFS), but seems to have no benefit in the longer-running overall survival (OS) measurement. And that one's the key.

There's no way to put a good spin on it, either. The same press release that announced the results also announced that the company was going to have to "initiate a significant workforce reduction" in order to make it through the two other ongoing cabozantinib trials (for renal cell carcinoma and advanced hepatocellular carcinoma). Exelixis has had some pretty brutal workforce reductions over the years already, so this would appear to be cutting down as far as things can be cut (from 330 employees down to 70). And those two remaining indications are tough ones, too - if the compound shows efficacy, it'll be very good news, but those are not the first battlefields you'd choose to fight on. The prostate results don't offer much room for optimism, but on the other hand, the compound has orphan drug status for medullary thyroid cancer, for which it has shown real benefit in a disease that otherwise has no real treatment at all.

So Exelixis will try to stay alive long enough to get through these last trials, and if nothing comes up there, I'd have to think that this will be it for them. You wouldn't have predicted this back in about 2002, but you can't predict anything important in this industry to start with.

Comments (6) + TrackBacks (0) | Category: Cancer | Clinical Trials

August 22, 2014

The Palbociclib Saga: Or Why We Need a Lot of Drug Companies

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Posted by Derek

Science has an article by journalist Ken Garber on palbociclib, the Pfizer CDK4 compound that came up here the other day when we were discussing their oncology portfolio. You can read up on the details of how the compound was put in the fridge for several years, only to finally emerge as one of the company's better prospects. The roots of the project go back to about 1995 at Parke-Davis:

Because the many CDK family members are almost identical, “creating a truly selective CDK4 inhibitor was very difficult,” says former Parke-Davis biochemist Dave Fry, who co-chaired the project with chemist Peter Toogood. “A lot of pharmaceutical companies failed at it, and just accepted broad-spectrum CDK inhibitors as their lead compounds.” But after 6 years of work, the pair finally succeeded with the help of some clever screens that could quickly weed out nonspecific “dirty” compounds.

Their synthesis in 2001 of palbociclib, known internally as PD-0332991, was timely. By then, many dirty CDK inhibitors from other companies were already in clinical trials, but they worked poorly, if at all. Because they hit multiple CDK targets, these compounds caused too much collateral damage to normal cells. . .Eventually, most efforts to fight cancer by targeting the cell cycle ground to a halt. “Everything sort of got hung up, and I think people lost enthusiasm,” Slamon says.

PD-0332991 fell off the radar screen. Pfizer, which had acquired Warner-Lambert/Parke-Davis in 2000 mainly for the cholesterol drug Lipitor, did not consider the compound especially promising, Fry says, and moved it forward haltingly at best. “We had one of the most novel compounds ever produced,” Fry says, with a mixture of pride and frustration. “The only compound in its class.”

A major merger helped bury the PD-0332991 program. In 2003, Pfizer acquired Swedish-American drug giant Pharmacia, which flooded Pfizer's pipeline with multiple cancer drugs, all competing for limited clinical development resources. Organizational disarray followed, says cancer biologist Dick Leopold, who led cancer drug discovery at the Ann Arbor labs from 1989 to 2003. “Certainly there were some politics going on,” he says. “Also just some logistics with new management and reprioritization again and again.” In 2003, Pfizer shut down cancer research in Ann Arbor, which left PD-0332991 without scientists and managers who could demand it be given a chance, Toogood says. “All compounds in this business need an advocate.”

So there's no doubt that all the mergers and re-orgs at Pfizer slowed this compound down, and no doubt a long list of others, too. The problems didn't end there. The story goes on to show how the compound went into Phase I in 2004, but only got into Phase II in 2009. The problem is, well before that time it was clear that there were tumor types that should be more sensitive to CDK4 inhibition. See this paper from 2006, for example (and there were some before this as well).

It appears that Pfizer wasn't going to develop the compound at all (thus that long delay after Phase I). They made it available as a research tool to Selina Chen-Kiang at Weill Cornell, who saw promising results with mantle cell lymphoma, then Dennis Slamon and RIchard Finn at UCLA profiled the compound in breast cancer lines and took it into a small trial there, with even more impressive results. And at this point, Pfizer woke up.

Before indulging in a round of Pfizer-bashing, though, It's worth remembering that stories broadly similar to this are all too common. If you think that the course of true love never did run smooth, you should see the course of drug development. Warner-Lambert (for example) famously tried to kill Lipitor more than once during its path to the market, and it's a rare blockbuster indeed that hasn't passed through at least one near-death-experience along the way. It stands to reason: since the great majority of all drug projects die, the few that make it through are the ones that nearly died.

There are also uncounted stories of drugs that nearly lived. Everyone who's been around the industry for a while has, or has heard, tales of Project X for Target Y, which was going along fine and looked like a winner until Company Z dropped for Stupid Reason. . .uh, Aleph. (Ran out of letters there). And if only they'd realized this, that, and the other thing, that compound would have made it to market, but no, they didn't know what they had and walked away from it, etc. Some of these stories are probably correct: you know that there have to have been good projects dropped for the wrong reasons and never picked up again. But they can't all be right. Given the usual developmental success rates, most of these things would have eventually wiped out for some reason. There's an old saying among writers that the definition of a novel is a substantial length of narrative fiction that has something wrong with it. In the same way, every drug that's on the market has something wrong with it (usually several things), and all it takes is a bit more going wrong to keep it from succeeding at all.

So where I fault Pfizer in all this is in the way that this compound got lost in all the re-org shuffle. If it had developed more normally, its activity would have been discovered years earlier. Now, it's not like there are dozens of drugs that haven't made it to market because Pfizer dropped the ball on them - but given the statistics, I'll bet that there are several (two or three? five?) that could have made it through by now, if everyone hadn't been so preoccupied with merging, buying, moving, rearranging, and figuring out if they were getting laid off or not.

The good thing is that other companies stepped into the field on the basis of those earlier publications, and found CDK4/6 inhibitors of their own (notably Novartis and Lilly). This is why I think that huge mergers hurt the intellectual health of the drug industry. Take it to the reducio ad not all that absurdum of One Big Drug Company. If we had that, and only that, then whole projects and areas of research would inevitably get shelved, and there would be no one left to pick them up at all. (I'll also note, in passing, that should all of the CDK inhibitors make it to market, that there will be yahoos who decry the whole thing as nothing but a bunch of fast-follower me-too drugs, waste of time and money, profits before people, and so on. Watch for it.)

Comments (13) + TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History

August 20, 2014

Did Pfizer Cut Back Some of Its Best Compounds?

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Posted by Derek

John LaMattina has a look at Pfizer's oncology portfolio, and what their relentless budget-cutting has been doing to it. The company is taking some criticism for having outlicensed two compounds (tremelimumab to AstraZeneca and neratinib to Puma) which seem to be performing very well after Pfizer ditched them. Here's LaMattina (a former Pfizer R&D head, for those who don't know):

Unfortunately, over 15 years of mergers and severe budget cuts, Pfizer has not been able to prosecute all of the compounds in its portfolio. Instead, it has had to make choices on which experimental medicines to keep and which to set aside. However, as I have stated before, these choices are filled with uncertainties as oftentimes the data in hand are far from complete. But in oncology, Pfizer seems to be especially snake-bit in the decisions it has made.

That goes for their internal compounds, too. As LaMattina goes one to say, palbociclib is supposed to be one of their better compounds, but it was shelved for several years due to more budget-cutting and the belief that the effort would be better spent elsewhere. It would be easy for an outside observer to whack away at the company and wonder how incompetent they could be to walk away from all these winners, but that really isn't fair. It's very hard in oncology to tell what's going to work out and what isn't - impossible, in fact, after compounds have progressed to a certain stage. The only way to be sure is to take these things on into the clinic and see, unfortunately (and there you have one of the reasons things are so expensive around here).

Pfizer brought up more interesting compounds than it later was able to develop. It's a good question to wonder what they could have done with these if they hadn't been pursuing their well-known merger strategy over these years, but we'll never know the answer to that one. The company got too big and spent too much money, and then tried to cure that by getting even bigger. Every one of those mergers was a big disruption, and you sometimes wonder how anyone kept their focus on developing anything. Some of its drug-development choices were disastrous and completely their fault (the Exubera inhaled-insulin fiasco, for example), but their decisions in their oncology portfolio, while retrospectively awful, were probably quite defensible at the time. But if they hadn't been occupied with all those upheavals over the last ten to fifteen years, they might have had a better chance on focusing on at least a few more of their own compounds.

Their last big merger was with Wyeth. If you take Pfizer's R&D budget and Wyeth's and add them, you don't get Pfizer's R&D post-merger. Not even close. Pfizer's R&D is smaller now than their budget was alone before the deal. Pyrrhus would have recognized the problem.

Comments (20) + TrackBacks (0) | Category: Business and Markets | Cancer | Drug Development | Drug Industry History

August 15, 2014

Incomprehensible Drug Prices? Think Again.

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Posted by Derek

There's a post by Peter Bach, of the Center for Health Policy and Outcomes, that's been getting a lot of attention the last few days. It's called "Unpronounceable Drugs, Incomprehensible Prices", and you know what it says.

No, really, you do, even if you haven't seen it. Too high, unconscionable, market can't support, what they can get away with, every year, too high. Before I get to the uncomfortable parts of my own take on this, let me stipulate a couple of things up front: (1) I do think that the industry is inviting trouble for itself by the way it it raising prices. It is in drug companies' short term interest to do so, but long term I worry that it's going to bring on some sort of price-control regimen. (2) Some drug prices probably are too high (but see below for what that means). Big breakthroughs can, at least in theory, command high prices, but not everything deserves to be priced at the level it is.

I was about to say "see below" again, but this paragraph is below, so here goes. Let me quote a bit from Bach's article:

Cancer drug prices keep rising. The industry says this reflects the rising costs of drug development and the business risks they must take when testing new drugs. I think they charge what they think they can get away with, which goes up every year. . .Regardless of the estimate, the pricing of new drugs for cancer and now other common diseases has come unglued from the rationale the industry has long espoused. Instead, pricing is explained by a phenomenon of increasing boldness by the industry against a backdrop of regulators and insurers who have no legal authority to dictate or even propose alternative pricing models.

Bach's first assertion is correct: drug companies are charging what they think they can get away with. In that, they are joined by pretty much every other business in the entire country. I did a post once where I imagined car sales transplanted into the world of drug sales- you couldn't just walk in and buy a car, for example. No, you had to go to a car consultant first, licensed by the state, who would examine your situation and determine the sort of car you needed. Once they'd given you a car prescription, you could then go to a dealer.

Well, we don't have that, but what car companies do charge is, well, what they can get away with. The same as steel companies, soft drink companies, cardboard box companies, grocery stores, and people who are selling their houses. You charge what you think the market will bear. Even people selling basic necessities of life like food and shelter charge what they think the market will bear. It's true that health care does feel different from any of those (a point that I went into in that post linked in the last paragraph), and there's the root of many a problem.

And, some will say, a big difference is that none of these other sellers have patents on their side, the legal right to put the screws on. But remember the flip side of the patent system: the legal certainty that you will lose that pricing power on a set date. The pricing of new drugs is completely driven by their expected patent lifetimes, because almost all the money that the developing company is ever going to make off the drug is going to have to be made during that period.

And sometimes that period isn't very long. The patent clock starts ticking a long time before a drug ever gets on the market; there are often only five to ten years left when it's finally approved for sale. There are other factors, too. Everyone is talking about the price of Sovaldi for hepatitis C, but no as many people have thought about the fact that the drug is, in fact, so effective that it has blown two other recently approved Hep C treatments right out of the market, well before their patent lifetimes had even expired. There really is competition in the drug business, and that sector shows it in action.

Now, what there isn't so much of is competition on price, true. And that's what you do see in the other businesses I named above. There are grocery stores that occupy the "Wonderful Prestigious High Quality" part of the market, and others that occupy the "Low Low Prices Every Day" part. (And interestingly, if you Venn-diagram out what's on the shelves of those two, there's still some overlap, allowing you to watch people paying wildly different prices for blueberries that came off the same truck, not to mention even less perishable stuff like aluminum foil). You don't see this in the drug industry, partly because for patented drugs we're never selling the same blueberries. the same gasoline, or the same khaki trousers. Even the biggest "me-too" drugs still differ from each other to some degree.

And that brings up another point. Bach uses (as his example of pricing in the cancer field) two Alk compounds, Xalkori (crizotinib) from Pfizer and Zykadia (ceritinib) from Novartis. Xalkori was first, and Bach makes a lot of the fact that Zykadia is priced higher, even though he says that Pfizer ran bigger clinical trials, had to work out the associated diagnostic test with the FDA, and launch the new mechanism into the oncology market. Novartis, he says, got to piggy-back on all that, and yet their drug is priced higher. There can be no other reason for that pricing decision, Bach says, other than that they can.

Let's go into some details that Bach's article leaves out. Zykadia is indeed second to market. But the time gap between the two drugs means that Novartis was working on it before they knew that Xalkori worked in the clinic. Bach makes an error here made by many others who have not actually done drug discovery work: the time course of these things is longer than it looks. A screen had to be run against Alk, compounds had to be confirmed, a medicinal chemistry team had to optimize them and make lots of new structures, all of which except one fell by the side of the road. The compound had to go through animal tests for efficacy and safety, and it had to be scaled up and formulated. And so on, and so on. Novartis did not sit back, watch Xalkori succeed, and then decide "Hey, we should get us some of that action, too".

Now Zykadia is, as Bach says, a second-line therapy. But it's approved for patients who do not respond to, or have become intolerant to Xalkori. So this "me-too" drug is, in fact, different enough to work on patients for whom Xalkori has failed. In fact, most patients will start to show relapse inside of a year on Xalkori, so it would appear that most non-small-cell lung cancer patients with multiyear survival are probably going to end up taking both compounds. Cancers mutate quickly, and we need all the options we can get - and guess what, some of those options are going to be second to market, because they can't all be first.

Another point to note is that while Zykadia was indeed approved on the basis of a smaller clinical trial set, that's because it received "breakthrough" designation from the FDA for accelerated review and approval. Startlingly, it actually got approved after Phase I trials alone. (Not bad for what Bach characterizes as a simple copycat drug, by the way). Novartis has run the compound in more clinical trials than that, and they continue to do so. It's not like they slipped in with a mere 163 patients and then trotted off to the FDA while brushing the dust off their hands. To find this out, by the way, you'll want to use "LDK378", the internal Novartis designation for the drug, and I'm passing this information on to Bach for free. shows 13 trials in the US when you do that, and there are others outside the country as well.

Bach's article, as mentioned, plays down any differences between these two drugs, saying that "they have not been directly compared". But that's not accurate. Let me quote from that link in the paragraph just above:

As described by Shaw and colleagues in the New England Journal of Medicine, ceritinib has striking activity in ALK-rearranged NSCLC, both in treatment-naïve patients and in those who experienced tumor progression on crizotinib. . .The drug has clear pharmacological advantages over crizotinib. Its surprising level of activity in crizotinib-resistant tumors may be explained by its greater potency and its particular ability to inhibit ALK with gatekeeper mutations that confer resistance to crizotinib.

The two drugs have had a very important comparison: people who are going to die on Xalkori are going to survive longer if they switch to Zykadia. "Me-too" drug, my ass.

But rather than end on that note, tempting as that is, let me circle back to pricing once again. The price for these cancer drugs is not borne by individual patients emptying their piggy banks. It is borne by insurance, both private and government. And drug companies do indeed price their drugs at what the think the insurance plans will pay for them. This is not a secret, and should not be a surprise, and I continue to be baffled by people who react to this with horror and disbelief. Prices appear when you find out what the payers will pay. If Pfizer, Novartis, or Gilead priced their drugs at fifty million dollars a dose, no insurance company would reimburse. But the insurance companies are paying the current prices, and if they believe that they will be put out of business by doing so, they need to stop doing that. And they could.

They will, too, if we in the industry keep pushing them towards doing it. That's our big problem in drug development: our productivity has been too low, and we're making up for it by charging more money. But that can't go on forever. There are walls closing in on us from both sides, and we're going to have to scramble out from between them at some point. Pricing power can only take you so far.

Comments (43) + TrackBacks (0) | Category: Cancer | Clinical Trials | Drug Prices | Regulatory Affairs | Why Everyone Loves Us

August 11, 2014

Is The Current Patent System Distorting Cancer Research?

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Posted by Derek

Via the Economist's "Free Exchange" blog comes this provocative paper (PDF) from the University of Chicago, Harvard, and MIT. Its authors are looking at the effect of patents on the oncology drug market, and they conclude that the current system is probably hurting patients (and the broader economy).

That's a big statement to make, so the first thing to do is dig into the paper and see how it was arrived at. The authors are looking at effective patent terms: how long an invention really has an exclusive market term. That's a big issue in drug development, of course, since the regulatory pathway to approval can be so long that only a few years are left on the patent by the time a drug can be sold.

. . .Since society cares about an invention’s total useful life, but private firms care only about monopoly life, a distortion emerges not just in the level of R&D (as arises in standard models), but also in the composition of R&D: society might value invention A more highly than invention B, but private industry may choose to develop B but not A. Note that, other things equal, commercialization lag lowers both monopoly life and total useful life: both society and private firms prefer inventions to reach the market quickly. But, under a fixed patent term, commercialization lag reduces monopoly life more rapidly than total useful life, hence the distortion away from inventions with both a long total useful life and a long commercialization lag.

The problem with oncology, the paper claims, is that drug firms therefore have an incentive to work on compounds whose clinical trials are shorter, because they have a better chance of a longer effective patent lifetime). Slow-moving cancers, which might be more treatable, are relatively neglected, because there is less likelihood of return from them given the patent timelines.

Cancer drug development tends to be specific to a cancer type (e.g. prostate) and stage of disease (e.g. metastatic). . .providing a natural framework for estimating how expected commercialization lags (as proxied by survival time) and R&D investments vary across different groups of patients. Aggregating survival information from patient-level cancer registry data, we document stark variation in survival times across patients of different cancer types and stages of disease. In order to measure R&D investments on cancer treatments relevant to each cancer type and stage of disease, we use newly-constructed data from a clinical trial registry that has cataloged cancer clinical trials since the 1970s. The key feature of this data which makes it amenable to our analysis is that for each clinical trial, the registry lists each of the specific patient groups eligible to enroll in the trial - thus allowing a match between our measures of expected commercialization lag (as measured by survival time) and R&D activity (as measured by clinical trial investments) across cancer types and stages of disease.

They show that there is much more clinical focus on the severe short-time-course cancers than on the slow-moving localized types, and they ascribe this to distortion caused by patent terms. But as far as I can tell, the authors don't consider some other factors, and as someone who's done drug discovery work in oncology, I'd like to bring these out as well.

There's no doubt that patent lifetimes are a factor, since these allow a company to recoup its development costs - and the costs of all the other failed projects. It's worth remembering that the overall clinical failure rate is still roughly 90%, so there are a lot of costs to be made up whenever sometime actually does work. But imagine that patent terms were suddenly doubled to forty years instead of twenty. This might bring in more investment into slower-moving long-term cancer projects, but I don't think it would be as simple as this paper's model suggests. Overall, a drug company would prefer not to tie up its time, effort, and capital for longer than necessary in the uncertain business of a clinical trial. Even with the prospect of a longer patent term reward at the end of the process, the disincentive for multiyear trials would still be there, because there are so many shorter alternatives in oncology. (That's as opposed to Alzheimer's, where it's long trials or nothing, at least until we understand a lot more about the disease). It's not like the slower-moving cancers are any easier to understand, find targets for, or progress into the clinic: they're all hard.

This is even more the case when you consider that the oncology field has a good number of small companies in it. The barriers to oncology drug development are lower than in some other areas - it's easier to identify patients, and there's a lot of unmet medical need. And those relatively short clinical trial times are another incentive: to do another thought experiment, if you suddenly required all drug companies working on oncology to work only on the slower-moving cancers, there would be far fewer drugs in development, since most of the smaller companies would drop out. They don't have the funds to keep going that long. So while short clinical trials may be a distortion in one direction, they have distorted the market in another, arguably beneficial direction as well, by bringing more companies and more ideas into the field.

I say "beneficial", because some of the drug mechanisms that are being tried on the faster-moving cancers would also be of use on the slower, more localized ones. The genomic, metabolic, and proteomic information learned by studying the faster-moving varieties (and the techniques used to do so) are immediately applicable to the slower-moving ones as well. It's not a zero-sum game.

There's also that unmet-medical-need factor to consider. It's easier for a company, especially a small one, to raise money and justify its spending to investors when it's working against form of cancer with a low survival rate and a relatively fast progression. The belief is that the regulatory barriers to approval are lower for such drugs, and that uptake by physicians would be faster if the drug gets approved. Side effects are also going to be more tolerated for more severe conditions, too, and oncology drugs, as is well known, tend to have some pretty significant ones.

The authors, after considering several alternatives, present evidence that when regulatory agencies allow surrogate endpoints as a factor for drug approval that investment in the longer-term cancers improves. They suggest that research into validated markers of this sort could have the best returns overall, compared to other possibilities (such as just lengthening patent terms, not that that's going to happen in the real world, anyway). And I agree with them there - but I also note that drug companies themselves have been seeking such surrogate endpoints on their own, for the same reasons. (These things speed up all trials, not just the longer ones). Large incentives for good clinical trial markers already exist, but such markers are pretty damned hard to come by, unfortunately.

But as for the main subject of this paper and its explanatory power, I'm not quite convinced. As far as I can see from going through the manuscript, none of the other factors mentioned above have been considered - everything is tied to the effective patent lifetime. And while that's probably real, and a partial surrogate for some of these issues, I have trouble buying it as the only thing that's going on. Now, this may be what economists do: find a correlation that is open to a mathematical treatment and run with it. But I don't see how you can make statements this sweeping without going into more of what (from my perspective) I see as the real world of drug discovery and development.

Comments (13) + TrackBacks (0) | Category: Cancer | Clinical Trials | Patents and IP

July 24, 2014

Phenotypic Assays in Cancer Drug Discovery

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Posted by Derek

The topic of phenotypic screening has come up around here many times, as indeed it comes up very often in drug discovery. Give your compounds to cells or to animals and look for the effect you want: what could be simpler? Well, a lot of things could, as anyone who's actually done this sort of screening will be glad to tell you, but done right, it's a very powerful technique.

It's also true that a huge amount of industrial effort is going into cancer drug discovery, so you'd think that there would be a natural overlap between these: see if your compounds kill or slow cancer cells, or tumors in an animal, and you're on track, right? But there's a huge disconnect here, and that's the subject of a new paper in Nature Reviews Drug Discovery. (Full disclosure: one of the authors is a former colleague, and I had a chance to look over the manuscript while it was being prepared). Here's the hard part:

Among the factors contributing to the growing interest in phenotypic screening in drug discovery in general is the perception that, by avoiding oversimplified reductionist assumptions regarding molecular targets and instead focusing on functional effects, compounds that are discovered in phenotypic assays may be more likely to show clinical efficacy. However, cancer presents a challenge to this perception as the cell-based models that are typically used in cancer drug discovery are poor surrogates of the actual disease. The definitive test of both target hypotheses and phenotypic models can only be carried out in the clinic. The challenge of cancer drug discovery is to maximize the probability that drugs discovered by either biochemical or phenotypic methods will translate into clinical efficacy and improved disease control.

Good models in living systems, which are vital to any phenotypic drug discovery effort, are very much lacking in oncology. It's not that you can't get plenty of cancer cells to grow in a dish - they'll take over your other cell cultures if they get a chance. But those aren't the cells that you're going to be dealing with in vivo, not any more. Cancer cells tend to be genetically unstable, constantly throwing off mutations, and the in vitro lines are adapted to living in cull culture. That's true even if you implant them back into immune-compromised mice (the xenograft models). The number of drugs that look great in xenograft models and failed out in the real world is too large to count.

So doing pure phenotypic drug discovery against cancer is very difficult - you go down a lot of blind alleys, which is what phenotypic screening is supposed to prevent. The explosion of knowledge about cellular pathways in tumor cells has led to uncountable numbers of target-driven approaches instead, but (as everyone has had a chance to find out), it's rare to find a real-world cancer patient who can be helped by a single-target drug. Gleevec is the example that everyone thinks of, but the cruel truth is that it's the exceptional exception. All those newspaper articles ten years ago that heralded a wonderful era of targeted wonder drugs for cancer? They were wrong.

So what to do? This paper suggests that the answer is a hybrid approach:

For the purpose of this article, we consider ‘pure’ phenotypic screening to be a discovery process that identifies chemical entities that have desirable biological (phenotypic) effects on cells or organisms without having prior knowledge of their biochemical activity or mode of action against a specific molecular target or targets. However, in practice, many phenotypically driven discovery projects are not target-agnostic; conversely, effective target-based discovery relies heavily on phenotypic assays. Determining the causal relationships between target inhibition and phenotypic effects may well open up new and unexpected avenues of cancer biology.

In light of these considerations, we propose that in practice a considerable proportion of cancer drug discovery falls between pure PDD and TDD, in a category that we term ‘mechanism-informed phenotypic drug discovery’ (MIPDD). This category includes inhibitors of known or hypothesized molecular targets that are identified and/or optimized by assessing their effects on a therapeutically relevant phenotype, as well as drug candidates that are identified by their effect on a mechanistically defined phenotype or phenotypic marker and subsequently optimized for a specific target-engagement MOA.

I've heard these referred to as "directed phenotypic screens", and while challenging, it can be a very fruitful way to go. Balancing the two ways of working is the tricky part: you don't want to slack up on the model just so it'll give you results, if those results aren't going to be meaningful. And you don't want to be so dogmatic about your target ideas that you walk away from something that could be useful, but doesn't fit your scheme. If you can keep all these factors in line, you're a real drug discovery scientist, and no mistake.

How hard this is can be seen from the paper's Table 1, where they look over the oncology approvals since 1999, and classify them by what approaches were used for lead discovery and lead optimization. There's a pile of 21 kinase inhibitors (and eight other compounds) over in the box where both phases were driven by inhibition of a known target. And there are ten compounds whose origins were in straight phenotypic screening, with various paths forward after that. But the "mechanism-informed phenotypic screen" category is the shortest list of the three lead discovery approaches: seven compounds, optimized in various ways. (The authors are upfront about the difficulties of assembling this sort of overview - it can be hard to say just what really happened during discovery and development, and we don't have the data on the failures).

Of those 29 pure-target-based drugs, 18 were follow-ons to mechanisms that had already been developed. At this point, you'd expect to hear that the phenotypic assays, by contrast, delivered a lot more new mechanisms. But this isn't the case: 14 follow-ons versus five first-in-class. This really isn't what phenotypic screening is supposed to deliver (and has delivered in the past), and I agree with the paper that this shows how difficult it has been to do real phenotypic discovery in this field. The few assays that translate to the clinic tend to keep discovering the same sorts of things. (And once again, the analogy to antibacterials comes to mind, because that's exactly what happens if you do a straight phenotypic screen for antibacterials. You find the same old stuff. That field, too, has been moving toward hybrid target/phenotypic approaches).

The situation might be changing a bit. If you look at the drugs in the clinic (Phase II and Phase III), as opposed to the older ones that have made it all the way through, there are still a vast pile of target-driven ones (mostly kinase inhibitors). But you can find more examples of phenotypic candidates, and among them an unusually high proportion of outright no-mechanism-known compounds. Those are tricky to develop in this field:

In cases where the efficacy arises from the engagement of a cryptic target (or mechanism) other than the nominally identified one, there is potential for substan- tial downside. One of the driving rationales of targeted discovery in cancer is that patients can be selected by pre- dictive biomarkers. Therefore, if the nominal target is not responsible for the actions of the drug, an incorrect diagnostic hypothesis may result in the selection of patients who will — at best — not derive benefit. For example, multiple clinical trials of the nominal RAF inhibitor sorafenib in melanoma showed no benefit, regardless of the BRAF mutation status. This is consistent with the evidence that the primary target and pharmacodynamic driver of efficacy for sorafenib is actually VEGFR2. The more recent clinical success of the bona fide BRAF inhibitor vemurafenib in melanoma demonstrates that the target hypothesis of BRAF for melanoma was valid.

So, if you're going to do this mechanism-informed phenotypic screening, just how do you go about it? High-content screening techniques are one approach: get as much data as possible about the effects of your compounds, both at the molecular and cellular level (the latter by imaging). Using better cell assays is crucial: make them as realistic as you can (three-dimensional culture, co-culture with other cell types, etc.), and go for cells that are as close to primary tissue as possible. None of this is easy, or cheap, but the engineer's triangle is always in effect ("Fast, Cheap, Good: Pick Any Two").

Comments (23) + TrackBacks (0) | Category: Cancer | Drug Assays | Drug Development

July 23, 2014

Neratinib Comes Through For Puma

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Posted by Derek

Yet another entry in the "Why do people keep investing in biopharma?" files. Take a look at the case of Puma Biotechnology. Their stock was as high as $140/share earlier in the year, and it gradually deflated to the high 50s/low 60s as time went on. But yesterday, after hours, they reported unexpectedly good Phase III results for neratinib in breast cancer, and as I write, they're at $228 or so, up about $167 per share.

It's another HER2/EGFR tyrosine kinase inhibitor (like Tykerb/lapatinib in the small molecule space, although neratinib is an irreversible inhibitor) and would be targeted at patients who are now taking Herceptin. Neratinib itself has not had a smooth path to this stage, though. Puma licensed the compound out from Pfizer, and took on the responsibility for all of the development. Pfizer ditched the compound a few years ago in a review of their oncology portfolio. I note that the two companies have reworked their licensing agreement on this news as well. Puma's entire business model is taking up oncology candidates that other companies have shed, and it certainly seems to have come through for them this time.

So chalk one up for irreversible kinase inhibitors, and (of course) for Puma. And for the patients who will be taking the drug, naturally, and lastly, for Puma's shareholders, who are having an excellent day indeed.

Comments (18) + TrackBacks (0) | Category: Business and Markets | Cancer | Clinical Trials

July 18, 2014

Thalidomide, Bound to Its Target

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Posted by Derek

There's a new report in the literature on the mechanism of thalidomide, so I thought I'd spend some time talking about the compound. Just mentioning the name to anyone familiar with its history is enough to bring on a shiver. The compound, administered as a sedative/morning sickness remedy to pregnant women in the 1950s and early 1960s, famously brought on a wave of severe birth defects. There's a lot of confusion about this event in the popular literature, though - some people don't even realize that the drug was never approved in the US, although this was a famous save by the (then much smaller) FDA and especially by Frances Oldham Kelsey. And even those who know a good amount about the case can be confused by the toxicology, because it's confusing: no phenotype in rats, but big reproductive tox trouble in mice and rabbits (and humans, of course). And as I mentioned here, the compound is often used as an example of the far different effects of different enantiomers. But practically speaking, that's not the case: thalidomide has a very easily racemized chiral center, which gets scrambled in vivo. It doesn't matter if you take the racemate or a pure enantiomer; you're going to get both of the isomers once it's in circulation.

The compound's horrific effects led to a great deal of research on its mechanism. Along the way, thalidomide itself was found to be useful in the treatment of leprosy, and in recent years it's been approved for use in multiple myeloma and other cancers. (This led to an unusual lawsuit claiming credit for the idea). It's a potent anti-angiogenic compound, among other things, although the precise mechanism is still a matter for debate - in vivo, the compound has effects on a number of wide-ranging growth factors (and these were long thought to be the mechanism underlying its effects on embryos). Those embryonic effects complicate the drug's use immensely - Celgene, who got it through trials and approval for myeloma, have to keep a very tight patient registry, among other things, and control its distribution carefully. Experience has shown that turning thalidomide loose will always end up with someone (i.e. a pregnant woman) getting exposed to it who shouldn't be - it's gotten to the point that the WHO no longer recommends it for use in leprosy treatment, despite its clear evidence of benefit, and it's down to just those problems of distribution and control.

But in 2010, it was reported that the drug binds to a protein called cereblon (CRBN), and this mechanism implicated the ubiquitin ligase system in the embryonic effects. That's an interesting and important pathway - ubiquitin is, as the name implies, ubiquitous, and addition of a string of ubiquitins to a protein is a universal disposal tag in cells: off to the proteosome, to be torn to bits. It gets stuck onto exposed lysine residues by the aforementioned ligase enzyme.

But less-thorough ubiquitination is part of other pathways. Other proteins can have ubiquitin recognition domains, so there are signaling events going on. Even poly-ubiquitin chains can be part of non-disposal processes - the usual oligomers are built up using a particular lysine residue on each ubiquitin in the chain, but there are other lysine possibilities, and these branch off into different functions. It's a mess, frankly, but it's an important mess, and it's been the subject of a lot of work over the years in both academia and industry.

The new paper has the crystal structure of thalidomide (and two of its analogs) bound to the ubiquitin ligase complex. It looks like they keep one set of protein-protein interactions from occurring while the ligase end of things is going after other transcription factors to tag them for degradation. Ubiquitination of various proteins could be either up- or downregulated by this route. Interestingly, the binding is indeed enantioselective, which suggests that the teratogenic effects may well be down to the (S) enantiomer, not that there's any way to test this in vivo (as mentioned above). But the effects of these compounds in myeloma appear to go through the cereblon pathway as well, so there's never going to be a thalidomide-like drug without reproductive tox. If you could take it a notch down the pathway and go for the relevant transcription factors instead, post-cereblon, you might have something, but selective targeting of transcription factors is a hard row to hoe.

Comments (9) + TrackBacks (0) | Category: Analytical Chemistry | Biological News | Cancer | Chemical News | Toxicology

May 28, 2014

Would You Have Advanced BBI608?

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Posted by Derek

Over the weekend, Dainippon Sumitomo got some very bad news about a compound they were developing against cancer stem cells. It's BBI608, which they picked up by buying Boston Biomedical a couple of years ago, for pretty substantial money. The compound was in a colorectal cancer trial, but the first interim analysis of the treatment group was so bad that enrollment was stopped entirely.
Cancer stem cells - now that's a field with a lot of promise and a lot of risk. No one, it's safe to say, really understands what's going on there. And you can find some people who doubt the whole concept. Are there really pluripotent cells (a small population) driving some kinds of tumors? Evidence points that way, but getting a handle on them and figuring out their role has been hard. These latest results are not going to clear things up much, either.

I have to say, though, I would have been wary about shelling out $200 million up front for a compound that looks like this. That's BBI608 to the left, and yep, it's a big ol' quinone. I will freely admit my own biases here: I strike quinones (and their hydroquinone partners) off any list of screening hits I get. Life's too short. There are just too many things that can go wrong with dosing such an obvious, screaming, reactive redox compound in a living system. People who've worked with me can corroborate my statements; I've drawn red X marks through compounds that look a lot like this one and never looked back. Note that I am not saying that no quinones can ever be drugs. I'm just saying that the odds are stacked against them.

It's not like the activity you get is spurious - quite the contrary. Quinones can do a lot of things inside cells, which make them over-represented in cellular and phenotypic assays (assuming you let them into your compound collection in the first place). But those activities can change, depending on what sort of oxidative or metabolic stress the cells are under (and many other factors besides). BBI608 must have had some pretty compelling early-stage data to make Dainippon Sumitomo jump at the chance to buy it (and its company), but look at it now.

I wouldn't have even trusted this one as a tool compound, given the number of possible activities (even Boston Biotech kept taking about "inhibiting multiple pathways"). What kind of tool compound is it, given these clinical data? It's true that by tossing this structure into the trash that I wouldn't have had a company that got bought out for $2.6 billion dollars. And I wouldn't have had the satisfaction of taking a compound into the clinic with hopes of success, misguided or not (I haven't had that satisfaction too often, come to think of it). So there's that. But on the other hand, I've been working on things during that time that at least haven't failed yet, and the next molecule I do help push into the clinic will not, I assure you, look like this one, because I want to give it every chance I can to have it actually work.

Comments (25) + TrackBacks (0) | Category: Cancer | Clinical Trials

May 22, 2014

A Horrible, Expensive, and Completely Avoidable Drug Development Mixup

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Posted by Derek

TIC10.jpgC&E News has a story today that is every medicinal chemist's nightmare. We are paid to find and characterize chemical matter, and to develop it (by modifying structures and synthesizing analogs) into something that can be a drug. Key to that whole process is knowing what structure you have in the first place, and now my fellow chemists will see where this is going and begin to cringe.

Shown at left are two rather similar isomeric structures. The top one was characterized at Penn State a few years ago by Wafik El-Deiry's lab as a stimulator of the TRAIL pathway, which could be a useful property against some tumor types (especially glioblastoma). (Article from Nature News here). Their patent, US8673923, was licensed to Oncoceutics, a company formed by El-Deiry, and the compound (now called ONC201) was prepared for clinical trials.

Meanwhile, Kim Janda at Scripps was also interested in TRAIL compounds, and his group resynthesized TIC10. But their freshly prepared material was totally inactive - and let me tell you, this sort of thing happens all too often. The usual story is that the original "hit" wasn't clean, and that its activity was due to metal contamination or colorful gunk, but that wasn't the case here. Janda requested a sample of TIC10 from the National Cancer Institute, and found that (1) it worked in the assays, and (2) it was clean. That discrepancy was resolved when careful characterization, including X-ray crystallography, showed that (3) the original structure had been misassigned.

It's certainly an honest mistake. Organic chemists will look at those two structures and realize that they're both equally plausible, and that you could end up with either one depending on the synthetic route (it's a question of which of two nitrogens gets alkylated first, and with what). It's also clear that telling one from the other is not trivial. They will, of course, have the same molecular weight, and any mass spec differences will be subtle. The same goes for the NMR spectra - they're going to look very similar indeed, and a priori it could be very hard to have any confidence that you'd assigned the right spectrum to the right structure. Janda's lab saw some worrisome correlation patterns in the HMBC spectra, but X-ray was the way to go, clearly - these two molecules have quite different shapes, and the electron density map would nail things down unambiguously.

To confuse everyone even more, the Ang. Chem. paper reports that a commercial supplier (MedKoo Biosciences) has begun offering what they claim is TIC10, but their compound is yet a third isomer, which has no TRAIL activity, either. (It's the "linear" isomer from the patent, but with the 2-methylbenzyl on the nitrogen in the five-membered ring instead).

So Janda's group had found that the published structure was completely dead, and that the newly assigned structure was the real active compound. They then licensed that structure to Sorrento Therapeutics, who are. . .interested in taking it towards clinical trials. Oh boy. This is the clearest example of a blown med-chem structural assignment that I think I've ever seen, and it will be grimly entertaining to see what happens next.

When you go back and look at the El-Deiry/Oncoceutics patent, you find that its claim structure is pretty unambiguous. TIC10 was a known compound, in the NCI collection, so the patent doesn't claim it as chemical matter. Claim 1, accordingly, is written as a method-of-treatment:

"A method of treatment of a subject having brain cancer, comprising: administering to the subject a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and a pharma­ceutically accepted carrier."

And it's illustrated by that top structure shown above - the incorrect one. That is the only chemical structure that appears in the patent, and it does so again and again. All the other claims are written dependent on Claim 1, for treatment of different varieties of tumors, etc. So I don't see any way around it: the El-Deiry patent unambiguously claims the use of one particular compound, and it's the wrong compound. In fact, if you wanted to go to the trouble, you could probably invalidate the whole thing, because it can be shown (and has been) that the chemical structure in Claim 1 does not produce any of the data used to back up the claims. It isn't active at all.

And that makes this statement from the C&E News article a bit hard to comprehend: "Lee Schalop, Oncoceutics’ chief business officer, tells C&EN that the chemical structure is not relevant to Oncoceutics’ underlying invention. Plans for the clinical trials of TIC10 are moving forward." I don't see how. A quick look through the patent databases does not show me anything else that Oncoceutics could have that would mitigate this problem, although I'd be glad to be corrected on this point. Their key patent, or what looks like it to me, has been blown up. What do they own? Anything? But that said, it's not clear what Sorrento owns, either. The C&E News article quotes two disinterested patent attorneys as saying that Sorrento's position isn't very clear, although the company says that its claims have been written with these problems in mind. Could, for example, identifying the active form have been within the abilities of someone skilled in the art? That application doesn't seem to have published yet, so we'll see what they have at that point.

But let's wind up by emphasizing that "skilled in the art" point. As a chemist, you'd expect me to say this, but this whole problem was caused by a lack of input from a skilled medicinal chemist. El-Deiry's lab has plenty of expertise in cancer biology, but when it comes to chemistry, it looks like they just took what was on the label and ran with it. You never do that, though. You never, ever, advance a compound as a serious candidate without at least resynthesizing it, and you never patent a compound without making sure that you're patenting the right thing. What's more, the Oncoceutics patent estate in this area, unless I'm missing some applications that haven't published yet, looks very, very thin.

One compound? You find one compound that works and you figure that it's time to form a company and take it into clinical trials, because one compound equals one drug? I was very surprised, when I saw the patent, that there was no Markush structure and no mention of any analogs whatsoever. No medicinal chemist would look at a single hit out of the NCI collection and say "Well, we're done - let's patent that one single compound and go cure glioblastoma". And no competent medicinal chemist would look at that one hit and say "Yep, LC/MS matches what's on the label - time to declare it our development candidate". There was (to my eyes) a painfully inadequate chemistry follow-through on TCI10, and the price for that is now being paid. Big time.

Comments (31) + TrackBacks (0) | Category: Analytical Chemistry | Cancer | Patents and IP

May 1, 2014

Merrimack Wins One

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Posted by Derek

You don't get the chance to say "positive Phase III results in advanced pancreatic cancer" very often, but it looks like Merrimack Pharmaceuticals is able to today. The company has had some real highs and lows over the last few years, but they've made the money hold out long enough to see this. In combination with 5-fluorouracil and leucovorin (but not as a stand-alone), the company MM-398 showed a real increase in survival.

As you might expect, that increase can be looked at more than one way. The standard-of-care group made it for about four months, and the treatment group for about six. You can say "just two months more" or "fifty per cent improvement", as you wish. I hope that I never have to think about advanced pancreatic cancer survival figures in detail, is all I can say. It's worth noting that MM-398 is not some new compound or new mechanism - it's a new way to dose the well-known drug irinotecan, which is already part of the standard regiment for the disease. The company has made a liposomal formulation, and that data would indicate that this really does make a difference. Congratulations to them - that's a very, very tough patient population to see anything happen in.

Comments (8) + TrackBacks (0) | Category: Cancer | Clinical Trials

April 7, 2014

Is Palbociclib Promising? Or Not?

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Posted by Derek

Here's a good test for whatever news outlets you might be using for biotech information. How are they handling Pfizer's release of palbociclib information from the AACR meeting over the weekend?

Do a news search for the drug's name, and you'll see headline after headline. Many of them include the phrase "Promising Results". And from one standpoint, those words are justified. The drug showed a near-doubling in progression-free survival (PFS) when added to the standard of care, and you'd think that that has to be good. But a first analysis of overall survival (OS) shows no statistically significant improvement.

Now, how can that be? One possibility is that the drug helps hold advanced breast cancer back, until a population of cells breaks through - and when they do, it's a very fast-moving bunch indeed. Pfizer, for its part, is certainly hoping that further collection of data will start to show a real OS effect. They're going to need to - Avastin's provisional approval for breast cancer was based on earlier PFS numbers, which did not hold up when OS data came in. And that approval was revoked, as it should have been. Now, Avastin also had side effect issues, and quality-of-life issues, so these cases aren't directly comparable. But the FDA really wants to see a survival benefit, and that's what a new cancer drug really should offer. "You'll die at the same time, but with fewer tumors, and out more money" is not an appealing sales pitch. This issue has come up several times before, with other drugs, and it will come up again.

You'd think that a PFS effect like palbociclib's should translate into a real survival benefit, and as more data are added, it may well. But it's surely not going to be as impressive as people had hoped for, or it would have been apparent in the data we have. So take a look at the stories you're reading on the drug: if they mention this issue, good. If they just talk about what a promising drug for breast cancer palbociclib is, then that reporter (and that news outlet) is not providing the full story. (Here's one that does).

Update: there is an ongoing Phase III that's more specifically looking at overall survival. Its results will be awaited with great interest. . .

Comments (32) + TrackBacks (0) | Category: Cancer | Press Coverage

Cancer Immunotherapy's Growing Pains

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Posted by Derek

Cancer immunotherapy, which I've written about several times here (and which has claimed the constant attention of biopharma investors for some time now) has run into an inevitable difficulty: its patients are very sick, and its effects are very strong. Sloan-Kettering announced over the weekend that it's having to halt recruitment in a chimeric antigen receptor (CAR) T-cell trial against non-Hodgkin's lymphoma:

Six patients died of either disease relapse or progression, said MSK, while two patients died in remission from complications related to allogeneic bone marrow transplantation. An additional two patients died within two weeks of receiving a CAR-T cell infusion.

"The first of these two patients had a prior history of cardiac disease and the second patient died due to complications related to persistent seizure activity," noted MSK's presentation. "As a matter of routine review of adverse events on study, our center made a decision to pause enrollment and review these two patients in detail."

This study is associated with Juno Therapeutics, and the company says that it expects to continue once the review is finished. There's a huge amount of activity in this area, with Juno as one of the main players, and Novartis (who are working with the team at Penn) as another. Unfortunately, that activity is both legal and scientific; the patent situation in this area has yet to be clarified. This is an extremely promising approach, but it has a long way to go.

Comments (8) + TrackBacks (0) | Category: Cancer | Clinical Trials

March 27, 2014

Dichloroacetic Acid, In a New Form

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Posted by Derek

Remember dichloroacetic acid? In 2007, there was a stir about it as a cancer therapy, and on internet forums you still see it referenced as a "cancer cure" that no drug company will touch because it's unpatentable/doesn't have to be taken forever/too cheap/not evil enough, etc.

The people spreading that stuff around don't know how to use PubMed, because a look through the literature will show that DCA is still an active area of research (in some cases, involving people who've taken it on their own). Interestingly, PubMed also makes it apparent that the rest of the literature on the compound is in its role as a water pollutant. But the problem with it as a drug is that it has poor pharmacokinetics. Its site of action is the mitochondrion, but it doesn't do a very good job of getting there (as one would expect from a small molecular weight carboxylic acid, especially one that's as ionized as this one is at body pH).

So here's an attempt to do something about that. The authors, from the University of Georgia, tether several DCA molecules to a scaffold that should do a better job of targeting mitochondria. They go as far as cellular data to prove the point, but there's nothing in vivo (I'm not sure what would happen in that case, but it would seem worth finding out).

This, one should note, is a new molecule, and one that was perfectly capable of being patented - it has novelty, and it apparently has more utility for its stated purpose. Every time you hear about how Evil Pharma won't work on X, or Y, or Z, because "they can't patent it", keep in mind that we here at Evil Pharma know a lot of ways to patent things. Part of what makes us so darn evil, you know.

Comments (18) + TrackBacks (0) | Category: Cancer

March 20, 2014

Years Worth of the Stuff

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Posted by Derek

bAP15.pngThis time last year I mentioned a particularly disturbing-looking compound, sold commercially as a so-called "selective inhibitor" of two deubiquitinase enzymes. Now, I have a fairly open mind about chemical structures, but that thing is horrible, and if it's really selective for just those two proteins, then I'm off to truck-driving school just like Mom always wanted.

Here's an enlightening look through the literature at this whole class of compound, which has appeared again and again. The trail seems to go back to this 2001 paper in Biochemistry. By 2003, you see similar motifs showing up as putative anticancer agents in cell assays, and in 2006 the scaffold above makes its appearance in all its terrible glory.

The problem is, as Jonathan Baell points out in that post, that this series has apparently never really had a proper look at its SAR, or at its selectivity. It wanders through a series of publications full of on-again off-again cellular readouts, with a few tenuous conclusions drawn about its structure - and those are discarded or forgotten by the time the next paper comes around. As Baell puts it:

The dispiriting thing is that with or without critical analysis, this compound is almost certainly likely to end up with vendors as a “useful tool”, as they all do. Further, there will be dozens if not hundreds of papers out there where entirely analogous critical analyses of paper trails are possible.

The bottom line: people still don’t realize how easy it is to get a biological readout. The more subversive a compound, the more likely this is. True tools and most interesting compounds usually require a lot more medicinal chemistry and are often left behind or remain undiscovered.

Amen to that. There is way too much of this sort of thing in the med-chem literature already. I'm a big proponent of phenotypic screening, but setting up a good one is harder than setting up a good HTS, and working up the data from one is much harder than working up the data from an in vitro assay. The crazier or more reactive your "hit" seems to be, the more suspicious you should be.

The usual reply to that objection is "Tool compound!" But the standards for a tool compound, one used to investigate new biology and cellular pathways, are higher than usual. How are you going to unravel a biochemical puzzle if you're hitting nine different things, eight of which you're totally unaware of? Or skewing your assay readouts by some other effect entirely? This sort of thing happens all the time.

I can't help but think about such things when I read about a project like this one, where IBM's Watson software is going to be used to look at sequences from glioblastoma patients. That's going to be tough, but I think it's worth a look, and the Watson program seems to be just the correlation-searcher for the job. But the first thing they did was feed in piles of biochemical pathway data from the literature, and the problem is, a not insignificant proportion of that data is wrong. Statements like these are worrisome:

Over time, Watson will develop its own sense of what sources it looks at are consistently reliable. . .if the team decides to, it can start adding the full text of articles and branch out to other information sources. Between the known pathways and the scientific literature, however, IBM seems to think that Watson has a good grip on what typically goes on inside cells.

Maybe Watson can tell the rest of us, then. Because I don't know of anyone actually doing cell biology who feels that way, not if they're being honest with themselves. I wish the New York Genome Center and IBM luck in this, and I still think it's a worthwhile thing to at least try. But my guess is that it's going to be a humbling experience. Even if all the literature were correct in every detail, I think it would be one. And the literature is not correct in every detail. It has compounds like that one at the top of the entry in it, and people seem to think that they can draw conclusions from them.

Comments (19) + TrackBacks (0) | Category: Biological News | Cancer | Chemical Biology | Drug Assays | The Scientific Literature

March 10, 2014

Repurposing for Cervical Cancer

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Posted by Derek

One of the questions I was asked after my talk at Illinois was about repurposing drugs. I replied that there might be some opportunities there, but I didn't think that there were many big ones that had been missed, unless new biology/target ID turned up. Well, here's a news story that contradicts that view of mine, and I'm welcome to be wrong this time.

Researchers in Manchester have been working on the use of lopinavir (an existing drug for HIV) as a therapy for HPV, the cause of most cervical cancers. There's a vaccine for it now, but that doesn't do much for women who are already diagnosed with probable or confirmed disease. But lopinavir therapy seems to do good, and plenty of it. A preliminary trial in Kenya has apparently shown a very high response rate, and they're now raising money for a larger (up to 1,000 patient) trial. I hope that it works out as it appears to - with any luck, HPV-driven disease will gradually disappear from the world in the coming decades, but there will be plenty of patients in the meantime.

As that Daily Telegraph article shows, it wasn't easy getting this work going, because of availability of the drug in the right formulation. Congratulations to the Manchester group and their collaborators in Kenya for being so persistent.

Comments (6) + TrackBacks (0) | Category: Cancer | Clinical Trials | Infectious Diseases

March 4, 2014

More Good PD-1 News in Cancer

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Posted by Derek

PD-1 therapies are a big, big deal in oncology these days, and with results like this, no wonder. It's a negative regulator of T-cell function, and blocking it appears to recruit a much stronger immune response to tumor cells. Bristol-Myers Squibb, Merck, and others have antibodies in the clinic, and results are piling up to suggest that these are going to be big.

The BMS entry, BMS-936558 (nivolumab), had already shown some promising Phase II results in non small-cell lung cancer, renal carcinoma, and colorectal cancer. Many patients don't respond, but the ones that do seem to show real benefit. (And it's worth noting that there are whole tumor types that don't necessarily respond - as far as I know, no one's gotten a PD-1 response in pancreatic cancer yet, which confirms its nastiness).

The new results are for metastatic melanoma, a famous impossible-to-treat condition. Kinase inhibitors like Zelboraf have shown some results, but not without problems, and the cancer always finds a way around and comes back. But this PD-1 antibody seems to have more long-lasting effects: the large study group (Dana-Farber, Johns Hopkins, Yale and more) on this paper report that of 107 patient treated, 33 showed actual tumor regressions. Overall, that is, even counting the ones that did not show as strong a response, medial overall survival rates were 62% after one year and 43% after two years, which is a real improvement. Average life expectancy at the start was one year. 17 patients discontinued therapy, but still continued to show response after the antibody dosing was halted, and the overall survival numbers strongly suggest that the treatment is having a real effect on new tumor formation and progression.

So the immunotherapy wave continues in oncology, and may well not have even crested yet. Let's hope it hasn't; this is good stuff.

Comments (13) + TrackBacks (0) | Category: Cancer | Clinical Trials

February 25, 2014

For Immediate Rewording. Uh, Release.

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Posted by Derek

Here's a nice look at why you should always think about the source of the financial and business information you read. It details the response to a recent Pfizer press release about palbociclib, a CDK inhibitor that's in late clinical trials.

Someone at The Wall Street Journal wrote that it had "the potential. . .to transform the standard of care for post-menopausal women with ER+ and HER2- advanced breast cancer." Problem is, that phrase was lifted directly out of the press release itself (and sure sounds like it), and you really would hope for better from the WSJ. What we're seeing here is actually Pfizer's own spin on the (as yet unpresented) results of the PALOMA-1 clinical trial. Everything a company says at this point will be couched in terms of "could" and "has the potential" and "we hope", and will come with one of those paragraphs at the end about "forward-looking statements". When it comes to the first statements about clinical trials results, if there are no numbers, there is nothing to talk about.

Paul Raeburn, the Knight Science Journalism blog author who picked up on this, also found that someone at the AP (and others) went for Pfizer's spin, too:

The problem is that this story was covered by business reporters rather than medical reporters, who by and large are too smart to fall for a company's claim about a drug without seeing the evidence presented, reviewed, and debated.

The further problem is that because they are so smart, medical writers mostly declined to cover this story. Which left the business writers out there alone, telling the story the company wanted them to tell.

Well, "medical writer" is a broad term, and believe me, there are some slackjaws in that crowd, too. But point taken - anyone who's been paying attention, or anyone who's willing to spend a few minutes on Google, should have realized that Pfizer is trying to make the case for accelerated approval of palbociclib, especially after the recent failure of dacomitinib and strong competition from Novartis in exactly the same therapeutic space.

Pfizer, of course, is not going to come out and talk about how delighted they are about the Phase II results unless they can back that up with something. I hope that palbociclib bowls people over - a new therapy for breast cancer would be good news. But we haven't seen the data yet, and data are all that will (or should) make pulses race over at the FDA. So I think that the Pfizer press release was worth noting, but stories like the Fierce Biotech one linked in the paragraph above are the way to do it. Put the news in context - don't just reword the press release.

Comments (17) + TrackBacks (0) | Category: Cancer | Press Coverage

February 6, 2014

On Vitamin C, And On Linus Pauling

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Posted by Derek

Well, just after blasting antioxidant supplements for cancer patients (and everyone else) comes this headline: "Vitamin C Injections Ease Ovarian Cancer Treatments". Here's the study, in Science Translational Medicine. So what's going on here?

A closer look shows that this, too, appears to fit into the reactive-oxygen-species framework that I was speaking about:

Drisko and her colleagues, including cancer researcher Qi Chen, who is also at the University of Kansas, decided that the purported effects of the vitamin warranted a closer look. They noticed that earlier trials had partially relied on intravenous administration of high doses of vitamin C, or ascorbate, whereas the larger follow-up studies had used only oral doses of the drug.

This, they reasoned, could be an important difference: ascorbate is processed by the body in different ways when administered orally versus intravenously. Oral doses act as antioxidants, protecting cells from damage caused by reactive compounds that contain oxygen. But vitamin C given intravenously can have the opposite effect by promoting the formation of one of those compounds: hydrogen peroxide. Cancer cells are particularly susceptible to damage by such reactive oxygen-containing compounds.

Drisko, Chen and their colleagues found that high concentrations of vitamin C damaged DNA and promoted cell death in ovarian cancer cells grown in culture. In mice grafted with human ovarian cancer cells, treatment with intravenous vitamin C combined with conventional chemotherapy slowed tumour growth, compared to chemotherapy treatment alone.

The concentrations attained by the intravenous route are apparently necessary to get these effects, and you can't reach those by oral dosing. This 2011 review goes into the details - i.v. ascorbate reaches at least 100x the blood concentrations provided by the maximum possible oral dose, and at those levels it serves, weirdly, as a percursor of hydrogen peroxide (and a much safer one than trying to give peroxide directly, as one can well imagine). There's a good amount of evidence from animal models that this might be a useful adjunct therapy, and I'm glad to see it being tried out in the clinic.

So does this mean that Linus Pauling was right all along? Not exactly. This post at Science-Based Medicine provides an excellent overview of that question. It reviews the earlier work on intravenous Vitamin C, and also Pauling's earlier advocacy. Unfortunately, Pauling was coming at this from a completely different angle. He believed that oral Vitamin C could prevent up to 75% of cancers (his words, sad to say). His own forays into the clinic with this idea were embarrassing, and more competently run trials (several of them) have failed to turn up any benefit. Pauling had no idea that for Vitamin C to show any efficacy, that it would have to be run up to millimolar concentrations in the blood, and he certainly had no idea that it would work by actually promoting reactive oxygen species. (He had several other mechanisms in mind, such as inhibition of hyaluronidase, which do not seem to be factors in the current studies at all). In fact, Pauling might well have been horrified. Promoting rampaging free radicals throughout the bloodstream was one of the last things he had in mind; he might have seen this as no better than traditional chemotherapy (since it's also based on a treatment that's slightly more toxic to tumor cells than it is to normal ones). At the same time, he also showed a remarkable ability to adapt to new data (or to ignore it), so he might well have claimed victory, anyway.

This brings up another topic - not Vitamin C, but Pauling himself. As I've been writing "The Chemistry Book" (coming along fine, by the way), one of the things I've enjoyed is a chance to re-evaluate some of the people and concepts in the field. And I've come to have an even greater appreciation of just what an amazing chemist Linus Pauling was. He seems to show up all over the 20th century, and in my judgment could have been awarded a second science Nobel, or part of one, without controversy. I mean, you have The Nature of the Chemical Bond (a tremendous accomplishment by itself), the prediction of noble gas fluorides as possible, the alpha-helix and beta-pleated sheet structures of proteins, the mechanism of sickle cell anemia (and the concept of a "molecular disease"), the suggestion that enzymes work by stabilizing transitions states, and more. Pauling shows up all over the place - encouraging the earliest NMR work ("Don't listen to the physicists"), taking a good cut at working out the structure of DNA, all sorts of problems. He was the real deal, and accomplished about four or five times as much as anyone would consider a very good career.

But that makes it all the more sad to see what became of him in his later years. I well remember his last hurrah, which was being completely wrong about quasicrystals, from when I was in graduate school. But naturally, I'd also heard of his relentless advocacy for Vitamin C, which gradually (or maybe not so gradually) caused people to think that he had slightly lost his mind. Perhaps he had; there's no way of knowing. But the way he approached his Vitamin C work was a curious (and sad) mixture of the same boldness that had served him so well in the past, but now with a messianic strain that would probably have proven fatal to much of his own earlier work. Self-confidence is absolutely necessary for a great scientist, but too much of it is toxic. The only way to find out where the line stands is to cross it, but you won't realize it when you have (although others will).

We remember Isaac Newton for his extraordinary accomplishments in math and physics, not for his alchemical and religious calculations (to which he devoted much time, and which shocked John Maynard Keynes when he read Newton's manuscripts). Maybe in another century or two, Pauling will be remembered for his accomplishments, rather than for the times he went off the rails.

Comments (25) + TrackBacks (0) | Category: Cancer | Chemical News

February 5, 2014

The Evidence Piles Up: Antioxidant Supplements Are Bad For You

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Posted by Derek

You may remember a study that suggested that antioxidant supplement actually negated the effects of exercise in muscle tissue. (The reactive oxygen species generated are apparently being used by the cells as a signaling mechanism, one that you don't necessarily want to turn off). That was followed by another paper that showed that cells that should be undergoing apoptosis (programmed cell death) could be kept alive by antioxidant treatment. Some might read that and not realize what a bad idea that is - having cells that ignore apoptosis signals is believed to be a common feature in carcinogenesis, and it's not something that you want to promote lightly.

Here are two recent publications that back up these conclusions. The BBC reports on this paper from the Journal of Physiology. It looks like a well-run trial demonstrating that antioxidant therapy (Vitamin C and Vitamin E) does indeed keep muscles from showing adaptation to endurance training. The vitamin-supplemented group reached the same performance levels as the placebo group over the 11-week program, but on a cellular level, they did not show the (beneficial) changes in mitochondria, etc. The authors conclude:

Consequently, vitamin C and E supplementation hampered cellular adaptions in the exercised muscles, and although this was not translated to the performance tests applied in this study, we advocate caution when considering antioxidant supplementation combined with endurance exercise.

Then there's this report in The Scientist, covering this paper in Science Translational Medicine. The title says it all: "Antioxidants Accelerate Lung Cancer Progression in Mice". In this case, it looks like reactive oxygen species should normally be activating p53, but taking antioxidants disrupts this signaling and allows early-stage tumor cells (before their p53 mutates) to grow much more quickly.

So in short, James Watson appears to be right when he says that reactive oxygen species are your friends. This is all rather frustrating when you consider the nonstop advertising for antioxidant supplements and foods, especially for any role in preventing cancer. It looks more and more as if high levels of extra antioxidants can actually give people cancer, or at the very least, help along any cancerous cells that might arise on their own. Evidence for this has been piling up for years now from multiple sources, but if you wander through a grocery or drug store, you'd never have the faintest idea that there could be anything wrong with scarfing up all the antioxidants you possibly can.

The supplement industry pounces on far less compelling data to sell its products. But here are clear indications that a large part of their business is actually harmful, and nothing is heard except the distant sound of crickets. Or maybe those are cash registers. Even the wildly credulous Dr. Oz reversed course and did a program last year on the possibility that antioxidant supplements might be doing more harm than good, although he still seems to be pitching "good" ones versus "bad". Every other pronouncement from that show is immediately bannered all over the health food aisles - what happened to this one?

This shouldn't be taken as a recommendation to go out of the way to avoid taking in antioxidants from food. But going out of your way to add lots of extra Vitamin C, Vitamin E, N-acetylcysteine, etc., to your diet? More and more, that really looks like a bad idea.

Update: from the comments, here's a look at human mortality data, strongly suggesting no benefit whatsoever from antioxidant supplementation (and quite possibly harm from beta-carotene, Vitamin A, and Vitamin E),

Comments (37) + TrackBacks (0) | Category: Biological News | Cancer

January 28, 2014

Dacomitinib Doesn't Come Through

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Posted by Derek

Lest you think that it's only small companies that wipe out in Phase III oncology trials, consider Pfizer's news yesterday about dacomitinib. Two Phase III studies in non-small cell lung cancer (NSCLC) missed their endpoints, a real problem for a compound that was supposed to be one of the showpieces of the company oncology portfolio.

The compound (structure here) is another of the current crop of irreversible kinase inhibitors (which is one reason why 2013's crop of approved drugs looked a bit odd). In this case, it's picking up Cys773, on the edge of the ATP binding pocket. The compound hits across the HER kinase family, and we have now found out that that's not enough for this variety of lung cancer, at any rate. It had looked more promising in Phase II (don't they all), so we can assume that a lot of what-went-wronging has been going on at Pfizer, both to keep from repeating this experience and to figure out if there are some identifiable patient subsets that might be worth following up on.

Even if there are, dacomitinib is not going to be the drug that Pfizer hoped for. That drug would have hit the survival endpoints in these two trials.

Comments (17) + TrackBacks (0) | Category: Cancer | Clinical Trials

January 14, 2014

Trouble With Stapled Peptides? A Strong Rebuttal.

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Posted by Derek

Here's a good paper on the design of stapled peptides, with an emphasis on what's been learned about making them cell-penetrant. It's also a specific rebuttal to a paper from Genentech (the Okamoto one referenced below) detailing problems with earlier reported stapled peptides:

In order to maximize the potential for success in designing stapled peptides for basic research and therapeutic development, a series of important considerations must be kept in mind to avoid potential pitfalls. For example, Okamoto et al. recently reported in ACS Chemical Biology that a hydrocarbon-stapled BIM BH3 peptide (BIM SAHB) manifests neither improved binding activity nor cellular penetrance compared to an unmodified BIM BH3 peptide and thereby caution that peptide stapling does not necessarily enhance affinity or biological activity. These negative results underscore an important point about peptide stapling: insertion of any one staple at any one position into any one peptide to address any one target provides no guarantee of stapling success. In this particular case, it is also noteworthy that the Walter and Eliza Hall Institute (WEHI) and Genentech co-authors based their conclusions on a construct that we previously reported was weakened by design to accomplish a specialized NMR study of a transient ligand−protein interaction and was not used in cellular studies because of its relatively low α-helicity, weak binding activity, overall negative charge, and diminished cellular penetrance. Thus, the Okamoto et al. report provides an opportunity to reinforce key learnings regarding the design and application of stapled peptides, and the biochemical and biological activities of discrete BIM SAHB peptides.

You may be able to detect the sound of teeth gritting together in that paragraph. The authors (Loren Walensky of Dana-Farber, and colleagues from Dana-Farber, Albert Einstein, Chicago, and Yale), point out that the Genentech paper took a peptide that's about 21% helical, and used a staple modification that took it up to about 39% helical, which they say is not enough to guarantee anything. They also note that when you apply this technique, you're necessarily altering two amino acids at a minimum (to make them "stapleable"), as well as adding a new piece across the surface of the peptide helix, so these changes have to be taken into account when you compare binding profiles. Some binding partners may be unaffected, some may be enhanced, and some may be wiped out.

It's the Genentech team's report of poor cellular uptake that you can tell is the most irritating feature of their paper to these authors, and from the way they make their points, you can see why:

The authors then applied this BIM SAHBA (aa 145−164) construct in cellular studies and observed no biological activity, leading to the conclusion that “BimSAHB is not inherently cell-permeable”. However, before applying stapled peptides in cellular studies, it is very important to directly measure cellular uptake of fluorophore-labeled SAHBs by a series of approaches, including FACS analysis, confocal microscopy, and fluorescence scan of electrophoresed lysates from treated cells, as we previously reported. Indeed, we did not use the BIM SAHBA (aa 145−164) peptide in cellular studies, specifically because it has relatively low α-helicity, weakened binding activity, and overall negative charge (−2), all of which combine to make this particular BIM SAHB construct a poor candidate for probing cellular activity. As indicated in our 2008 Methods in Enzymology review, “anionic species may require sequence modification (e.g., point mutagenesis, sequence shift) to dispense with negative charge”, a strategy that emerged from our earliest studies in 2004 and 2007 to optimize the cellular penetrance of stapled BID BH3 and p53 peptides for cellular and in vivo analyses and also was applied in our 2010 study involving stapled peptides modeled after the MCL-1 BH3 domain. In our 2011 Current Protocols in Chemical Biology article, we emphasized that “based on our evaluation of many series of stapled peptides, we have observed that their propensity to be taken up by cells derives from a combination of factors, including charge, hydrophobicity, and α-helical structure, with negatively charged and less structured constructs typically requiring modification to achieve cell penetrance. . .

They go on to agree with the Genentech group that the peptide they studied has poor uptake into cells, but the tell-us-something-we-don't-know tone comes through pretty clearly, I'd say. The paper goes on to detail several other publications where these authors worked out the behavior of BIM BH3 stapled peptides, saying that "By assembling our published documentation of the explicit sequence compositions of BIM SAHBs and their distinct properties and scientific applications, as also summarized in Figure 1, we hope to resolve any confusion generated by the Okamoto et al. study".

They do note that the Genentech (Okamoto) paper did use one of their optimized peptides in a supplementary experiment, which shows that they were aware of the different possibilities. That one was apparently showed no effects on the viability of mouse fibroblasts, but this new paper says that a closer look (at either their own studies or at the published literature) would have shown them that the cells were actually taking up the peptide, but were relatively resistant to its effects, which actually helps establish something of a therapeutic window.

This is a pretty sharp response, and it'll be interesting to see if the Genentech group has anything to add in their defense. Overall, the impression is that stapled peptides can indeed work, and do have potential as therapeutic agents (and are in the clinic being tested as such), but that they need careful study along the way to make sure of their properties, their pharmacokinetics, and their selectivity. Just as small molecules do, when you get down to it.

Comments (6) + TrackBacks (0) | Category: Biological News | Cancer | Chemical Biology

January 7, 2014

Adoptive T-Cell Therapy for Cancer: The Short Version

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Posted by Derek

If you're looking for a good overview of the modified-T-cell immune therapies for cancer that have been making such headlines recently, this writeup at Nature is for you. It also makes clear that getting this to work across a broader number of tumor types is not going to be a job for the faint of heart. If the antigen that you're training all those T-cells to go after happens to exist somewhere else in the body (other than on the surface of the tumor cells), or if you have some cross-reactivity that you hadn't realized, the patients are going to be in for a very hard time indeed.

Designing effective treatments requires finding cell-surface antigens for T cells to target without damaging normal tissue. This specificity may prove more difficult than researchers initially thought. Many antigens found in cancer are also expressed in normal tissue — HER2, for example, which is the target of the antibody-based therapy trastuzumab (Herceptin), is also expressed in heart cells. Before researchers can make progress, they must understand how extensively each candidate target is expressed in all tissues of the body.

Recent studies have highlighted what can happen when T cells unexpectedly attack normal tissue. In a clinical trial of TCR-engineered T cells, researchers at the US National Cancer Institute were targeting the cancer-specific antigen MAGE-A3 when two of their nine patients slipped into a coma and died. It turns out that the cells also recognized another member of the MAGE-A family that the researchers later discovered is expressed in low levels in brain tissue. Another type of MAGE-A3-specific TCR caused two patients to die from heart failure when the TCR bound to a similar protein, called Titin, which is expressed on heart cells. Adaptimmune, the company based near Oxford, UK, that developed the T-cell receptor, has implemented more extensive safety testing techniques in an attempt to prevent unexpected reactions in the future.

I'm quite excited about this whole field, but there are very strong reasons why it's been tried (so far) almost entirely on people who are near death. The immune system is to be feared.

Comments (15) + TrackBacks (0) | Category: Cancer

December 18, 2013

Lab Mice Are Being Kept Too Cold, Apparently

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Posted by Derek

Earlier, the unsuitability of mice in inflammation models was shown in a paper that should have been noted by anyone in the field. Just last month, a paper in Science detailed the problems with many animal studies (mouse and otherwise), particularly the smaller ones, which can suffer from bad statistics and poor protocols.

Now we have this, from PNAS. The authors, from the Roswell Park Institute and the EPA, say that standard rodent facility conditions are actually causing unintended chronic physiological stress:

We show here that fundamental aspects of antitumor immunity in mice are significantly influenced by ambient housing temperature. Standard housing temperature for laboratory mice in research facilities is mandated to be between 20–26 °C; however, these subthermoneutral temperatures cause mild chronic cold stress, ac- tivating thermogenesis to maintain normal body temperature. When stress is alleviated by housing at thermoneutral ambient temperature (30–31 °C), we observe a striking reduction in tumor formation, growth rate and metastasis. . .Overall, our data raise the hypothesis that suppression of antitumor immunity is an outcome of cold stress-induced thermo- genesis. Therefore, the common approach of studying immunity against tumors in mice housed only at standard room temperature may be limiting our understanding of the full potential of the antitumor immune response.

As mentioned in that last line, the problem seems to be with the adaptive immune system - this effect is driven by CD8+ T cells in almost every case, and sometimes by changes in CD4+ cells as well. Overall, housing mice at the recommended temperatures, which are on the cool side, seems to promote a general immunosuppression, which I think it's safe to say is not a factor that many people are taking into account. The animals have similar core body temperatures, but the extra burden of maintaining that in the cooler rooms is tipping some sort of balance - keeping all those immune systems running is apparently energetically costly, and they get downregulated.

This study looked at several sorts of tumorigenesis, but only for solid tumors, so the effects on leukemia, etc., are still unknown. You'd have to think, though, that several other disease areas could be affected by this situation as well - for example, how much of the uselessness of mice in inflammation models is caused by these changes? I'm simultaneously glad to see these things being uncovered, while being worried about how long it's taken to uncover them: what else are we missing?

Comments (43) + TrackBacks (0) | Category: Animal Testing | Cancer

December 11, 2013

David Cameron, The Press, Alzheimer's, and Hope

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Posted by Derek

One should be cheering the news that Great Britain will double funding for Alzheimer's and dementia research. But there's something odd about the way it's being presented, at least to my eyes. Here's a story from the Guardian that might illustrate what I mean:

The health secretary, Jeremy Hunt, said he hoped the dementia summit would have the same effect as the G8 summit in Gleneagles on HIV/Aids in 2005.

"Today should be an optimistic day," he told BBC Breakfast. "Tony Blair had the G8 summit in Gleneagles in 2005 on HIV/Aids and actually that did turn out in retrospect to be a turning point in the battle against Aids.

"I think if you bring the world's leaders together, health ministers from across the world, and we are all resolved that we really are going to do something about this as we face up to an ageing society."

If 2005 was some sort of widely-recognized turning point in HIV control, I must have missed it. I'll be glad to be corrected, but the last sentence in that quote makes me wonder, because it isn't a sentence. Try it out: the first part isn't connected with the second. He thinks that if you bring the world's leaders together, then. . .what will happen? "If" implies some sort of resolution in a sentence, and there isn't any. How about the second part? They're all resolved that they're really going to do something - fine, but isn't that the easiest part? The simplest part? I mean, coming out and saying that you'd like to "do something" about a problem that everyone would like to see solved is not that big a step, is it?

Well, doubling research funding is certainly doing something, there's no taking away from that. Much is made in the various press articles about Lilly's Alzheimer's scan, which Britain's National Heath Service is going to make available to some patients. Now, Lilly has been talking bravely about Alzheimer's for some time now, and to be fair to them, they've been spending pretty bravely, too. No doubt their hope has been that their imaging agent would match up with some successful therapy they'd develop, but the "successful therapy" part has been the hard one.

But British Prime Minister David Cameron has also been talking about finding a cure by 2025. I hope we do - I may need it by then - but it's going to take a generous slug of luck for that to happen. I don't hold out much hope for anything currently in development as a cure, although I'd like to be wrong about that. And something that's not in development would barely make it through, on an optimistic timetable, by 2025. We certainly don't know enough about Alzheimer's to say that we're on track, so someone will have to get lucky. You wouldn't know that from the British newspapers, though. They've also been excited about the potential of Eli Lilly's solanezumab, which must make the UK the only area outside of Indianapolis where that state of mind obtains.

That's the part that worries me about the public statements in this area. Politicians (and CEOs) are prone to ringing declarations that make it sound as if all that's really needed is gumption and willpower - good faith will carry the day. But that just isn't true in research. It really isn't. Nerve and perseverance are necessary, and how, but they're nowhere near sufficient. To pretend otherwise is to engage in magical thinking, and the history of Big Proclamations in the biomedical field should be enough to prove that to anyone.

Back in 2003, we were supposedly going to eliminate death and suffering from cancer by 2015 (and Senator Arlen Spector asked if maybe we couldn't move the timetable up to 2010). On a lesser level, back in 2009, there were statements that a cure for the common cold was at hand. Sorry about that. The British press has a particular weakness for proclaimed Alzheimer's cures, not that the US press doesn't go for them, too.

No, saying it will not make it so. I don't know how to make it so, other than by spending a lot of money and a lot of time, and working really hard, and hoping for the best. But that's not the stuff of headlines.

Comments (60) + TrackBacks (0) | Category: Alzheimer's Disease | Cancer

December 4, 2013

Cancer Cell Line Assays: You Won't Like Hearing This

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Posted by Derek

Here's some work that gets right to the heart of modern drug discovery: how are we supposed to deal with the variety of patients we're trying to treat? And the variety in the diseases themselves? And how does that correlate with our models of disease?

This new paper, a collaboration between eight institutions in the US and Europe, is itself a look at two other recent large efforts. One of these, the Cancer Genome Project, tested 138 anticancer drugs against 727 cell lines. Its authors said at the time (last year) that "By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies". The other study, the Cancer Cell Line Encyclopedia, tested 24 drugs against 1,036 cell lines. That one appeared at about the same time, and its authors said ". . .our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of ‘personalized’ therapeutic regimens."

Well, will they? As the latest paper shows, the two earlier efforts overlap to the extent of 15 drugs, 471 cell lines, 64 genes and the expression of 12,153 genes. How well do they match up? Unfortunately, the answer is "Not too well at all". The discrepancies really come out in the drug sensitivity data. The authors tried controlling for all the variables they could think of - cell line origins, dosing protocols, assay readout technologies, methods of estimating IC50s (and/or AUCs), specific mechanistic pathways, and so on. Nothing really helped. The two studies were internally consistent, but their cross-correlation was relentlessly poor.

It gets worse. The authors tried the same sort of analysis on several drugs and cell lines themselves, and couldn't match their own data to either of the published studies. Their take on the situation:

Our analysis of these three large-scale pharmacogenomic studies points to a fundamental problem in assessment of pharmacological drug response. Although gene expression analysis has long been seen as a source of ‘noisy’ data, extensive work has led to standardized approaches to data collection and analysis and the development of robust platforms for measuring expression levels. This standardization has led to substantially higher quality, more reproducible expression data sets, and this is evident in the CCLE and CGP data where we found excellent correlation between expression profiles in cell lines profiled in both studies.

The poor correlation between drug response phenotypes is troubling and may represent a lack of standardization in experimental assays and data analysis methods. However, there may be other factors driving the discrepancy. As reported by the CGP, there was only a fair correlation (rs < 0.6) between camptothecin IC50 measurements generated at two sites using matched cell line collections and identical experimental protocols. Although this might lead to speculation that the cell lines could be the source of the observed phenotypic differences, this is highly unlikely as the gene expression profiles are well correlated between studies.

Although our analysis has been limited to common cell lines and drugs between studies, it is not unreasonable to assume that the measured pharmacogenomic response for other drugs and cell lines assayed are also questionable. Ultimately, the poor correlation in these published studies presents an obstacle to using the associated resources to build or validate predictive models of drug response. Because there is no clear concordance, predictive models of response developed using data from one study are almost guaranteed to fail when validated on data from another study, and there is no way with available data to determine which study is more accurate. This suggests that users of both data sets should be cautious in their interpretation of results derived from their analyses.

"Cautious" is one way to put it. These are the sorts of testing platforms that drug companies are using to sort out their early-stage compounds and projects, and very large amounts of time and money are riding on those decisions. What if they're gibberish? A number of warning sirens have gone off in the whole biomarker field over the last few years, and this one should be so loud that it can't be ignored. We have a lot of issues to sort out in our cell assays, and I'd advise anyone who thinks that their own data are totally solid to devote some serious thought to the possibility that they're wrong.

Here's a Nature News summary of the paper, if you don't have access. It notes that the authors of the two original studies don't necessarily agree that they conflict! I wonder if that's as much a psychological response as a statistical one. . .

Comments (21) + TrackBacks (0) | Category: Biological News | Cancer | Chemical Biology | Drug Assays

November 8, 2013

The Other Shoe Drops at Ariad

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Posted by Derek

Ever since Iclusig (ponatinib) (note: fixed that name as an update) ran into trouble with blood-cloting side effects, Ariad has had a huge uncertain cloud blocking out its sunlight. Now that the FDA has told them to take the drug off the market completely, it was clear what was going to happen. Happen it has: the company is laying off a large part of its workforce.

It's very much in doubt whether Iclusig will ever come back. Update: in Europe, the EMA has now said that Iclusig can remain on the market "with increased caution").And if it doesn't, it's very much in doubt whether Ariad will, or how long that might take. There's a large, mostly-completed building around the corner from me covered in blue-green glass that was going to be the home of a larger, more solvent Ariad, and no one knows what's going to happen to that, either. It's a rough business.

Update: turns out the blue-green glass one was going to be Aveo, which cratered earlier this year. Who's going to occupy that, one wonders? Ariad's is the less-complete large framework going up across from the (incongruous) Mormon church. That's a pretty large building, or will be, and you wonder who will end up in there. There are so many biopharma construction sites in this town that you need a guidebook.

Comments (23) + TrackBacks (0) | Category: Business and Markets | Cancer | Regulatory Affairs

November 1, 2013

Just Build The Thing

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Posted by Derek

Here's a paper that's just come out in JACS that's worth a look on more than one level. It describes a way to image prostate cancers in vivo by targeting the GPR receptors on the cell surfaces, which are overexpressed in these tumors. Now, this is already done, using radiolabeled bombesin peptides as ligands, but this new work brings a new dimension to the idea.
What the authors have done is targeted the cell surface with antagonists and agonists at the same time, by hooking these onto a defined molecular framework. That's poly-proline, which is both soluble and adopts a well-defined structure once it's in solution. The bombesin derivatives are attached via a click Huisgen triazole linkage, and since you can slot in an azidoproline wherever you want, this lets you vary the distance between the two peptides up and down the scale. The hope is that having both kinds of ligand going at the same time might combine their separate advantages (binding potency and uptake into the cells).

And that idea seems to work: one of the combinations (the one with about a 20A spacing between the two ligands) works noticeably better than either radiolabeled peptide alone, with greater uptake and longer half-life. I'd say that proof of concept has been achieved, and the authors are planning to extend the idea to other known cell-surface-binding oncology ligands used diagnostically and/or therapeutically. Each of these will have to be worked out empirically, since there's no way of knowing what sort of spacing will be needed, of course.

That's the second thing I wanted to emphasize about this paper. Note how quickly I ran through its basic concepts above - I hope it was intelligible, but I think that the idea (which seems well worth exploring) can be expressed pretty easily. What's striking is how quickly these sorts of things can be realized these days. We've learned more about appropriate scaffolds (one of the authors of this paper, Helma Wennemers, has put in a good amount of work on the polyproline idea). And thanks to the near-universal applicability of the "click" triazole reaction, one can assemble hybrid structures like this with a high chance of success. That's not something to take for granted - doing bespoke chemistry every time on such molecules is no fun. You find yourself getting bogged down in the details rather than getting a chance to see if the main idea is worth anything or not.

There was talk before this last Nobel season of Barry Sharpless getting a second prize for the click work. Some have said that this doesn't make sense, because the click reaction that's been used the most (azide/acetylene cycloaddition) was certainly not a new one. But did anyone else see its possibilities, or the possibilities of any such universal connector reactions? Both providing such reactions and publicizing what could be done with them have been Sharpless's contributions, and the impossible-to-keep-up-with literature using them is testimony to how much was waiting to be exploited. So how come nobody did?

Comments (6) + TrackBacks (0) | Category: Cancer | Chemical Biology

October 18, 2013

Ariad (And Its Drug) In Trouble

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Posted by Derek

Ariad's Inclusig (ponatimib) is in even more trouble than it looked like, and that was already a lot. The company announced earlier this morning that its Phase III trial comparing the drug to Gleevec (imatinib) is not just on hold - it's been stopped, and patients are being taken off the drug. That can't be good news for the drug's current approved status, either:

Iclusig is commercially available in the U.S. and EU for patients with resistant or intolerant CML and Philadelphia-chromosome positive acute lymphoblastic leukemia. ARIAD continues to work with health authorities to make appropriate changes to the Iclusig product labeling to reflect the recently announced safety findings from the pivotal PACE trial that was the basis of its marketing approvals.

If the approval trial has now shown such unfavorable safety, is approval still warranted at all? That's what investors are wondering, and I would imagine that the oncologists who would be prescribing Inclusig are wondering the same thing. This is bad news for everyone. There are patients who very much need a drug like this for resistant CML, and Ariad (needless to say) needs to be selling it. I believe that the company is putting up a new building, not far from where I work, and you have to wonder if there are some clauses in the contract that are going to need to be invoked. Do sudden adverse events with your main commercial product count as force majeure?

Comments (8) + TrackBacks (0) | Category: Cancer | Regulatory Affairs | Toxicology

October 17, 2013

The Reproducibility Initiative is Open

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Posted by Derek

Looks like the Reproducibility Initiative might be getting off the ground. This press release from the Center for Open Science says that they have a $1.3 million grant to start validating high-profile results in the oncology research literature. This will be done through the Science Exchange site, with results freely available to all comers.

I'm happy to see something like this coming together, but I don't know how far that money's going to go. The press release talks about 50 key papers that they'd like to reproduce, and I don't see how 1.3 million dollars will be enough to get through that list. (Is there a list of the papers anywhere? I can't find it). Some of the key tests will be relatively quick and cheap, but not all of them. But I agree with the COS that one of the important things here is to get this idea out into the real world, to get people used to it, and to establish it as useful. If they pick their targets carefully, the money should allow that to happen.

Comments (9) + TrackBacks (0) | Category: Cancer | The Scientific Literature

September 11, 2013

Merck Does Something. Or Not. Maybe Something Else Instead.

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Posted by Derek

There's some Merck news today, via FiercePharma. First off, their R&D head Roger Perlmutter sat down with some of the most prominent analysts for a chat about the company's direction - and they came out with two completely different stories. Big changes? Minor ones? I wonder if people were taking away what they wanted to hear to confirm what they'd already decided Merck should be doing. Seamus Fernandez, for example, apparently came away saying that he thought a major R&D restructuring was inevitable, but that's what he thought before he sat down. This sort of thing is worth keeping in mind when you hear some Wall St. types (particularly on the "sell side") going on authoritatively about what's happening inside a given company.

The other news is that Merck is handing off one of their oncology programs (the WEE-1 kinase inhibitor MRK-1775) to AstraZeneca. If I were a mean person given to saying unkind things, I'd say that this drug is at least now going to get a lot more money spent on it, because that's what AZ has been famous for. But I'll stick with what John Carroll had to say on Twitter: "So if $MRK thought 1775 was any damn good, would they outlicense it to $AZN?"

Comments (19) + TrackBacks (0) | Category: Business and Markets | Cancer | Drug Development

August 29, 2013

How Goes the War?

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Posted by Derek

There's an article at The Atlantic titled "More Money Won't Win the War on Cancer". I agree with the title, although it's worth remembering that lack of money will certainly lose it. Money, in basic research, is very much in the "necessary but not sufficient" category.

The article itself is making the case of a book by Clifton Leaf, The Truth in Small Doses, a project that started with this article in Fortune in 2004. Here's the pitch:

What if a lack of research funding isn’t really the problem? One reason we aren’t making faster progress against cancer, according to Leaf, is because the federal grant process often chases the brightest minds from academic labs, and for those who do stay, favors low-risk “little questions” over swinging for the fences.

“More money by itself is not going to solve anything,” Leaf said. “Let’s say we doubled the [National Institutes of Health] budget, that isn’t going to make the lives of researchers better.”

The problem, as Leaf sees it, is with the business of cancer research. Over the last decade or so, “doing science” has reached a crisis stage—a claim many in the cancer community agree with, even if they don’t quite see eye-to-eye with Leaf on all of his conclusions.

His take is that the grant-money situation is making academic researchers spend more and more time just trying to get (or stay) funded, and that they tend to avoid anything that might sound a bit unusual in their applications. He also fears that academic researchers are taking too long to get established, that what might be some of their more creative years are being wasted in lengthy post-docs and struggles for tenure. I think that these are real problems, although they've been coming on for a long time now.

The article seems a bit too focused on the academic side of things; I don't know yet if the book makes the same mistake. Looking at it from industry, I think that the odds are that the first fundamental insights are more likely to come from academia, but I also think that the heavy lifting of turning these into real treatments will be done by industry. The difference between these has come up many times on this site, but it's safe to say that the general public does not appreciate it. The only place a breakthrough in the lab means an instant breakthrough in the clinic is in the movies.

To the extent, though, that people are told that "More Money" is the answer in this field, I think it's good to make the point that it isn't necessarily the limiting factor. Problem is, there's no way to hold a charity insight-raiser, or to set up a box to Donate Good Ideas For the Cure. Medical research, whether industrial or academic, is a pretty esoteric field to most people. There's not much way for an interested lay person to help out directly; the technical background is too much of a barrier. So people raise money, (while some just raise "awareness", a particularly slippery term), because it's the only way that they feel that they can make any difference.

Also, as has been said many times before, the "war on cancer" term is an unfortunate one, because it makes it sound as if there's a single enemy to be defeated. What we have is a war on our own ignorance of biology and medicinal chemistry, and that's going to be a long one. But perhaps I'm making the mistake that oncology pioneer Sidney Farber warned about:

(The patients) with cancer who are going to die this year cannot wait; nor is it necessary, in order to make great progress in the cure for cancer, for us to have the full solution of all the problems of basic research…the history of Medicine is replete with examples of cures obtained years, decades, and even centuries before the mechanism of action was understood for these cures"

Problem is, the only way I can think of to come up with cures without such understanding is to do a lot of out-there clinical trials, at high risk. Farber himself took that approach, famously, and managed to win out. But I'm not sure what appetite we'd have for it on a broad scale.

By the way, if you take a look at the comments section to the Atlantic piece, you'll find the usual stuff. You know - the drug companies don't want to cure cancer, no way. If people would just follow Doctor So-And-So's Miracle Diet, they'd be fine. According to these folks, all this talk of cancer research is a sham to start with. Of course, the number of such "cures" is beyond counting, and since so many of them claim to cure most everything, you'd think that they can't all be right. But somehow this doesn't seem to faze their adherents, who are often enthusiasts for several broad miracle cures simultaneously.

Comments (33) + TrackBacks (0) | Category: Cancer

August 26, 2013

Amgen Buys Onyx

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Posted by Derek

So Amgen's bid for Onyx look like it's going through, and the reaction of John Carroll at FiercePharma was to tweet "Expect big layoffs soon". He took some flak for being such a downer, but he's right, as far as I can see. Amgen isn't buying Onyx for their research staff, or any of their people at all. As that Bloomberg story linked to above has it, "Amgen to Buy Onyx for $10.4 Billion to Gain Cancer Drug".

That's Kyprolis (carfilzomib), their proteasome inhibitor, and that's all they need from Onyx, who bought the compound anyway when they acquired Proteolix a few years ago. So since I don't want to be a downer either, especially on Monday morning, I'd be interested to see if anyone can make another case. . .

Comments (19) + TrackBacks (0) | Category: Business and Markets | Cancer

August 15, 2013

Aileron Reports Some Stapled Peptide Results

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Posted by Derek

Here's a publication from Aileron Therapeutics on their stapled-peptide efforts against MDM2/p53 for cancer. (I wrote about that target here, so you can check out the links in that post for background). This compound (ATSP-7041) goes after both MDM2 and MDMX, activating the suppressed p53 pathway, and it seems to do a good job of it. The company's been talking about these results at conferences, but this is the official publication of all that data.

Stapled peptides as a class of potential drugs have been the subject of controversy, but this one is heading towards the clinic, by all accounts. There are several other compounds out there in the same MDM2 space, though, so it'll be interesting to see how they all fare in the real world. And it's also worth noting that a good number of the people on this PNAS paper may well have been let go by Aileron in the last few months. . .

Comments (5) + TrackBacks (0) | Category: Cancer

August 14, 2013

Another T-Cell Advance Against Cancer

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Posted by Derek

The technique of using engineered T cells against cancerous cells may be about to explode ever more than it has already. One of the hardest parts of getting this process scaled up has been the need to extract each patient's own T cells and reprogram them. But in a new report in Nature Biotechnology, a team at Sloan-Kettering shows that they can raise cells of this type from stem cells, which were themselves derived from T lymphocytes from another healthy donor. As The Scientist puts it:

Sadelain’s team isolated T cells from the peripheral blood of a healthy female donor and reprogrammed them into stem cells. The researchers then used disabled retroviruses to transfer to the stem cells the gene that codes for a chimeric antigen receptor (CAR) for the antigen CD19, a protein expressed by a different type of immune cell—B cells—that can turn malignant in some types of cancer, such as leukemia. The receptor for CD19 allows the T cells to track down and kill the rogue B cells. Finally, the researchers induced the CAR-modified stem cells to re-acquire many of their original T cell properties, and then replicated the cells 1,000-fold.

“By combining the CAR technology with the iPS technology, we can make T cells that recognize X, Y, or Z,” said Sadelain. “There’s flexibility here for redirecting their specificity towards anything that you want.”

You'll note the qualifications in that extract. The cells that are produced in this manner aren't quite the same as the ones you'd get by re-engineering a person's own T-cells. We may have to call them "T-like" cells or something, but in a mouse lymphoma model, they most certainly seem to do the job that you want them to. It's going to be harder to get these to the point of trying them out in humans, since they're a new variety of cell entirely, but (on the other hand) the patients you'd try this in are not long for this world and are, in many cases, understandably willing to try whatever might work.

Time to pull the camera back a bit. It's early yet, but these engineered T-cell approaches are very impressive. This work, if it holds up, will make them a great easier to implement. No doubt, at this moment, there are Great Specific Antigen Searches underway to see what other varieties of cancer might respond to this technique. And this, remember, is not the only immunological approach that's showing promise, although it must be the most dramatic.

So. . .we have to consider a real possibility that the whole cancer-therapy landscape could be reshaped over the next decade or two. Immunology has the potential to disrupt the whole field, which is fine by me, since it could certainly use some disruption, given the state of the art. Will we look back, though, and see an era where small-molecule therapies gave people an extra month here, an extra month there, followed by one where harnessing the immune system meant sweeping many forms of cancer off the board entirely? Speed the day, I'd say - but if you're working on those small-molecule therapies, you should keep up with these developments. It's not time to consider another line of research, not yet. But the chances of having to do this, at some point, are not zero. Not any more.

Comments (20) + TrackBacks (0) | Category: Biological News | Cancer

August 12, 2013

Cancer and Autism: Slow Down

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Posted by Derek

The New York Times had a rather confusing story the other day about the PTEN gene, autism, and cancer. Unfortunately, it turned into a good example of how not to explain a subject like this, and it missed out (or waited too long) to explain a number of key concepts. Things like "one gene can be responsible a lot of different things in a human phenotype", and "genes can have a lot of different mutations, which can also do different things", and "autism's genetic signature is complex and not well worked out, not least because it's such a wide-ranging diagnosis", and (perhaps most importantly, "people with autism are not doomed to get cancer".

Let me refer you to Emily Willingham at Forbes, who does a fine job of straightening things out here. I fear that what can happen at the Times (and other media outlets as well) is that when a reporter scrambles a science piece, there's no one else on the staff who's capable of noticing it. So it just runs as is.

Comments (5) + TrackBacks (0) | Category: Cancer | The Central Nervous System

July 25, 2013

Kevan Shokat At The Challenges in Chemical Biology Conference

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Posted by Derek

Kevan Shokat is now talking about his lab's work on using Drosophila models for kinase inhibitor discovery in oncology. I always like hearing about this sort of thing; very small living models have a lot of appeal for drug discovery.

You'd think that screening in fruit flies would be problematic for understanding human efficacy, but if you pick your targets carefully, you can get it to work. In Shokat's case, he's looking at a kinase called Ret, which is a target in thyroid cancer and is quite highly conserved across species. They set up a screen where active compounds would rescue a lethal phenotype (which gives you a nice high signal-to-noise), and screened about a thousand likely kinase inhibitor molecules.

Here's the paper that discusses much of what Shokat's group found. It turned out that Ret kinase inhibition alone was not the answer - closely related compounds with very similar Ret activity had totally different phenotypes in the flies. The key was realizing that some of them were hitting and missing other kinases in the pathways (specifically Raf and TOR) that could cancel out (or enhance) the effects. This was a very nice job of direct discovery of the right sort of kinase fingerprint needed for a desired effect. We need more tiny critters for screens like these.

Comments (6) + TrackBacks (0) | Category: Cancer | Chemical Biology

July 24, 2013

Stuart Schreiber at the Challenges in Chemical Biology Conference

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Posted by Derek

I'm listening to Stuart Schreiber make his case for diversity-oriented synthesis (DOS) as a way to interrogate biochemistry. I've written about this idea a number of times here, but I'm always glad to hear the pitch right from the source.

Schreiber's team has about 100,000 compounds from DOS now, all of which are searchable at PubChem. He says that they have about 15mg of each of them in the archives, which is a pretty solid collection. They've been trying to maximize the biochemical diversity of their screening (see here and here for examples), and they're also (as noted here) building up a collection of fragments, which he says will be used for high-concentration screening.

He's also updating some efforts with the Gates Foundation to do cell-based antimalarial screening with the DOS compounds. They have 468 compounds that they're now concentrating on, and checking these against resistant strains indicates that some of them may well be working through unusual mechanisms (others, of course, are apparently hitting the known ones). He's showing structures, and they are very DOSsy indeed - macrocycles, spiro rings, chirality all over. But since these assay are done in cells, some large hoops have already been jumped through.

He's also talking about the Broad Institutes efforts to profile small-molecule behavior in numerous tumor cell lines. Here's a new public portal site on this, and there's apparently a paper accepted at Cell on it as well. They have hundreds of cell lines, from all sorts of sources, and are testing those against an "informer set" of small-molecule probes and known drugs. They're trying to make this a collection of very selective compounds, targeting a wide variety of different targets throughout the cell. There are kinase inhibitors, epigenetic compounds, and a long list of known oncology candidates, as well as many other compounds that don't hit obvious cancer targets.

They're finding out a lot of interesting things about target ID with this set. Schreiber says that this work has made him more interested in gene expression profiles than in mutations per se. Here, he says, is an example of what he's talking about. Another example is the recent report of the natural product austocystin, which seems to be activated by CYP metabolism. The Broad platform has identified CYP2J2 as the likely candidate.

There's an awful lot of work on these slides (and an awful lot of funding is apparent, too). I think that the "Cancer Therapeutics Response Portal" mentioned above is well worth checking out - I'll be rooting through it after the meeting.

Comments (23) + TrackBacks (0) | Category: Cancer | Chemical Biology | Infectious Diseases

More Details on T-Cell Leukemia Therapy

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Posted by Derek

There's an excellent overview at Science of the work of David Porter and Carl June at the University of Pennsylvania on T-cell-based cancer therapy. It turns out that when the dramatic reports came out on their first three patients, the team was out of funding and trying to see if they could get someone interested. They did:

. . .Porter and June weighed their next step. They were itching to test the cell therapy in more people with leukemia, and to do that they needed money that they didn’t have. “We basically decided that we would just publish with three patients,” June says. Getting the word out, he hoped, could shift the dynamic in their favor. Porter was game to try, but skeptical that any reputable journal would accept a paper with an n of 3.

He turned out to be wrong. The New England Journal of Medicine welcomed a report about Olson and his mouse dose of T cells. Science Translational Medicine, Science’s sister journal, snapped up a manuscript detailing all three patients. The papers were published simultaneously on 10 August 2011. . .Porter was en route to vacation in western Maryland with his family when the embargo lifted. His phone started ringing. “I was in the car for 8 hours that day,” he says. “I spent 8 hours straight on my phone, answering e-mail, answering phone calls. It was a story that took us all by surprise. It kind of went viral.” June fielded 5000 requests from patients and their families for the therapy. Eight hundred media outlets worldwide covered the story.

And the funding reappeared, as well it might. Now the problem is turning this into something that can be used routinely, and that is nontrivial, as we technical types say. T-cell therapy is patient-specific. You don't just start treating everyone with injections out of the vials that you keep in the fridge - every patient is a new experiment, and the process starts from scratch. That means that many sources of error and variability that are ironed out with a traditional drug therapy are still going to be present, every time, for every person, and it also means that the cost is going to be high. But it may well be worth every bit of the trouble and expense.

The article gives a good look at how hard it is for a discovery like this to be born. The first person to try modifying T cells as an anticancer agent was probably Zelig Eshhar at the Weizmann Institute, back in the 1980s. Then a few other labs picked up the idea, notably Michel Sadelain at Sloan-Kettering, Steven Rosenberg at NCI, and Malcolm Brenner at Baylor, but technical difficulties slowed things down at every turn. Isolating the T cells reproducibly, inserting new genes into them, figuring out what genes to insert, getting everything successfully back into a patient - each of these steps took years of work and frustration.

Success came as everyone narrowed down on the CD19 protein on the surface of B cells. Those were attractive targets, because you can actually survive without them - which was a key hurdle, because once you unleash the T cells, they're probably going to kill off everything they're targeted for. It turns out that the CD19 marker is basically universal in B-cell leukemias, so this looked like the best targets on several grounds. There were actually four other trials (using very similar approaches) running at other centers when Porter and June got going.

But the combination of stimulatory signals and the choice of vector in the Penn trials set off the extraordinary clinical effects. There was no way to know this - in fact, some other approaches looked a bit more promising. But that's clinical research, and that's oncology, for sure.

Unfortunately, but predictably, there have been legal problems. St. Jude and Penn are involved in lawsuits about prior research agreements, and whether the current therapies are covered under them. I assume that this will be worked out, to the enrichment of a phalanx of lawyers, but it's unfortunate. It doesn't seem to be slowing anyone down much, though, which is the good news. Trials are underway all over the place on variations of this idea, and the Penn group is about as busy as they could possibly be:

Still, physicians like Porter and Grupp are mindful that this isn’t life-changing for every- one. “When I’m doing informed consent with these families, the first thing I say is, ‘Forget everything you’ve read about this,’ ” Grupp says. “Nothing could possibly be as promis- ing as the various articles about this make it seem.” Only four people, including Emily, have been followed for more than a year. A looming question is whether CAR therapy can work in solid tumors, and June and others are opening clinical trials to try and find out.

Nearly 3 years after the summer that changed everything, the Penn group is still working flat out to keep up: enrolling as many patients on the trials as they can, working with drug regulators to discuss how best to study the cells with an eye toward approval, collaborating with Novartis to train their employees and streamline the cell-generating process.

This all should be seen in a larger context of immunotherapy, too. People have been trying to recruit the immune system for years in the fight against tumor cells, with mixed success. But we may be just on the verge of knowing enough about what we're doing to get more of these to work. At this point, it would not surprise me if immune system approaches become the dominant form of treatment for several types of cancer over the next 25 years. The next few years will tell us.

Comments (7) + TrackBacks (0) | Category: Cancer | Clinical Trials

May 14, 2013

A Specific Crowdfunding Example

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Posted by Derek

I mentioned Microryza in that last post. Here's Prof. Michael Pirrung, at UC Riverside, with an appeal there to fund the resynthesis of a compound for NCI testing against renal cell carcinoma. It will provide an experienced post-doc's labor for a month to prepare an interesting natural-product-derived proteasome inhibitor that the NCI would like to take to their next stage of evaluation. Have a look - you might be looking at the future of academic research funding, or at least a real part of it.

Comments (14) + TrackBacks (0) | Category: Cancer | General Scientific News

May 6, 2013

The Medical Periodic Table

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Posted by Derek

Here's the latest "medical periodic table", courtesy of this useful review in Chemical Communications. Element symbols in white are known to be essential in man. The ones with a blue background are found in the structures of known drugs, the orange ones are used in diagnostics, and the green ones are medically useful radioisotopes. (The paper notes that titanium and tantalum are colored blue due to their use in implants).
I'm trying to figure out a couple of these. Xenon I've heard of as a diagnostic (hyperpolarized and used in MRI of lung capacity), but argon? (The supplementary material for the paper says that argon plasms has been used locally to control bleeding in the GI tract). And aren't there marketed drugs with a bromine atom in them somewhere? At any rate, the greyed-out elements end up that way through four routes, I think. Some of them (francium, and other high-atomic-number examples) are just too unstable (and thus impossible to obtain) for anything useful to be done with them. Others (uranium) are radioactive, but have not found a use that other radioisotopes haven't filled already. Then you have the "radioactive but toxic) category, the poster child of which is plutonium. (That said, I'm pretty sure that popular reports of its toxicity are exaggerated, but it still ain't vanilla pudding). Then you have the nonradioactive but toxic crowd - cadmium, mercury, beryllium and so on. (There's another question - aren't topical mercury-based antiseptics still used in some parts of the world? And if tantalum gets on the list for metal implants, what about mercury amalgam tooth fillings?) Finally, you have elements that are neither hot not poisonous, but that no one has been able to find any medical use for (scandium, niobium, hafnium). Scandium and beryllium, in fact, are my nominees for "lowest atomic-numbered elements that many people have never heard of", and because of nonsparking beryllium wrenches and the like, I think scandium might win out. I've never found a use for it myself, either. I have used a beryllium-copper wrench (they're not cheap) in a hydrogenation room.

The review goes on to detail the various classes of metal-containing drugs, most prominent of them being, naturally, the platinum anticancer agents. There are ruthenium complexes in the clinic in oncology, and some work has been done with osmium and iridium compounds. Ferrocenyl compounds have been tried several times over the years, often put in place of a phenyl ring, but none of them (as far as I know) have made it into the general pharmacopeia. What I didn't know what that titanocene dichloride has been into the clinic (but with disappointing results). And arsenic compounds have a long (though narrow) history in medicinal chemistry, but have recently made something of a comeback. The thioredoxin pathway seems to be a good fit for exotic elements - there's a gadolinium compound in development, and probably a dozen other metals have shown activity of one kind or another, both in oncology and against things like malaria parasites.

Many of these targets, though, are in sort of a "weirdo metal" category in the minds of most medicinal chemists, and that might not reflect reality very well. There's no reason why metal complexes wouldn't be able to inhibit more traditional drug targets as well, but that brings up another concern. For example, there have been several reports of rhodium, iridium, ruthenium, and osmium compounds as kinase inhibitors, but I've never quite been able to see the point of them, since you can generally get some sort of kinase inhibitor profile without getting that exotic. But what about the targets where we don't have a lot of chemical matter - protein/protein interactions, for example? Who's to say that metal-containing compounds wouldn't work there? But I doubt if that's been investigated to any extent at all - not many companies have such things in their compound collections, and it still might turn out to be a wild metallic goose chase to even look. No one knows, and I wonder how long it might be before anyone finds out.

In general, I don't think anyone has a feel for how such compounds behave in PK and tox. Actually "in general" might not even be an applicable term, since the number and types of metal complexes are so numerous. Generalization would probably be dangerous, even if our base of knowledge weren't so sparse, which sends you right back into the case-by-case wilderness. That's why a metal-containing compound, at almost any biopharma company, would be met with the sort of raised eyebrow that Mr. Spock used to give Captain Kirk. What shots these things have at becoming drugs will be in nothing-else-works areas (like oncology, or perhaps gram-negative antibiotics), or against exotic mechanisms in other diseases. And that second category, as mentioned above, will be hard to get off the ground, since almost no one tests such compounds, and you don't find what you don't test.

Comments (57) + TrackBacks (0) | Category: Cancer | Odd Elements in Drugs | Toxicology

May 2, 2013

Aveo Gets Bad News on Tivozanib

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Posted by Derek

The kinase inhibitor tivozanib (for renal cell carcinoma) was shot down this morning at an FDA committee hearing. There are going to be a lot of arguments about this decision, because feelings have been running high on both sides of the issue.

And this has been an issue for over a year now. As that FierceBiotech story puts it:

Tivozanib hit its primary endpoint, demonstrating a slim but statistically significant improvement in progression-free-survival of patients with advanced renal cell carcinoma when compared to Nexavar (sorafenib). But the sorafenib arm experienced a slightly better overall survival rate, and Aveo has been trying to explain it away ever since.

The developer had to start in the spring of 2012 at a pre-NDA meeting. According to the review document, "the FDA expressed concern about the adverse trend in overall survival in the single Phase III trial and recommended that the sponsor conduct a second adequately powered randomized trial in a population comparable to that in the US."

The Phase III in question was performed in Eastern Europe, and one of the outcomes of today's decision may be a reluctance to rely on that part of the world for pivotal trials. I'm honestly not sure how much of tivozanib's problems were due to that (if the data had been stronger, no one would be wondering). But if the patient population in the trial was far enough off the intended US market to concern the FDA, then there was trouble coming from a long way away.

Aveo, though, may not have had many options by this time. This is one of those situations where a smaller company has enough resources to barely get something through Phase III, so they try to do it as inexpensively as they can (thus Eastern Europe). By the time things looked dicey, there wasn't enough cash to do anything over, so they took what they had to the FDA and hoped for the best. The agency's suggestion to do a US trial must have induced some despair, since (1) they apparently didn't have the money to do it, and (2) this meant that the chances of approval on the existing data were lower than they'd hoped.

One of the other big issues that this decision highlights is in trial design. This was a "crossover" trial, where patients started out on one medication and then could be switched to another as their condition progressed. So many crossed over to the comparison drug (Nexavar, sorafenib) that it seems to have impaired the statistics of the trial. Were the overall survival numbers slightly better in the eventual Nexavar group because they'd been switched to that drug, or because they'd gotten tivozanib first? That's something you'd hope that a more expensive/well-run Phase III would have addressed, but in the same way that this result casts some doubt on the Eastern European clinical data, it casts some doubt on crossover trial design in this area.

Update: a big problem here was that there were many more patients who crossed over to tivozanib from Nexavar than the other way around. That's a design problem for you. . .

What a mess - and what a mess for Aveo, and their investors. I'm not sure if they've got anything else; it looks like they'd pretty much bet the company on this. Which must have been like coming to the showdown at the poker table with a low three-of-a-kind, knowing that someone else probably has it beat. . .

Comments (27) + TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs

April 29, 2013

Costing Just Too Much

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Posted by Derek

There's been a lot of rumbling recently about the price of new cancer drugs (see this article for a very typical reaction). It's a topic that's come up around here many times, as would be only natural - scrolling back in this category will turn up a whole list of posts.

I see that Bernard Munos has weighed in on the topic in Forbes. He's not being Doctor Feelgood about it, either:

All this adds up to a giant pushback against the astronomical drug prices that are becoming commonplace. It seems that price tags of $100,000 or above are becoming the norm. Of 12 cancer drugs approved in 2012, 11 cost more than that. As more drugs are offered at that level and their sponsors get away with it, it seems to set a floor that emboldens drug companies to push the envelope. They are badly misjudging the brewing anger.

The industry’s standard defense has been to run warm-hearted stories about the wonders of biomedical innovation, and to point out that drugs represent only 10% of healthcare costs. Both arguments miss the point. Everyone loves biomedical innovation, but the industry’s annual output of 25 to 35 new drugs is a lousy return for its $135 billion R&D spending. . .

That's a real problem. We in the industry concentrate on our end of it, where we wonder how we can spend this much for our discovery efforts and survive. But there are several sides to the issue. From one angle, as long as we can jack up the prices high enough on what does get through, we can (in theory) stay in business. That's not going to happen. There are limits to what we can charge, and we're starting to bang up against them, in the way that a Martingale player at a roulette table learns why casinos have betting limits at the tables. It's not a fun barrier to bump into.

And there's the problem Munos brings up, which is one that investors have been getting antsy about for some time: return on capital. The huge amounts of money going out the door are (at least in some cases) not sustainable. But we're not spending our money as if there were a problem:

Perhaps the mood would be different if the industry was a model of efficiency, but this is hardly the case. Examples of massive waste are on display everywhere: Pfizer wants to flatten a 750,000-square-foot facility in Groton, CT, and won’t entertain proposals for alternative uses. Lilly writes off over $100 million for a half-built insulin plant in Virginia, only to restart the project a few years later in Indiana. AstraZeneca shutters its R&D labs at Alderley Park and goes on to spend $500 million on a new facility in Cambridge.

Munos is right. We have enough trouble already without asking for more. Don't we?

Comments (37) + TrackBacks (0) | Category: Cancer | Drug Prices | Why Everyone Loves Us

April 24, 2013

Watching PARP1 Inhibitors Fail To Work, Cell By Cell

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Posted by Derek

Here's something that's been sort of a dream of medicinal chemists and pharmacologists, and now can begin to be realized: single-cell pharmacokinetics. For those outside the field, you should know that we spend a lot of time on our drug candidates, evaluating whether they're actually getting to where we want them to. And there's a lot to unpack in that statement: the compound (if it's an oral dose) has to get out of the gut and into the bloodstream, survive the versatile shredding machine of the liver (which is where all the blood from from the gut goes first), and get out into the general circulation.

But all destinations are not equal. Tissues with greater blood flow are always going to see more of any compound, for starters. Compounds can (and often do) stick to various blood components preferentially (albumin, red blood cells themselves, etc.), and ride around that way, which can be beneficial, problematic, or a complete non-issue, depending on how the med-chem gods feel about you that week. The brain is famously protected from the riff-raff in the blood supply, so if you want to get into the CNS, you have more to think about. If your compound is rather greasy, it may find other things it likes to stick to rather than hang around in solution anywhere.

And we haven't even talked about the cellular level yet. Is your target on the outside of the cells, or do you have to get in? If you do, you might find your compounds being pumped right back out. There are ongoing nasty arguments about compounds being pumped in in the first place, too, as opposed to just soaking through the membranes. The inside of a cell is a strange place, too, once you're there. The various organelles and structures all have their own affinities for different sorts of compounds, and if you need to get into the mitochondria or the nucleus, you've got another membrane barrier to cross.
At this point, things really start to get fuzzy. It's only been in recent years that it's been possible to follow the traffic of individual species inside a cell, and it's still not trivial, by any means. Some of the techniques used to do it (fluorescent tags of various kinds) also can disturb the very systems you're trying to study. This latest paper uses such a fluorescent label, so you have to keep that in mind, but it's still quite impressive. The authors took a poly(ADP) ribose polymerase 1 (PARP1) inhibitor (part of a class that has had all kinds of trouble in the clinic, despite a lot of biological rationale), attached a fluorescent tag, and watched in real time as it coursed through the vasculature of a tumor (on a time scale of seconds), soaked out into the intracellular space (minutes), and was taken up into the cells themselves (within an hour). Looking more deeply, they could see the compound accumulating in the nucleus (where PARP1 is located), so all indications are that it really does reach its target, and in sufficient amounts to have an effect.

But since it doesn't, there must be something about PARP1 and tumor biology that we're not quite grasping. Inhibiting DNA repair by this mechanism doesn't seem to be the death blow that we'd hoped for, but we now know that that's the place to figure out the failure of these inhibitors. Blaming some problems of delivery and distribution won't cut it.

Comments (24) + TrackBacks (0) | Category: Cancer | Pharmacokinetics

April 22, 2013

Cancer: Back to N-of-One

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Posted by Derek

From Nature comes this news of an effort to go back to oncology clinical trials and look at the outliers: the people who actually showed great responses to otherwise failed drugs.

By all rights, Gerald Batist’s patient should have died nine years ago. Her pancreatic cancer failed to flinch in the face of the standard arsenal — surgery, radiation, chemotherapy — and Batist, an oncologist at McGill University in Montreal, Canada, estimated that she had one year to live. With treatment options dwindling, he enrolled her in a clinical trial of a hot new class of drugs called farnesyltransferase inhibitors. Animal tests had suggested that the drugs had the potential to defeat some of the deadliest cancers, and pharmaceutical firms were racing to be the first to bring such compounds to market.

But the drugs flopped in clinical trials. Companies abandoned the inhibitors — one of the biggest heartbreaks in cancer research over the past decade. For Batist’s patient, however, the drugs were anything but disappointing. Her tumours were resolved; now, a decade later, she remains cancer free. And Batist hopes that he may soon find out why.

That's a perfect example, because pancreatic cancer has a well-deserved reputation as one of the most intractable tumor types, and the farnesylation inhibitors were indeed a titanic bust after much anticipation.. So that combination - a terrible prognosis and an ineffective class of compounds - shouldn't have led to anything, but it certainly seems to have in that case. If there was something odd about the combination of mutations in this patient that made her respond, could there be others that would as well? It looks as if that sort of thing could work:

Early n-of-1 successes have bolstered expectations. When David Solit, a cancer researcher also at Memorial Sloan-Kettering, encountered an exceptional responder in a failed clinical trial of the drug everolimus against bladder cancer, he decided to sequence her tumour. Among the 17,136 mutations his team found, two stood out — mutations in each of these genes had been shown to make cancer growth more dependent on the cellular pathway that everolimus shut down1. A further search revealed one of these genes — called TSC1 — was mutated in about 8% of 109 patients in their sample, a finding that could resurrect the notion of using everolimus to treat bladder cancer, this time in a trial of patients with TSC1 mutations.

So we are indeed heading to that dissection of cancer into its component diseases, which are uncounted thousands of cellular phenotypes, all leading to unconstrained growth. It's going to be quite a slog through the sequencing jungle along the way, though, which is why I don't share the optimism of people like Andy von Eschenbach and others who talk about vast changes in cancer therapy being just about to happen. These n-of-1 studies, for example, will be of direct benefit to very few people, the ones who happen to have rare and odd tumor types (that looked like more common ones at first). But tracking these things down is still worthwhile, because eventually we'll want to have all these things tracked down. Every one of them. And that's going to take quite a while, which means we'd better get starting on the ones that we know how to do.

And even then, there's going to be an even tougher challenge: the apparently common situation of multiple tumor cells types in what looks (without sequencing) like a single cancer. How to deal with these, in what order, and in what combinations - now that'll be hard. But not impossible and "not impossible" is enough to go on. Like Francis Bacon's "New Atlantis", what we have before us is the task of understanding ". . .the knowledge of causes, and secret motions of things; and the enlarging of the bounds of human empire, to the effecting of all things possible". Just don't put a deadline on it!

Comments (12) + TrackBacks (0) | Category: Cancer | Clinical Trials

April 18, 2013

Super-Enhancers in Cell Biology: ENCODE's Revenge?

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Posted by Derek

I've linked to some very skeptical takes on the ENCODE project, the effort that supposedly identified 80% of our DNA sequence as functional to some degree. I should present some evidence for the other side, though, as it comes up, and some may have come up.

Two recent papers in Cell tell the story. The first proposes "super-enhancers" as regulators of gene transcription. (Here's a brief summary of both). These are clusters of known enhancer sequences, which seem to recruit piles of transcription factors, and act differently from the single-enhancer model. The authors show evidence that these are involved in cell differentiation, and could well provide one of the key systems for determining eventual cellular identity from pluripotent stem cells.

Interest in further understanding the importance of Mediator in ESCs led us to further investigate enhancers bound by the master transcription factors and Mediator in these cells. We found that much of enhancer-associated Mediator occupies exceptionally large enhancer domains and that these domains are associated with genes that play prominent roles in ESC biology. These large domains, or super-enhancers, were found to contain high levels of the key ESC transcription factors Oct4, Sox2, Nanog, Klf4, and Esrrb to stimulate higher transcriptional activity than typical enhancers and to be exceptionally sensitive to reduced levels of Mediator. Super-enhancers were found in a wide variety of differentiated cell types, again associated with key cell-type-specific genes known to play prominent roles in control of their gene expression program

On one level, this is quite interesting, because cellular differentiation is a process that we really need to know a lot more about (the medical applications are enormous). But as a medicinal chemist, this sort of news sort of makes me purse my lips, because we have enough trouble dealing with the good old fashioned transcription factors (whose complexes of proteins were already large enough, thank you). What role there might be for therapeutic intervention in these super-complexes, I couldn't say.

The second paper has more on this concept. They find that these "super-enhancers" are also important in tumor cells (which would make perfect sense), and that they tie into two other big stories in the field, the epigenetic regulator BRD4 and the multifunctional protein cMyc:

Here, we investigate how inhibition of the widely expressed transcriptional coactivator BRD4 leads to selective inhibition of the MYC oncogene in multiple myeloma (MM). BRD4 and Mediator were found to co-occupy thousands of enhancers associated with active genes. They also co-occupied a small set of exceptionally large super-enhancers associated with genes that feature prominently in MM biology, including the MYC oncogene. Treatment of MM tumor cells with the BET-bromodomain inhibitor JQ1 led to preferential loss of BRD4 at super-enhancers and consequent transcription elongation defects that preferentially impacted genes with super-enhancers, including MYC. Super-enhancers were found at key oncogenic drivers in many other tumor cells.

About 3% of the enhancers found in the multiple myeloma cell line turned out to be tenfold-larger super-enhancer complexes, which bring in about ten times as much BRD4. It's been recently discovered that small-molecule ligands for BRD4 have a large effect on the cMyc pathway, and now we may know one of the ways that happens. So that might be part of the answer to the question I posed above: how do you target these things with drugs? Find one of the proteins that it has to recruit in large numbers, and mess up its activity at a small-molecule binding site. And if these giant complexes are even more sensitive to disruptions in these key proteins than usual (as the paper hypothesizes), then so much the better.

It's fortunate that chromatin-remodeling proteins such as BRD4 are (at least in some cases) filling that role, because they have pretty well-defining binding pockets that we can target. Direct targeting of cMyc, by contrast, has been quite difficult indeed (here's a new paper with some background on what's been accomplished so far).

Now, to the level of my cell biology expertise, the evidence that these papers have looks reasonably good. I'm certainly willing to believe that there are levels of transcriptional control beyond those that we've realized so far, weary sighs of a chemist aside. But I'll be interested to see the arguments over this concept play out. For example, if these very long stretches of DNA turn out indeed to be so important, how sensitive are they to mutation? One of the key objections to the ENCODE consortium's interpretation of their data is that much of what they're calling "functional" DNA seems to have little trouble drifting along and picking up random mutations. It will be worth applying this analysis to these super-regulators, but I haven't seen that done yet.

Comments (5) + TrackBacks (0) | Category: Biological News | Cancer

April 2, 2013

Stealing A Compound, To Set Up in China

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Posted by Derek

Here's a strange case worth keeping an eye on. Via Deborah Blum's Twitter feed we have this report of a researcher in Wisconsin being charged with economic espionage - specifically, investigational oncology.

Huajun Zhao, 42, faces a single count of economic espionage, according to a federal criminal complaint, an offense punishable by up to 15 years in prison and a $500,000 fine. . .

. . .According to the complaint, Zhao worked as an associate researcher at the college, assisting professor Marshall Anderson by conducting experiments in pharmacology.

On Feb. 22, Anderson set down three pill bottle-size containers of a cancer research compound called C-25, and later noticed they were missing from his desk. After searching extensively for the bottles, he reported them lost or stolen on Feb. 26.

The next day, security video showed Zhao entering Anderson's office on Feb. 22, and leaving shortly after. No one else was seen entering the office on the videos. Security officials questioned Zhao, who didn't admit or deny taking the compound, but said he couldn't understand the questions, and that, regardless, everything would be resolved in 10 days.

The public safety manager of the college, Jessica Luedtke, contacted the FBI. She said Zhao had been disciplined months earlier for putting lab data on his personal computer. The college staff also discovered that on a professional researcher's website, Zhao claimed to have discovered a cancer-fighting compound that he wanted to bring back to China, where he had been from December till mid-February.

Since his return, his résumé lists him as an assistant professor at Zhejiang University in China.

There's more evidence presented in the article. The professor involved works on mitochondrial apoptosis and on Nf-kappaB inhibitors, but I've been unable to find any publications on the "C-25" compound itself. None of Prof. Anderson's recent papers seem to have an "H. Zhou" or anything similar in the list of co-authors, so that doesn't narrow things down, either.

This is quite odd. People do indeed steal compounds by a variety of means, but it doesn't always work out very well. But those examples involve taking things from industrial labs - stealing an academic compound like this is presumably being done to advance one's own career, rather than being a path to direct wealth. According to the report, a grant application was found on Zhou's computer, claiming that he had discovered this compound and proposing funding for more studies. It does make you wonder what it is, and what sort of tenure-achieving, publication-spinning, grant-renewing powers it has. Or perhaps it really does have promising oncology activity, and Zhou pictured himself getting into the business? More details as they become available. . .

Comments (41) + TrackBacks (0) | Category: Cancer | The Dark Side

April 1, 2013

Novartis Loses the Glivec Patent Fight in India

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Posted by Derek

This story is all over the news today, but it's my impression that most of the stories leave out crucial details. This is not just a big multinational drug company being put in its place by Indian courts, nor is it some crazy ruling with no basis in fact. Here's the story, as best I understand it.

Novartis has never had a patent for imatinib (Glivec/Gleevec) in India. I'm not completely sure why that is, but I would think it's because that back when the compound was being developed was the era when Indian drug patents did not exist. As the country has entered the WTO, it's had to comply with the world's intellectual property framework, and it's safe the say that the dust has not yet settled from this process.

So when Novartis filed for an imatinib patent in India, it was for a different polymorph of the drug, which they hoped would be patentable chemical matter. The Indian patent office disagreed in 2006, saying that this was merely a reformulation of an existing compound (which had been approved in the US back in 2001), and rejected the application. Novartis has been appealing that decision through the Indian court system ever since, and this latest ruling is the last, from the Indian Supreme Court. As the court's decision says:

In the application it claimed that the invented product, the beta crystal form of Imatinib Mesylate, has (i) more beneficial flow properties: (ii) better thermodynamic stability; and (iii) lower hygroscopicity than the alpha crystal form of Imatinib Mesylate. It further claimed that the aforesaid properties makes the invented product “new” (and superior!) as it “stores better and is easier to process”; has “better processability of themethanesulfonic acid addition salt of a compound of formula I”, and has a “further advantage for processing and storing.”

Novartis, for its part, feels that they have been done in by one particular section of Indian patent law, section 3(d). This was put in to prevent companies from "evergreening" their drug patent estates, and it requires proof of enhanced efficacy for new forms of existing compounds in order for them to be patentable. (That's as opposed to the situation in most other patent regimes, where once you've shown that you have a new substance, the uses you already knew about for its earlier form are enough to establish utility, to go along with the novelty). Here's Novartis' take:

Glivec has been awarded patents in nearly 40 other countries, including China, Russia and Taiwan, but the IPAB is denying one for India. The IPAB acknowledges that Glivec satisfies the international requirements for novelty and inventiveness, but it does not find Glivec to meet the requirement under Section 3(d) of the Indian Patents Act of 2005. This act introduced a new efficacy enhancement hurdle for patenting new forms of known compounds. We believe that Section 3(d), the Indian legal paragraph intended as a hurdle for evergreening, should not be applicable to the breakthrough medicine Glivec, which has changed the lives of patients with rare cancers.

The misconception regarding the innovation of Glivec is based on a patent that was granted in 1993 (not in India) for the synthesis of the molecule imatinib. This molecule, without further development, could not safely be administered to patients and represented only the first step in the process to develop Glivec as a viable treatment for cancer. We selected the mesylate salt of imatinib and then developed the beta crystal form of imatinib mesylate to make it suitable for patients to take in a pill form that would deliver consistent, safe and effective levels of medicine.

Novartis claimed that the increased bioavailability qualified as increased efficacy, but the opposing argument was that therapeutically, the two compound forms were never shown to be differentiated. The Indian Supreme Court, in fact, noted in its decision that Novartis had never provided any data on the effect of bioavailability on therapeutic efficacy, with the implication being, I think, that if they had such data they surely would have presented it by now in order to strengthen their case. The court had this to say about the beta-crystalline form:

It is seen above that in the US the drug Gleevec came to the market in 2001. It is beyond doubt that what was marketed then was Imatinib Mesylate and not the subject product, Imatinib Mesylate in beta crystal form. It is also seen above that even while the appellant’s application for grant of patent lay in the “mailbox” awaiting amendments in the law of patent in India, the appellant was granted Exclusive Marketing Rights on November 10,2003, following which Gleevec was marketed in India as well. On its package, the drug was described as “Imatinib Mesylate Tablets 100 mg” and it was further stated that “each film coated tablet contains: 100 mg Imatinib (as Mesylate)”. On the package there is no reference at all to Imatinib Mesylate in beta crystalline form. What appears, therefore, is that what was sold as Gleevec was Imatinib Mesylate and not the subject product, the beta crystalline form of Imatinib Mesylate.

I'm of two minds about that argument. The packaging often does not describe individual polymorphs of compounds - both the original form of imatinib and the beta-crystalline form are properly described as "imatinib mesylate". At the same time, it does appear that the drug has been administered as the earlier form for some time. So the Indian court affirms their section 3(d), which is a high bar, but they do say that it should be one that is clearable in practice:

We have held that the subject product, the beta crystalline form of Imatinib Mesylate, does not qualify the test of Section 3(d) of the Act but that is not to say that Section 3(d) bars patent protection for all incremental inventions of chemical and pharmaceutical substances. It will be a grave mistake to read this judgment to mean that section 3(d) was amended with the intent to undo the fundamental change brought in the patent regime by deletion of section 5 from the Parent Act. That is not said in this judgment.”

We'll have to see how this works out in practice. India has a right, of course, to set its patent laws out in this way, but will it always work out like this when a section 3(d) issue comes up again? Or will that only be when it's a multinational company selling an expensive drug? Pricing, in fact, is not supposed to enter into this dispute, although for a while, it looked as if it would. The Indian appellate board, as Spicy IP reports, had originally tried to being in another interesting part of the patent law, section 3(b), which forbids patents for inventions that "offend public order or morality". They had tried the argument that Novartis' pricing offended public morality, but the Indian Supreme Court, to their credit, declined to pursue that line of thought.

So this case is not the end of drug patents in India. It's not supposed to be some mighty victory for the generic drug makers there, either, although I'm sure they're happy with it. (I might note that all the preening in the Indian press about the country being the "pharmacy to the world" would be more justified if any of the drugs being made had actually been discovered in India, through the ingenuity of Indian drug companies, risking Indian capital and shareholders' money. But they weren't).

What it does mean is that Indian drug patent law has gone from being nonexistent a few years ago, to being one of the strictest around. I hope that it's applied uniformly. Novartis has lost what was not a very strong case, to be honest, but the courts in India will hear stronger at some point.

Comments (29) + TrackBacks (0) | Category: Cancer | Patents and IP

March 27, 2013

A Therapy Named After You?

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Posted by Derek

Back last fall I wrote about Prof. Magnus Essand and his oncoloytic virus research. He's gotten a good amount of press coverage, and has been trying all sorts of approaches to get further work funded. But here's one that I hadn't thought of: Essand and his co-workers are willing to name the therapy after anyone who can pony up the money to get it into a 20-patient human trial.

The more I think about that, the less problem I have with it. This looks at first like a pure angel investor move, and if people want to take a crack at something like this with their own cash, let them do the due diligence and make the call. Actually, Essand believes that his current virus is unpatentable (due to prior publication), so this is less of an a angel investment and more sheer philanthropy. But I have no objections at all to that, either.

Update: here's more on the story.

Comments (12) + TrackBacks (0) | Category: Cancer | Clinical Trials | Drug Development

March 25, 2013

James Watson Likes Us, Anyway

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Posted by Derek

Around us we see changes in everything, but there are some constants that we can count on. James Watson, for example, is still James Watson:

While noting that genetics is vital, Watson said, "You could sequence 150,000 people with cancer and its not going to cure anyone. It might give you a few leads, but it's not, to me, the solution. The solution is good chemistry. And that's what's lacking. We have a world of cancer biology trained to think genes. They don't think chemistry at all."

Watson, who had his entire genome sequenced, said the current level of cancer research funding is enough to find a cure. But he added that "most of the experiments we do are irrelevant ... We're not going to cure cancer by doubling the money. We're going to do it by being more intelligent. The money thing is just a red herring of people not thinking."

Read the article for more - he has a number of other opinions that (as usual) he's not shy about sharing with the audience (!)

Comments (10) + TrackBacks (0) | Category: Cancer

March 22, 2013

Good News in Oncology: More Immune Therapy for Leukemia

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Posted by Derek

I've written a couple of times about the work at the University of Pennsylvania on modified T-cell therapy for leukemia (CLL). Now comes word that a different version of this approach seems to be working at Sloan-Kettering. Recurrent B-cell acute lymphoblastic leukemia (B-ALL) has been targeted there, and it's generally a more aggressive disease than CLL.

As with the Penn CLL studies, when this technique works, it can be dramatic:

One of the sickest patients in the study was David Aponte, 58, who works on a sound crew for ABC News. In November 2011, what he thought was a bad case of tennis elbow turned out to be leukemia. He braced himself for a long, grueling regimen of chemotherapy.

Brentjens suggested that before starting the drugs, Aponte might want to have some of his T-cells stored (chemotherapy would deplete them). That way, if he relapsed, he might be able to enter a study using the cells. Aponte agreed.

At first, the chemo worked, but by summer 2012, while he was still being treated, tests showed the disease was back.

“After everything I had gone through, the chemo, losing hair, the sickness, it was absolutely devastating,’’ Aponte recalled.

He joined the T-cell study. For a few days, nothing seemed to be happening. But then his temperature began to rise. He has no memory of what happened for the next week or so, but the journal article — where he is patient 5 — reports that his fever spiked to 105 degrees.

He was in the throes of a ‘‘cytokine storm,’’ meaning that the T-cells, in a furious battle with the cancer, were churning out enormous amounts of hormones called cytokines. Besides fever, the hormonal rush can make a patient’s blood pressure plummet and his heart rate shoot up. Aponte was taken to intensive care and treated with steroids to quell the reaction.

Eight days later, his leukemia was gone

He and the other patients in the study all received bone marrow transplantations after the treatment, and are considered cured - which is remarkable, since they were all relapsed/refractory, and thus basically at death's door. These stories sound like the ones from the early days of antibiotics, with the important difference that resistance to drug therapy doesn't spread through the world's population of cancer cells. The modified T-cell approach has already gotten a lot of attention, and this is surely going to speed things up even more. I look forward to the first use of it for a non-blood-cell tumor (which appears to be in the works) and to further refinements in generating the cells themselves.

Comments (11) + TrackBacks (0) | Category: Biological News | Cancer | Clinical Trials

Good News in Oncology: Oncolytic Virus Therapy

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Posted by Derek

The last few days have brought some good news on some unusual approaches to cancer therapy. First off was Amgen's report that they'd seen positive results in advanced melanoma using a modified HSV treatment. This is technology that they brought in by buying Biovex in 2011, and as a minor side effect, if it works, it'll be so much the better for Roger Perlmutter (now at Merck), since this was a deal made under his watch.

Specifically, the company says that 16% of patients showed a response (durable response rate, DRR) to the treatment, versus 2% of the control group. That's encouraging, but the big question is overall survival. DRR will get you little or nothing at the FDA, or shouldn't, if people don't actually live longer. We should have those numbers later this year - considering what sort of shape people are in with late-stage melanoma, you can look at the odds two different ways. The disease is so advanced, perhaps, that it'll be difficult for anything to show a benefit. Or, on the other hand, anything that doe have an effect will stand out, since the control group's course will be so relentless.

I hope this works, both for the patients and for the idea of using a virus to attack cancerous cells. That one's been kicking around for a long time, with several companies in the chase, and it has a lot of appealing features. But it also has a lot of tricky details, too - targeting the tumor cells over normal ones, finding the appropriate viral platform, delivering it safely to the patient, and more. There's also the question of whether you just want to lyse the tumor cells with a viral load, or also make them express some therapeutically useful protein. The Amgen/Biovex HSV virus in this latest trial, for example, also causes the cells to express GM-CSF for an additional immune response (with the control group getting GM-CSF alone).

So even though this has been actively researched in humans since the mid-1990s, I'd still call it the early days. Here's hoping for more encouraging news, from Amgen and the others in this chase.

Comments (7) + TrackBacks (0) | Category: Cancer | Clinical Trials

February 15, 2013

ABT-199 Clinical Trial Suspended (Updated)

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Posted by Derek

Abbott - whoops, pardon me, I mean AbbVie, damn that name - has been developing ABT-199, a selective Bcl-2-targeted oncology compound for CLL. Unlike some earlier shots in this area (ABT-263, navitoclax), it appeared to spare platelet function, and was considered a promising drug candidate in the mid-stage clinical pipeline.

Not any more, perhaps. Clinical work has been suspended after a patient death due to tumor lysis syndrome. This is a group of effects caused by sudden breakdown of the excess cells associated with leukemia. You get too much potassium, too much calcium, too much uric acid, all sorts of things at once, which lead to many nasty downstream events, among them irreversible kidney damage and death. So yes, this can be caused by a drug candidate working too well and too suddenly.

The problem is, as the Biotech Strategy Blog says in that link above, that this would be more understandable in some sort of acute leukemia, as opposed to CLL, which is the form that ABT-199 is being tested against. So there's going to be some difficulty figuring out how to proceed. My guess is that they'll be able to restart testing, but that they'll be creeping up on the dosages, with a lot of blood monitoring along the way, until they get a better handle on this problem - if a better handle is available, that is. ABT-199 looks too promising to abandon, and after all, we're talking about a fatal disease. But this is going to slow things down, for sure.

Update: I've had email from the company, clarifying things a bit: "While AbbVie has voluntarily suspended enrollment in Phase 1 trials evaluating ABT-199 as a single agent and in combination with other agents such as rituximab, dosing of active patients in ABT-199 trials is continuing. Previous and current trials have shown that dose escalation methods can control tumor lysis syndrome and we have every expectation that the trials will come off of clinical hold and that we will be able to initiate Phase 3 trials in 2013, as planned."

Comments (18) + TrackBacks (0) | Category: Cancer | Clinical Trials | Toxicology

January 28, 2013

Time to Refill Your Prescription For Zxygjfb

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Posted by Derek

The brand names of drugs are famously odd. But they seem to be getting odder. That's the conclusion of a longtime reader, who sent this along:

I was recently perusing through the recent drug approval list and was struck by how strange the trade names have become. Perhaps it is a request from the FDA so that there are fewer prescription errors, but some of these are really bizarre and don't quite roll off the tongue. USAN names I can understand, but trade names, to me anyway, used to be much more polished (Viagra, Lipitor etc). Could it have to do with the fact that most of these are for cancer? I have a list below comparing trade names from 2004 to those from the past year or so.

2004:    Vidaza;   Avastin;  Sensipar;  Cymbalta;   Tarceva;   Certican;   Factive;   Sinseron;   Alimta;  Lyrica;  Exanta

2012:   Fulyzaq;  Bosulif;  Xeljanz;  Myrbetriq;  Juxtapid;  Iclusig;  Fycompa;  Zelboraf;   Xalkori;  Jakafi;  Pixuvri

He's got a point; some of those look like someone rested an elbow on the keyboard when they were filling out the form. I'd be willing to bet that the oncology connection is a real one - those drugs don't get mass-market advertising at all, so they don't have to be catchy. This Reuters article also notes the trend in cancer drugs, and brings up the need for novelty. Not only is it good to have a name that stands out in the memory, it's a legal requirement to have one that can't be easily confused with another drug. That goes for handwriting as well:

"Regulators want a lot of pen strokes up and down that provide a much more unique-looking name. It is more readable or interpretable if it has a lot of (Zs and Xs)," said Brannon Cashion, Addison Whitney's president.

Whether anyone can actually pronounce the name is of less concern.

That's for sure, when you're talking about things like Xgeva (edit: fixed this name to eliminate the extra "r" I put into it. Can anyone blame me for getting it wrong?). But that one's a good case in point: the generic name is denosumab. That's a good ol' USAN name, with the "-mab" suffix telling you that it's a monoclonal antibody. It's sold in the oncology market as Xgreva for bone-related cancer complications, but it's also prescribed for postmenopausal women to halt loss of bone tissue. There, the same drug goes under the much more consumer-friendly name of Prolia. Now, that's a blandly uplifting name if I've ever heard one, whereas Xgeva sounds like the name of an alien race in a cheap science fiction epic ("An Xgeva ship has been detected in the quadrant, Captain!").

Or, like its recent peers, it also sounds like an excellent Scrabble word, were it to be allowed, which it wouldn't. Me, my proudest moment was playing "axolotl" one time for seven letters. Come to think of it, Axolotl would make a perfectly good drug name under the current conditions. . .

Update: I notice that the comments are filling up with alternative definitions of some of these names, many of which (not all!) sound more sensible.

Comments (31) + TrackBacks (0) | Category: Business and Markets | Cancer

January 17, 2013

More on Metformin and Cancer (and Alzheimer's)

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Posted by Derek

Metformin: what a weird compound it is. Very small, very polar, the sort of thing you'd probably cross off your list of screening hits. But it's been taken by untold millions of diabetics (and made untold billions of dollars in the process), because it really does reduce glucose levels. It does so though mechanisms that are still the subject of vigorous debate and which (I might add) were completely unknown when the drug was approved. (I keep running into people who think that mechanism-of-action is some sort of FDA requirement, but it most certainly is not. Not saying that it wouldn't help, but what the regulatory agencies want are efficacy and safety. As they should).

And evidence has been piling up that the compound does many other things besides. The situation is murky. There was a report in 2009 that suggested that it might exacerbate the pathology of Alzheimer's. But last summer there was a rodent study that showed (in obese mice) that the compound seemed to improve neurogenerative effects seen in the hippocampus. (Whether this operates in animals, or humans, who are not metabolically impaired is an open question, although metformin is right in the middle of the whole "Type III diabetes" debate about Alzheimer's, which I'm going to cover in another post at some point soon). Meanwhile, human studies (in the large populations taking the drug) are not saying one way or another just yet. This British analysis suggested that there might be an association, but it's not for sure.

Then there's oncology. In 2010 I wrote about the evidence linking metformin use with lower incidence of some types of cancer, and one proposal for the mechanism. Now another paper is out suggesting that the compound works in this regard through modifying the inflammatory cascade. (Note that James Watson also highlighted this lab's previous work in his recent paper, blogged about here). The summary:

. . .Taken together, our observations suggest that metformin inhibits the inflammatory pathway necessary for transformation and CSC formation. To link our results with previous work on metformin in the diabetic context, we speculate that metformin may block a metabolic stress response that stimulates the inflammatory pathway associated with a wide variety of cancers. . .

. . .We suspect that this glucose- and metabolism-mediated pathway operates in many different cell types, and hence might explain why metformin reduces incidence of different human cancers and why the combination of metformin and chemotherapy is effective on many cell types in the xenograft context. While this pathway is hypothetical and has not been described in molecular terms, our results suggest that components in this pathway might be potential targets for cancer therapy.

The pathway referred to is through Src and IkappaB (of the NF-kB pathway), among others; the paper goes into more detail for those who are interested. There's a lot of stuff going on in the clinic with metformin added to different chemotherapy regimes, and I very much look forward to seeing the results. On the molecular level, I'd agree with the statement above - there's a lot to dig into here. The whole intersection of metabolism and cancer is a very large, very complex (and very tricky) area, but you'd have to think that there's a lot of really useful stuff to be found in it.

Comments (17) + TrackBacks (0) | Category: Cancer | Diabetes and Obesity

January 11, 2013

Reactive Oxygen Species Are Your Friends!

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Posted by Derek

The line under James Watson's name reads, of course, "Co-discoverer of DNA's structure. Nobel Prize". But it could also read "Provocateur", since he's been pretty good at that over the years. He seems to have the right personality for it - both The Double Helix (fancy new edition there) and its notorious follow-up volume Avoid Boring People illustrate the point. There are any number of people who've interacted with him over the years who can't stand the guy.

But it would be a simpler world if everyone that we found hard to take was wrong about everything, wouldn't it? I bring this up because Watson has published an article, again deliberately provocative, called "Oxidants, Antioxidants, and the Current Incurability of Metastatic Cancers". Here's the thesis:

The vast majority of all agents used to directly kill cancer cells (ionizing radiation, most chemotherapeutic agents and some targeted therapies) work through either directly or indirectly generating reactive oxygen species that block key steps in the cell cycle. As mesenchymal cancers evolve from their epithelial cell progenitors, they almost inevitably possess much-heightened amounts of antioxidants that effectively block otherwise highly effective oxidant therapies.

The article is interesting throughout, but can fairly be described as "rambling". He starts with details of the complexity of cancerous mutations, which is a topic that's come up around here several times (as it does wherever potential cancer therapies are discussed, at least by people with some idea of what they're talking about). Watson is paying particular attention here to mesenchymal tumors:

Resistance to gene-targeted anti-cancer drugs also comes about as a consequence of the radical changes in underlying patterns of gene expression that accompany the epithelial-to-mesenchymal cell transitions (EMTs) that cancer cells undergo when their surrounding environments become hypoxic [4]. EMTs generate free-floating mesenchymal cells whose flexible shapes and still high ATP-generating potential give them the capacity for amoeboid cell-like movements that let them metastasize to other body locations (brain, liver, lungs). Only when they have so moved do most cancers become truly life-threatening. . .

. . .Unfortunately, the inherently very large number of proteins whose expression goes either up or down as the mesenchymal cancer cells move out of quiescent states into the cell cycle makes it still very tricky to know, beyond the cytokines, what other driver proteins to focus on for drug development.

That it does. He makes the case (as have others) that Myc could be one of the most important protein targets - and notes (as have others!) that drug discovery efforts against the Myc pathway have run into many difficulties. There's a good amount of discussion about BRD4 compounds as a way to target Myc. Then he gets down to the title of the paper and starts talking about reactive oxygen species (ROS). Links in the section below added by me:

That elesclomol promotes apoptosis through ROS generation raises the question whether much more, if not most, programmed cell death caused by anti-cancer therapies is also ROS-induced. Long puzzling has been why the highly oxygen sensitive ‘hypoxia-inducible transcription factor’ HIF1α is inactivated by both the, until now thought very differently acting, ‘microtubule binding’ anti-cancer taxanes such as paclitaxel and the anti-cancer DNA intercalating topoisomerases such as topotecan or doxorubicin, as well as by frame-shifting mutagens such as acriflavine. All these seemingly unrelated facts finally make sense by postulating that not only does ionizing radiation produce apoptosis through ROS but also today's most effective anti-cancer chemotherapeutic agents as well as the most efficient frame-shifting mutagens induce apoptosis through generating the synthesis of ROS. That the taxane paclitaxel generates ROS through its binding to DNA became known from experiments showing that its relative effectiveness against cancer cell lines of widely different sensitivity is inversely correlated with their respective antioxidant capacity. A common ROS-mediated way through which almost all anti-cancer agents induce apoptosis explains why cancers that become resistant to chemotherapeutic control become equally resistant to ionizing radiotherapy. . .

. . .The fact that cancer cells largely driven by RAS and Myc are among the most difficult to treat may thus often be due to their high levels of ROS-destroying antioxidants. Whether their high antioxidative level totally explains the effective incurability of pancreatic cancer remains to be shown. The fact that late-stage cancers frequently have multiple copies of RAS and MYC oncogenes strongly hints that their general incurability more than occasionally arises from high antioxidant levels.

He adduces a number of other supporting evidence for this line of thought, and then he gets to the take-home message:

For as long as I have been focused on the understanding and curing of cancer (I taught a course on Cancer at Harvard in the autumn of 1959), well-intentioned individuals have been consuming antioxidative nutritional supplements as cancer preventatives if not actual therapies. The past, most prominent scientific proponent of their value was the great Caltech chemist, Linus Pauling, who near the end of his illustrious career wrote a book with Ewan Cameron in 1979, Cancer and Vitamin C, about vitamin C's great potential as an anti-cancer agent [52]. At the time of his death from prostate cancer in 1994, at the age of 93, Linus was taking 12 g of vitamin C every day. In light of the recent data strongly hinting that much of late-stage cancer's untreatability may arise from its possession of too many antioxidants, the time has come to seriously ask whether antioxidant use much more likely causes than prevents cancer.

All in all, the by now vast number of nutritional intervention trials using the antioxidants β-carotene, vitamin A, vitamin C, vitamin E and selenium have shown no obvious effectiveness in preventing gastrointestinal cancer nor in lengthening mortality [53]. In fact, they seem to slightly shorten the lives of those who take them. Future data may, in fact, show that antioxidant use, particularly that of vitamin E, leads to a small number of cancers that would not have come into existence but for antioxidant supplementation. Blueberries best be eaten because they taste good, not because their consumption will lead to less cancer.

Now this is quite interesting. The first thing I thought of when I read this was the work on ROS in exercise. This showed that taking antioxidants appeared to cancel out the benefits of exercise, probably because reactive oxygen species are the intracellular signal that sets them off. Taken together, I think we need to seriously consider whether efforts to control ROS are, in fact, completely misguided. They are, perhaps, "essential poisons", without which our cellular metabolism loses its way.

Update: I should also note the work of Joan Brugge's lab in this area, blogged about here. Taken together, you'd really have to advise against cancer patients taking antioxidants, wouldn't you?

Watson ends up the article by suggesting, none too diplomatically, that much current cancer research is misguided:

The now much-touted genome-based personal cancer therapies may turn out to be much less important tools for future medicine than the newspapers of today lead us to hope [54]. Sending more government cancer monies towards innovative, anti-metastatic drug development to appropriate high-quality academic institutions would better use National Cancer Institute's (NCI) monies than the large sums spent now testing drugs for which we have little hope of true breakthroughs. The biggest obstacle today to moving forward effectively towards a true war against cancer may, in fact, come from the inherently conservative nature of today's cancer research establishments. They still are too closely wedded to moving forward with cocktails of drugs targeted against the growth promoting molecules (such as HER2, RAS, RAF, MEK, ERK, PI3K, AKT and mTOR) of signal transduction pathways instead of against Myc molecules that specifically promote the cell cycle.

He singles out the Cancer Genome Atlas project as an example of this sort of thing, saying that while he initially supported it, he no longer does. It will, he maintains, tend to find mostly cancer cell "drivers" as opposed to "vulnerabilities". He's more optimistic about a big RNAi screening effort that's underway at his own Cold Spring Harbor, although he admits that this enthusiasm is "far from universally shared".

We'll find out which is the more productive approach - I'm glad that they're all running, personally, because I don' think I know enough to bet it all on one color. If Watson is right, Pfizer might be the biggest beneficiary in the drug industry - if, and it's a big if, the RNAi screening unearths druggable targets. This is going to be a long-running story - I'm sure that we'll be coming back to it again and again. . .

Comments (21) + TrackBacks (0) | Category: Biological News | Cancer

January 3, 2013

Overselling p53 Drugs

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Posted by Derek

You may have seen some "wonder drug" news stories over the holiday break about compounds targeting p53 - many outlets picked up this New York Times story. The first paragraph probably got them:

For the first time ever, three pharmaceutical companies are poised to test whether new drugs can work against a wide range of cancers independently of where they originated — breast, prostate, liver, lung. The drugs go after an aberration involving a cancer gene fundamental to tumor growth. Many scientists see this as the beginning of a new genetic age in cancer research.

Now, to read that, you might think we're talking mutated p53, which is indeed found in a wide variety of cancers. It's the absolute first thing you think of when you think of a defective protein that's strongly associated with cancer. And everyone has been trying to target it for years and years now, for just that reason, but without too much success. If you know drug development, you might have seen this article and done what I did - immediately read on wondering who the heck it was with a broad-based p53 therapy and how you missed it.

That's when you find, though, that this is p53 and MDM2. MDM2 is one of those Swiss-army-knife proteins that interacts with a list of other important regulatory proteins as long as your leg. (Take a look at the last paragraph of that Wikipedia link and you'll see what I mean). Its relationship with p53 has been the subject of intense research for many years now - it's a negative regulator, binding to p53 and keeping it from initiating its own transcriptional activity. Since a lot of that transcriptional activity is involved with telling a cell to kill itself, that's the sort of thing you'd normally want to have repressed, but the problem in some tumor lines is that MDM2 never gets around to leaving, allowing damaged cancerous cells to carry on regardless.

So, as that newspaper piece says, there have been several long-running efforts to find compounds that will block the p53/MDM2 interaction. The first big splashes in the area were the "Nutlin" compounds, from Roche - named after Nutley, New Jersey, much good did it do the research site in the end. The tangled history of Nutlin-3 in the clinic is worth considering when you think about this field. But for some kinds of cancer, notably many lipsarcomas, this could be an excellent target. That link discusses some results with RG7112, which is one of the drugs that the Times is talking about. Note that the results are, on one level, quite good. This is a tumor type that isn't affected by much, and 14 out of the 20 patients showed stable disease on treatment. But then again, only one patient showed a response where the tumor actually became smaller, and some showed no effect at all. There were also twelve serious adverse events in eight patients. That's not the sort of thing that you might have expected, given the breathless tone of the press coverage. Now, these results are absolutely enough to go on to a larger trial, and if they replicate (safety profile permitting), I'd certainly expect the drug to be approved, and to save the lives of some liposarcoma patients who might otherwise have no options. That's good news.

But is it "the beginning of a new genetic age in cancer research", to quote Gina Kolata's article? I don't see how. The genetic age of cancer has been underway for some time now, and it's been underway in the popular press for even longer. As for this example, there are several types of cancer for which a p53/MDM2 compound could be useful, but liposarcoma is probably the first choice, which is why it's being concentrated on in the clinic. And as far as I know, the number of cancer patients with mutated p53 proteins well outnumber the ones with intact p53 and overexpressed MDM2. These new compounds won't do anything for those people at all.

I sound like such a curmudgeon. But shouldn't there be some level of press coverage in between total silence and Dawn Of A Glorious New Era? I suppose that "Progress Being Made On Tough Drug Target" isn't the sort of hed that makes Page One. But that's the sort of headline that research programs generate.

Comments (23) + TrackBacks (0) | Category: Cancer | Clinical Trials | Press Coverage

December 17, 2012

Stapled Peptides Take a Torpedo

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Posted by Derek

I wrote here about "stapled peptides", which are small modified helical proteins. They've had their helices stabilized by good ol' organic synthesis, with artificial molecular bridging between the loops. There are several ways to do this, but they all seem to be directed towards the same end.

That end is something that acts like the original protein at its binding site, but acts more like a small molecule in absorption, metabolism, and distribution. Bridging those two worlds is a very worthwhile goal indeed. We know of hordes of useful proteins, ranging from small hormones to large growth factors, that would be useful drugs if we could dose them without their being cleared quickly (or not making it into the bloodstream in the first place). Oral dosing is the hardest thing to arrange. The gut is a very hostile place for proteins - there's a lot of very highly developed machinery in there devoted to ripping everything apart. Your intestines will not distinguish the live-saving protein ligand you just took from the protein in a burrito, and will act accordingly. And even if you give things intravenously, as is done with the protein drugs that have actually made it to clinical use (insulin, EPO, etc.), getting their half-lives up to standard can be a real challenge.

So the field of chemically modified peptides and proteins is a big one, because the stakes are high. Finding small molecules that modulate protein-protein interactions is quite painful; if we could just skip that part, we'd be having a better time of it in this industry. There's an entire company (Aileron, just down the road from me) working on this idea, and many others besides. So, how's it going?

Well, this new paper will cause you to wonder about that. It's from groups in Australia and at Genentech, (Note: edited for proper credit here) and they get right down to it in the first paragraph:

Stabilized helical peptides are designed to mimic an α-helical structure through a constraint imposed by covalently linking two residues on the same helical face (e.g., residue i with i + 4). “Stapling” the peptide into a preformed helix might be expected to lower the energy barrier for binding by reducing entropic costs, with a concomitant increase in binding affinity. Additionally, stabilizing the peptide may reduce degradation by proteases and, in the case of hydrocarbon linkages, reportedly enhance transport into cells, thereby improving bioavailability and their potential as therapeutic agents. The findings we present here for the stapled BH3 peptide (BimSAHB), however, do not support these claims, particularly in regards to affinity and cell permeability.

They go on to detail their lack of cellular assay success with the reported stapled peptide, and suggest that this is due to lack of cell permeability. And since the non-stapled peptide control was just as effective on artificially permeabilized cells, they did more studies to try to figure out what the point of the whole business is. A detailed binding study showed that the stapled peptide had lower affinity for its targets, with slower on-rates and faster off-rates. X-ray crystallography suggested that the modifying the peptide disrupted several important interactions.

Update: After reading the comments so far, I want to emphasize that this paper, as far as I can see, is using the exact same stapled peptide as was used in the previous work. So this isn't just a case of a new system behaving differently; this seems to be the same system not behaving the way that it was reported to.

The entire "staple a peptide to make it a better version of itself" idea comes in for some criticism, too:

Our findings recapitulate earlier observations that stapling of peptides to enforce helicity does not necessarily impart enhanced binding affinity for target proteins and support the notion that interactions between the staple and target protein may be required for high affinity interactions in some circumstances.19 Thus, the design of stapled peptides should consider how the staple might interact with both the target and the rest of the peptide, and particularly in the latter case whether its introduction might disrupt otherwise stabilizing interactions.

That would be more in line with my own intuition, for what it's worth, which is that making such changes to a peptide helix would turn it into another molecule entirely, rather than (necessarily) making it into an enhanced version of what it was before. Unfortunately, at least in this case, this new molecule doesn't seem to have any advantages over the original, at least in the hands of the Genentech group. This is, as they say, very much in contrast to the earlier reports. How to resolve the discrepancies? And how to factor in that Roche has a deal with Aileron for stapled-peptide technology, and this very article is (partly) from Genentech, now a part of Roche? A great deal of dust has just been stirred up; watching it settle will be interesting. . .

Comments (29) + TrackBacks (0) | Category: Cancer | Chemical Biology | Pharmacokinetics

December 10, 2012

More on Penn's T-Cell Therapy

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Posted by Derek

There's more news on the T-cell therapy work that I wrote about here and here. The New York Times has an update, and the news continues to be encouraging. So far about a dozen leukemia patients have been treated, and while not everyone has responded, there have been several dramatic remissions. Considering that every candidate for treatment so far has been at the edge of the grave (advanced resistant disease, multiple chemotherapy failures), there's definitely something here.

This will have to be done patient-by-patient. But leukemia varies patient by patient, too, and effective therapies are probably going to have to get this granular (or more). So be it. The challenges now are to find out how to make the success rates even higher, and how to deliver this sort of treatment to larger numbers of people. Challenge accepted, as they say. . .

Comments (6) + TrackBacks (0) | Category: Cancer

November 15, 2012

A Good Example of Phenotypic Screening

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Posted by Derek

I like to highlight phenotypic screening efforts here sometimes, because there's evidence that they can lead to drugs at a higher-than-usual rate. And who couldn't use some of that? Here's a new example from a team at the Broad Institute.

They're looking at the very popular idea of "cancer stem cells" (CSCs), a population of cells in some tumors that appear to be disproportionately resistant to current therapies (and disproportionately responsible for tumor relapse and regrowth). This screen uses a surrogate breast cell line, with E-cadherin knocked down, which seems to give the dedifferentiated phenotype you'd want to target. That's a bit risky, using an artificial system like that, but as the authors correctly point out, isolating a pure population of the real CSCs is difficult-to-impossible, and they're very poorly behaved in cell culture. So until those problems are solved, you have your choice - work on something that might translate over to the real system, or ditch the screening idea for now entirely. I think the first is worth a shot, as long as its limitations are kept in mind.

This paper does go on to do something very important, though - they use an isogenic cell line as a counterscreen, very close to the target cells. If you find compounds that hit the targets but not these controls, you have a lot more confidence that you're getting at some difference that's tied to the loss of E-cadherin. Using some other cell line as a control leaves too many doors open too wide; you could see "confirmed hits" that are taking advantage of totally irrelevant differences between the cell lines instead.

They ran a library of about 300,000 compounds (the MLSMR collection) past the CSC model cells, and about 3200 had the desired toxic effect on them. At this point, the team removed the compounds that were flagged in PubChem as toxic to normal mammalian cell lines, and also removed compounds that had hit in more than 10% of the assays they'd been through, both of which I'd say are prudent moves. Retesting the remaining 2200 compounds gave a weird result: at the highest concentration (20 micromolar), 97 per cent of them were active. I probably would have gotten nervous at that point, wondering if something had gone haywire with the assay, and I'll bet that a few folks at the Broad felt the same way.

But when used the isogenic cell line, things narrowed down rather quickly. Only 26 compounds showed reasonable potency on the target cells along with at least a 25-fold window for toxicity to the isogenic cells. (Without that screen, then, you'd have been chasing an awful lot of junk). Then they ordered up fresh samples of these, which is another step that believe me, you don't want to neglect. A number of compounds appear to have not been quite what they were supposed to be (not an uncommon problem in a big screening collection; you trust the labels unconditionally at your own peril).

In the end, two acylhydrazone compounds ended up retaining their selectivity after rechecking. So you can see how things narrow down in these situations: 300K to 2K to 26 to 2, and that's not such an unusual progression at all. The team made a series of analogs around the lead chemical matter, and then settled on the acylhydrazone compound shown (ML239) as the best in show. It's not a beauty. There seems to be some rule that more rigorous and unusual a phenotypic screen, the uglier the compounds that emerge from it. I'm only half kidding, or maybe a bit less - there are some issues to think about in there, and that topic is worth a post of its own.
More specifically, the obvious concern in that fulvene-looking pyrrole thingie on the right (I use "thingie" in its strict technical sense here). That's not a happy-looking (that is, particularly stable-looking) group. The acylhydrazine part might raise eyebrows with some people, but Rimonabant (among other compounds) shows that that functional group can be part of a drug. Admittedly, Rimonabant went down with all hands, but it wasn't because of the acylhydrazine. And the trichloroaryl group isn't anyone's favorite, either, but in this context, it's just sort of a dessert topping, in an inverse sense.

But the compound appears to be the real thing, as a pharmacological tool. It was also toxic to another type of breast cancer cell that had had its E-cadherin disrupted, and to a further nonengineered breast cancer cell line. Now comes the question: how does this happen? Gene expression profiling showed a variety of significant changes, with all sorts of cell death and free radical scavenging things altered. By contrast, when they did the same profiling on the isogenic controls, only five genes were altered to any significant extent, and none of those overlapped with the target cells. This is very strong evidence that something specific and important is being targeted here. A closer analysis of all the genes suggests the NF-kappaB system, and within that, perhaps a protein called TRIB3. Further experiments will have to be done to nail that down, but it's a good start. (And yes, in case you were wondering, TRIB3 does, in fact, stand for "tribble-3", and yes, that name did originate with the Drosophila research community, and how did you ever guess?)

So overall, I'd say that this is a very solid example of how phenotypic screening is supposed to work. I recommend it to people who are interested in the topic - and to people who aren't, either, because hey, you never know when it might come in handy. This is how a lot of new biology gets found, through identifying useful chemical matter, and we can never have too much of it.

Comments (23) + TrackBacks (0) | Category: Cancer | Chemical Biology | Drug Assays

October 30, 2012

JQ1: Giving Up a Fortune?

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Posted by Derek

The Atlantic is out with a list of "Brave Thinkers", and one of them is Jay Bradner at Harvard Medical School. He's on there for JQ1, a small-molecule bromodomain ligand that was reported in 2010. (I note, in passing, that once again nomenclature has come to the opposite of our rescue, since bromodomains have absolutely nothing to do with bromine, in contrast to 98% of all the other words that begin with "bromo-")

These sorts of compounds have been very much in the news recently, as part of the whole multiyear surge in epigenetic research. Drug companies, naturally, are looking to the epigenetic targets that might be amenable to small-molecule intervention, and bromodomains seem to qualify (well, some of them do, anyway).

At any rate, JQ1 is a perfectly reasonable probe compound for bromodomain studies, but it got a lot of press a couple of months ago as a potential male contraceptive. I found all that wildly premature - a compound like this one surely sets off all kinds of effects in vivo, and disruption of spermatogenesis is only one of them. Note (PDF) that it hits a variety of bromodomain subtypes, and we only have the foggiest notion of what most of these are doing in real living systems.

The Atlantic, for its part, makes much of Bradner's publishing JQ1 instead of patenting it:

The monopoly on developing the molecule that Bradner walked away from would likely have been worth a fortune (last year, the median value for U.S.-based biotech companies was $370 million). Now four companies are building on his discovery—which delights Bradner, who this year released four new molecules. “For years, drug discovery has been a dark art performed behind closed doors with the shades pulled,” he says. “I would be greatly satisfied if the example of this research contributed to a change in the culture of drug discovery.”

But as Chemjobber rightly says, the idea that Bradner walked away from a fortune is ridiculous. JQ1 is not a drug, nor is it ever likely to become a drug. It has inspired research programs to find drugs, but they likely won't look much (or anything) like JQ1, and they'll do different things (for one, they'll almost surely be more selective). In fact, chasing after that sort of selectivity is one of the things that Bradner's own research group appears to be doing - and quite rightly - while his employer (Dana-Farber) is filing patent applications on JQ1 derivatives. Quite rightly.

Patents work differently in small-molecule drug research than most people seem to think. (You can argue, in fact, that it's one of the areas where the system works most like it was designed to, as opposed to often-abominable patent efforts in software, interface design, business methods, and the like). People who've never had to work with them have ideas about patents being dark, hidden boxes of secrets, but one of the key things about a patent is disclosure. You have to tell people what your invention is, what it's good for, and how to replicate it, or you don't have a valid patent.

Admittedly, there are patent applications that do not make all of these steps easy - a case in point would be the ones from Exelixis - I wrote here about my onetime attempts to figure out the structures of some of their lead compounds from their patent filings. Not long ago I had a chance to speak with someone who was there at the time, and he was happy to hear that I'd come up short, saying that this had been exactly the plan). But at the same time, all their molecules were in there, along with all the details of how to make them. And the claims of the patents detailed exactly why they were interested in such compounds, and what they planned to do with them as drugs. You could learn a lot about what Exelixis was up to; it was just that finding out the exact structure of the clinical candidate that was tricky. A patent application on JQ1 would have actually ended up disclosing most (or all) of what the publication did.

I'm not criticizing Prof. Bradner and his research group here. He's been doing excellent work in this area, and his papers are a pleasure to read. But the idea that Harvard Medical School and Dana-Farber would walk away from a pharma fortune is laughable.

Comments (33) + TrackBacks (0) | Category: Cancer | Chemical Biology | Drug Development | Patents and IP

October 24, 2012

The Onion on Oncology Research

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I'd say they have it pretty close to reality:

". . .a new Mayo Clinic study with widespread implications for the treatment and potential cure of the disease has found that the malignant growths have begun cruelly mocking researchers. 

The findings—published this week in a rambling, expletive-laden 8,000-word article in The Journal Of The American Medical Association—provides the strongest evidence yet that abnormal cells targeted with cutting-edge cancer treatments are basically flipping off scientists left and right, and get a huge kick out of making oncologists feel like a bunch of bumbling dipshit chumps.

I feel that way about my reactions sometimes. And there were a few points during my PhD when I felt that the only explanation for the way things were going was the existence of a malignant force in the universe, one that for reasons beyond my comprehension was taking a personal interest in me.

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October 16, 2012

Texas And Its Cancer Funding

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Posted by Derek

Texas put up a lot of money a few years ago for cancer research. "A lot", in this case, means three billion, to be awarded by the Cancer Prevention Research Institute of Texas (CPRIT). This is where the money came to get K. C. Nicolaou for Rice University, for example, and much other research spending besides.

But - and I know that you'll be shocked to hear this - it turns out that the distribution of such funds can end up being tainted by politics. A number of high-profile resignations have shaken up the effort - here's an editorial by two of the most prominent (Nobel prominent, and now former) members who talk about what's gone wrong:

The past eight months were difficult. Controversy flared when several well-regarded, multi-investigator, multi-institutional collaborative research projects were put in the freezer for months - not brought to the Oversight Committee for funding after strong recommendation by the Scientific Review Council.

This delay was at least partially based on the concern that several of these projects came from one institution. CPRIT's executive director has offered different and conflicting explanations for this action.

Simultaneously, an expensive "commercialization" proposal, constructed and submitted in unorthodox ways that circumvented CPRIT's rules, was rushed to the Oversight Committee and approved for $20 million for its initial year of operations, despite the absence of description or scientific review of its drug development program. This was ultimately corrected, albeit with great effort. . .

Texans deserve to hear the truth about cancer. They must understand that miracles will not happen in a short time. Progress will not be made by those who simply proclaim without explanation that they can do better than hundreds of skillfully staffed and well-financed pharmaceutical and biotechnology companies. Real progress requires the concerted high-quality efforts of basic, translational and clinical investigators from the academic community collaborating with counterparts from the private sector when appropriate.

Here an example what they're talking about. It looks like the sort of stuff you'd expect - backdoor maneuvering to bypass peer review and speed up funding. Texas should have expecting trouble like this; there's no way that a pot of money this size could be distributed without grief. That would be true even if everything had gone smoothly - people outside research are often amazed when they realize the sums of money that can be thrown at these problems, sometimes to little visible effect. The history of the California Institute for Regenerative Medicine (CIRM), a state-funded stem cell research effort, is instructive here - they haven't quite had the controversies that Texas has, but the voters of California may well have expected more by now than they've feel they've received, which is a side effect of stem-cell hype. Add in some favoritism and fast dealing, and you have a real recipe for trouble.

Comments (14) + TrackBacks (0) | Category: Cancer

October 11, 2012

IGFR Therapies Wipe Out. And They're Not Alone.

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Posted by Derek

Here's a look at something that doesn't make many headlines: the apparent failure of an entire class of potential drugs. The insulin-like growth factor 1 receptor (IGF-1R) has been targeted for years now, from a number of different angles. There have been several antibodies tried against it, and companies have also tried small molecule approaches such as inhibiting the associated receptor kinase. (I was on such a project myself a few years back). So far, nothing has worked out.

And as that review shows, this was a very reasonable-sounding idea. Other growth factor receptors have been successful cancer targets (notably EGFR), and there was evidence of IGFR over-expression in several widespread cancer types (and evidence from mouse models that inhibiting it would have the desired effect). The rationale here was as solid as anything we have, but reality has had other ideas:

It is hardly surprising that even some of the field's pioneers are now pessimistic. “In the case of IGF-1R, one can protest that proper studies have not yet been carried out,” writes Renato Baserga, from the department of Cancer Biology, Thomas Jefferson University in Philadelphia. (J. Cell. Physiol., doi:10.1002/jcp.24217). A pioneer in IGF-1 research, Baserga goes on to list some avenues that may still be promising, such as targeting the receptor to prevent metastases in colorectal cancer patients. But in the end, he surmises: “These excuses are poor excuses, [they are] an attempt to reinvigorate a procedure that has failed.” Saltz agrees. “This may be the end of the story,” he says. “At one point, there were more than ten companies developing these drugs; now this may be the last one that gets put on the shelf.”

But, except for articles like these in journals like Nature Biotechnology, or mentions on web sites like this one, no one really hears about this sort of thing. We've talked about this phenomenon before; there's a substantial list of drug targets that looked very promising, got a lot of attention for years, but never delivered any sort of drug at all. Negative results don't make for much of a headline in the popular press, especially when the story develops over a multi-year period.

I think it would be worthwhile for people to hear about this, though. I once talked with someone who was quite anxious about an upcoming plane trip; they were worried on safety grounds. It occurred to me that if there were a small speaker on this person's desk announcing all the flights that had landed safely around the country (or around the world), that a few days of that might actually have an effect. Hundreds, thousands of announcements, over and over: "Flight XXX has landed safely in Omaha. Flight YYY has landed safely in Seoul. Flight ZZZ has landed safely in Amsterdam. . ." Such a speaker system wouldn't shut up for long suring any given day, that's for sure, and it would emphasize the sheer volume of successful air travel that takes place each day, over and over.

On the other hand, almost all drug research programs, or never even make it off the ground in the first place. In this field, actually getting a plane together, getting it into the air, and guiding it to a landing at the FDA only happens once in a rather long while, which is why there are plenty of people out there in early research who've never worked on anything that's made it to market. A list of all the programs that failed would be instructive, and might get across how difficult finding a drug really is, but no one's going to be able to put one of those together. Companies don't even announce the vast majority of their preclinical failures; they're below everyone else's limit of detection. I can tell you for sure that most of the non-delivering programs I've worked on have never seen daylight of any sort. They just quietly disappeared.

Comments (11) + TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History

October 3, 2012

A Lovely Petite Compound

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Posted by Derek

I can't resist pointing out this compound, which recently showed up in J. Med. Chem.. Now, that's a Bcl-2/Bcl-xl inhibitor, the star of the protein-protein interaction world, and there's probably never going to be a nice-looking compound that does the job in that system. The interacting surfaces are too wide and too shallow; it's a real triumph that people have compounds for this system at all. But people have, and there are compounds in the clinic.
But man, will you look at the things. This is one from Bristol-Myers Squibb the University of Michigan, and it is a beast in all directions. It weighs a mere 811 daltons, and is actually one of the more svelte compounds in the paper. Solubility, formulation, absorption, clearance. . .it all looks like fun. But we may well have to start learning how to deal with compounds like these, so we'd better steel ourselves.

Comments (33) + TrackBacks (0) | Category: Cancer | Chemical News

September 25, 2012

CNN's Cure for Cancer

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Posted by Derek

I've been meaning to write something about the M.D. Anderson announcement of "Moon Shot" programs for cancer therapies. Mostly something about how I'm very glad that they're spending a lot of time and money on this, because there are a lot of good people there, but also about how I truly hate the "Moon Shot" analogy for R&D. As has been said for years, decades. . .the Moon landing was a stupendous feat of applied engineering, but few (if any) new principles had to be discovered along the way. Attacking cancer, though, is like trying to engineer a moon landing when you're not sure where the moon is. Or what it's made out of. Or what the various kinds of rocket fuel might be.

And the whole thing was made much, much worse by CNN, who proclaimed "Cure for Cancer Close" as some sort of exclusive scoop. That ridiculous situation is summed up well here. As it turns out, this was a combination of the M.D. Anderson press release and one of those "We could save more people just by applying our existing knowledge more thoroughly" angles. All in all, a really shoddy performance, which I hope had people both at CNN and M. D. Anderson burying their heads in their hands.

Comments (12) + TrackBacks (0) | Category: Cancer | Press Coverage

September 10, 2012

Geron, And The Risk of Cancer Therapies

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Posted by Derek

Geron's telomerase inhibitor compound, imetalstat, showed a lot of interesting results in vitro, and has been in Phase II trials all this year. Until now. The company announced this morning that the interim results of their breast-cancer trial are so unpromising that it's been halted, and that lung cancer data aren't looking good, either. The company's stock has been cratering in premarket trading, and this stock analyst will now have some thinking to do, as will the people who followed his advice last week.

I'm sorry to see the first telomerase inhibitor perform so poorly; we need all the mechanisms we can get in oncology. And this is terrible news for Geron, since they'd put all their money down on this therapeutic area. But this is drug discovery; this is research: a lot of good, sensible, promising ideas just don't work.

That phrase comes to mind after reading this article from the Telegraph about some Swedish research into cancer therapy. It's written in a breathless style - here, see for yourself:

Yet as things stand, Ad5[CgA-E1A-miR122]PTD – to give it the full gush of its most up-to-date scientific name – is never going to be tested to see if it might also save humans. Since 2010 it has been kept in a bedsit-sized mini freezer in a busy lobby outside Prof Essand's office, gathering frost. ('Would you like to see?' He raises his laptop computer and turns, so its camera picks out a table-top Electrolux next to the lab's main corridor.)
Two hundred metres away is the Uppsala University Hospital, a European Centre of Excellence in Neuroendocrine Tumours. Patients fly in from all over the world to be seen here, especially from America, where treatment for certain types of cancer lags five years behind Europe. Yet even when these sufferers have nothing else to hope for, have only months left to live, wave platinum credit cards and are prepared to sign papers agreeing to try anything, to hell with the side-effects, the oncologists are not permitted – would find themselves behind bars if they tried – to race down the corridors and snatch the solution out of Prof Essand's freezer.

(By the way, does anyone have anything to substantiate that "five years behind Europe" claim? I don't.) To be sure, Prof. Essand tries to make plain to the reporter (Alexander Masters) that this viral therapy has only been tried in animals, that a lot of things work in animals that don't work in man, and so on. But given Masters' attitude towards medical research, there's only so much that you can do:

. . .Quacks provide a very useful service to medical tyros such as myself, because they read all the best journals the day they appear and by the end of the week have turned the results into potions and tinctures. It's like Tommy Lee Jones in Men in Black reading the National Enquirer to find out what aliens are up to, because that's the only paper trashy enough to print the truth. Keep an eye on what the quacks are saying, and you have an idea of what might be promising at the Wild West frontier of medicine. . .

I have to say, in my experience, that this is completely wrong. Keep an eye on what the quacks are saying, and you have an idea of what might have been popular in 1932. Or 1954. Quacks seize onto an idea and never, ever, let it go, despite any and all evidence, so quackery is an interminable museum of ancient junk. New junk is added all the time, though, one has to admit. You might get some cutting-edge science, if your idea of cutting-edge is an advertisement in one of those SkyMall catalogs you get on airplanes. A string of trendy buzzwords super-glued together does not tell you where science is heading.

But Masters means well with this piece. He wants to see Essend's therapy tried out in the clinic, and he wants to help raise money to do that (see the end of the article, which shows how to donate to a fund at Uppsala). I'm fine with that - as far as I can tell, longer shots than this one get into the clinic, so why not? But I'd warn people that their money, as with the rest of the money we put into this business, is very much at risk. If crowdsourcing can get some ideas a toehold in the clinical world, I'm all for it, but it would be a good thing in general if people realized the odds. It would also be a good idea if more people realized how much money would be needed later on, if things start to look promising. No one's going to crowdsource a Phase III trial, I think. . . .

Comments (12) + TrackBacks (0) | Category: Cancer | Clinical Trials | Drug Development

August 10, 2012

Making Tumor Cells More Vigorous Through. . .Chemotherapy?

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Posted by Derek

Here's some food for thought: in some cases, chemotherapy may actually accelerate the growth of tumor cells. This study has found that noncancerous cells (which are also affected, to various degrees, by most chemotherapy agents) can secrete Wnt16B in response to treatment, and that this protein is taken up by nearby tumor cells.

And that's not good. Here's the full paper, which looks at prostate cells. The secretion of the Wnt protein is mediated by NF-kappa-B in response to the DNA damage caused by many therapeutic agents, and it acts as a paracrine signal for the surrounding cells. And the resulting initiation of the Wnt pathway is bad news, because that's already been implicated in tumor cell biology. Here's the bad news slide: conditioned media from cultures of the normal prostate fibroblast cells, after exposure to therapeutic agents, causes prostate tumor cells to proliferate and become more mobile, an effect that can be canceled out by blocking Wnt16b.

Finding out that this can be set off by normal cells in the neighborhood means that we may need to do some rethinking about how chemotherapy is administered. But it would also seem to open a window to block Wnt signaling as an adjunct therapy. That's already been the subject of a good amount of research, since the importance to tumor biology was already known - here's a recent review. Development of these agents now looks more useful than ever. . .

Comments (19) + TrackBacks (0) | Category: Cancer

August 9, 2012

Getting Drug Research Really, Really Wrong

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Posted by Derek

The British Medical Journal says that the "widely touted innovation crisis in pharmaceuticals is a myth". The British Medical Journal is wrong.

There, that's about as direct as I can make it. But allow me to go into more detail, because that's not the the only thing they're wrong about. This is a new article entitled "Pharmaceutical research and development: what do we get for all that money?", and it's by Joel Lexchin (York University) and Donald Light of UMDNJ. And that last name should be enough to tell you where this is all coming from, because Prof. Light is the man who's publicly attached his name to an estimate that developing a new drug costs about $43 million dollars.

I'm generally careful, when I bring up that figure around people who actually develop drugs, not to do so when they're in the middle of drinking coffee or working with anything fragile, because it always provokes startled expressions and sudden laughter. These posts go into some detail about how ludicrous that number is, but for now, I'll just note that it's hard to see how anyone who seriously advances that estimate can be taken seriously. But here we are again.

Light and Lexchin's article makes much of Bernard Munos' work (which we talked about here), which shows a relatively constant rate of new drug discovery. They should go back and look at his graph, because they might notice that the slope of the line in recent years has not kept up with the historical rate. And they completely leave out one of the other key points that Munos makes: that even if the rate of discovery were to have remained linear, the costs associated with it sure as hell haven't. No, it's all a conspiracy:

"Meanwhile, telling "innovation crisis" stories to politicians and the press serves as a ploy, a strategy to attract a range of government protections from free market, generic competition."

Ah, that must be why the industry has laid off thousands and thousands of people over the last few years: it's all a ploy to gain sympathy. We tell everyone else how hard it is to discover drugs, but when we're sure that there are no reporters or politicians around, we high-five each other at how successful our deception has been. Because that's our secret, according to Light and Lexchin. It's apparently not any harder to find something new and worthwhile, but we'd rather just sit on our rears and crank out "me-too" medications for the big bucks:

"This is the real innovation crisis: pharmaceutical research and development turns out mostly minor variations on existing drugs, and most new drugs are not superior on clinical measures. Although a steady stream of significantly superior drugs enlarges the medicine chest from which millions benefit, medicines have also produced an epidemic of serious adverse reactions that have added to national healthcare costs".

So let me get this straight: according to these folks, we mostly just make "minor variations", but the few really new drugs that come out aren't so great either, because of their "epidemic" of serious side effects. Let me advance an alternate set of explanations, one that I call, for lack of a better word, "reality". For one thing, "me-too" drugs are not identical, and their benefits are often overlooked by people who do not understand medicine. There are overcrowded therapeutic areas, but they're not common. The reason that some new drugs make only small advances on existing therapies is not because we like it that way, and it's especially not because we planned it that way. This happens because we try to make big advances, and we fail. Then we take what we can get.

No therapeutic area illustrates this better than oncology. Every new target in that field has come in with high hopes that this time we'll have something that really does the job. Angiogenesis inhibitors. Kinase inhibitors. Cell cycle disruptors. Microtubules, proteosomes, apoptosis, DNA repair, metabolic disruption of the Warburg effect. It goes on and on and on, and you know what? None of them work as well as we want them to. We take them into the clinic, give them to terrified people who have little hope left, and we watch as we provide with them, what? A few months of extra life? Was that what we were shooting for all along, do we grin and shake each others' hands when the results come in? "Another incremental advance! Rock and roll!"

Of course not. We're disappointed, and we're pissed off. But we don't know enough about cancer (yet) to do better, and cancer turns out to be a very hard condition to treat. It should also be noted that the financial incentives are there to discover something that really does pull people back from the edge of the grave, so you'd think that we money-grubbing, public-deceiving, expense-padding mercenaries might be attracted by that prospect. Apparently not.

The same goes for Alzheimer's disease. Just how much money has the industry spent over the last quarter of a century on Alzheimer's? I worked on it twenty years ago, and God knows that never came to anything. Look at the steady march, march, march of failure in the clinic - and keep in mind that these failures tend to come late in the game, during Phase III, and if you suggest to anyone in the business that you can run an Alzheimer's Phase III program and bring the whole thing in for $43 million dollars, you'll be invited to stop wasting everyone's time. Bapineuzumab's trials have surely cost several times that, and Pfizer/J&J are still pressing on. And before that you had Elan working on active immunization, which is still going on, and you have Lilly's other antibody, which is still going on, and Genentech's (which is still going on). No one has high hopes for any of these, but we're still burning piles of money to try to find something. And what about the secretase inhibitors? How much time and effort has gone into beta- and gamma-secretase? What did the folks at Lilly think when they took their inhibitor way into Phase III only to find out that it made Alzheimer's slightly worse instead of helping anyone? Didn't they realize that Professors Light and Lexchin were on to them? That they'd seen through the veil and figured out the real strategy of making tiny improvements on the existing drugs that attack the causes of Alzheimer's? What existing drugs to target the causes of Alzheimer are they talking about?

Honestly, I have trouble writing about this sort of thing, because I get too furious to be coherent. I've been doing this sort of work since 1989, and I have spent the great majority of my time working on diseases for which no good therapies existed. The rest of the time has been spent on new mechanisms, new classes of drugs that should (or should have) worked differently than the existing therapies. I cannot recall a time when I have worked on a real "me-too" drug of the sort of that Light and Lexchin seem to think the industry spends all its time on.

That's because of yet another factor they have not considered: simultaneous development. Take a look at that paragraph above, where I mentioned all those Alzheimer's therapies. Let's be wildly, crazily optimistic and pretend that bapineuzumab manages to eke out some sort of efficacy against Alzheimer's (which, by the way, would put it right into that "no real medical advance" category that Light and Lexchin make so much of). And let's throw caution out the third-floor window and pretend that Lilly's solanezumab actually does something, too. Not much - there's a limit to how optimistic a person can be without pharmacological assistance - but something, some actual efficacy. Now here's what you have to remember: according to people like the authors of this article, whichever of these antibodies that makes it though second is a "me-too" drug that offers only an incremental advance, if anything. Even though all this Alzheimer's work was started on a risk basis, in several different companies, with different antibodies developed in different ways, with no clue as to who (if anyone) might come out on top.

All right, now we get to another topic that articles like this latest one are simply not complete without. That's right, say it together: "Drug companies spend a lot more on marketing than they do on research!" Let's ignore, for the sake of argument, the large number of smaller companies that spend all of their money on R&D and none on marketing, because they have nothing to market yet. Let's even ignore the fact that over the years, the percentage of money being spent on drug R&D has actually been going up. No, let's instead go over this in a way that even professors at UMDNJ and York can understand it:

Company X spends, let's say, $10 a year on research. (We're lopping off a lot of zeros to make this easier). It has no revenues from selling drugs yet, and is burning through its cash while it tries to get its first on onto the market. It succeeds, and the new drug will bring in $100 dollars a year for the first two or three years, before the competition catches up with some of the incremental me-toos that everyone will switch to for mysterious reasons that apparently have nothing to do with anything working better. But I digress; let's get back to the key point. That $100 a year figure assumes that the company spends $30 a year on marketing (advertising, promotion, patient awareness, brand-building, all that stuff). If the company does not spend all that time and effort, the new drug will only bring in $60 a year, but that's pure profit. (We're going to ignore all the other costs, assuming that they're the same between the two cases).

So the company can bring in $60 dollars a year by doing no promotion, or it can bring in $70 a year after accounting for the expenses of marketing. The company will, of course, choose the latter. "But," you're saying, "what if all that marketing expense doesn't raise sales from $60 up to $100 a year?" Ah, then you are doing it wrong. The whole point, the raison d'etre of the marketing department is to bring in more money than they are spending. Marketing deals with the profitable side of the business; their job is to maximize those profits. If they spend more than those extra profits, well, it's time to fire them, isn't it?

R&D, on the other hand, is not the profitable side of the business. Far from it. We are black holes of finance: huge sums of money spiral in beyond our event horizons, emitting piteous cries and futile streams of braking radiation, and are never seen again. The point is, these are totally different parts of the company, doing totally different things. Complaining that the marketing budget is bigger than the R&D budget is like complaining that a car's passenger compartment is bigger than its gas tank, or that a ship's sail is bigger than its rudder.

OK, I've spend about enough time on this for one morning; I feel like I need a shower. Let's get on to the part where Light and Lexchin recommend what we should all be doing instead:

What can be done to change the business model of the pharmaceutical industry to focus on more cost effective, safer medicines? The first step should be to stop approving so many new drugs of little therapeutic value. . .We should also fully fund the EMA and other regulatory agencies with public funds, rather than relying on industry generated user fees, to end industry’s capture of its regulator. Finally, we should consider new ways of rewarding innovation directly, such as through the large cash prizes envisioned in US Senate Bill 1137, rather than through the high prices generated by patent protection. The bill proposes the collection of several billion dollars a year from all federal and non-federal health reimbursement and insurance programmes, and a committee would award prizes in proportion to how well new drugs fulfilled unmet clinical needs and constituted real therapeutic gains. Without patents new drugs are immediately open to generic competition, lowering prices, while at the same time innovators are rewarded quickly to innovate again. This approach would save countries billions in healthcare costs and produce real gains in people’s health.

One problem I have with this is that the health insurance industry would probably object to having "several billion dollars a year" collected from it. And that "several" would not mean "two or three", for sure. But even if we extract that cash somehow - an extraction that would surely raise health insurance costs as it got passed along - we now find ourselves depending on a committee that will determine the worth of each new drug. Will these people determine that when the drug is approved, or will they need to wait a few years to see how it does in the real world? If the drug under- or overperforms, does the reward get adjusted accordingly? How, exactly, do we decide how much a diabetes drug is worth compared to one for multiple sclerosis, or TB? What about a drug that doesn't help many people, but helps them tremendously, versus a drug that's taken by a lot of people, but has only milder improvements for them? What if a drug is worth a lot more to people in one demographic versus another? And what happens as various advocacy groups lobby to get their diseases moved further up the list of important ones that deserve higher prizes and more incentives?

These will have to be some very, very wise and prudent people on this committee. You certainly wouldn't want anyone who's ever been involved with the drug industry on there, no indeed. And you wouldn't want any politicians - why, they might use that influential position to do who knows what. No, you'd want honest, intelligent, reliable people, who know a tremendous amount about medical care and pharmaceuticals, but have no financial or personal interests involved. I'm sure there are plenty of them out there, somewhere. And when we find them, why stop with drugs? Why not set up committees to determine the true worth of the other vital things that people in this country need each day - food, transportation, consumer goods? Surely this model can be extended; it all sounds so rational. I doubt if anything like it has ever been tried before, and it's certainly a lot better than the grubby business of deciding prices and values based on what people will pay for things (what do they know, anyway, compared to a panel of dispassionate experts?)

Enough. I should mention that when Prof. Light's earlier figure for drug expense came out that I had a brief correspondence with him, and I invited him to come to this site and try out his reasoning on people who develop drugs for a living. Communication seemed to dry up after that, I have to report. But that offer is still open. Reading his publications makes me think that he (and his co-authors) have never actually spoken with anyone who does this work or has any actual experience with it. Come on down, I say! We're real people, just like you. OK, we're more evil, fine. But otherwise. . .

Comments (74) + TrackBacks (0) | Category: "Me Too" Drugs | Business and Markets | Cancer | Drug Development | Drug Industry History | Drug Prices | The Central Nervous System | Why Everyone Loves Us

August 8, 2012

Does Aveo's Tivozanib Work, or Not?

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Posted by Derek

What makes a cancer drug effective? What if it stops cancer from spreading when you give it to patients - is that effective, or not? This topic has come up around here before, but there may be a rather stark example of it unfolding with Aveo Pharmaceuticals and their drug tivozanib.

Earlier this year, the company announced results of a trial in renal cell carcinoma of their drug versus the Bayer/Onyx drug Nexavar (sorafenib), which is the standard of care. It's not like Nexavar does a great job in that indication, though - when it was going through clinical trials, it ran in RCC patients versus placebo, since - you guessed it - placebo was the standard of care at the time. And while Nexavar did show a benefit under those conditions, there are still plenty of patients that don't respond. Thus tivozanib, and its window of opportunity. The compound itself is in the same broad chemical class (bi-aryl ureas) as sorafenib.

The Phase III results for the Aveo drug showed an improvement in progression-free survival - tracking the time it takes for the cancer to start spreading again. But progression-free survival does not necessarily mean "survival", not in the sense that cancer patients and their relatives really care about. Dying in the same amount of time, albeit with redistributed tumor tissue, is not the endpoint that people are waiting for.

The company is, of course, monitoring the patients that it's treated. And there's the problem: the current data show, after one year, that 77% of the tivozanib-treated patients are still alive. But 81% of the sorafenib patients have survived, and the FDA has officially expressed concern about the way things are going. That sent Aveo's stock down sharply the other day, as well it might. But there could be a way out:

Aveo said in today’s statement that basically it’s possible the preliminary survival data could be misleading. That’s because in cancer trials like this one, cancer patients whose disease worsens on one drug can then go on to get a second drug which may help them. In this case, Aveo said 53 percent of the patients who were randomly assigned to get the Bayer/Onyx drug went on to get subsequent therapy after their disease worsened—and “nearly all” of them were given Aveo’s tivozanib. By contrast, only 17 percent of the patients who were randomly assigned to initially get the Aveo drug went on to get a subsequent therapy. So it’s possible that the patients in the Bayer/Onyx control group may be ending up living longer at least partly because of the Aveo drug they got later on.

We'll have to wait for more data to sort all this out. Until that point, Aveo (and its shareholders) are probably in for a bumpy ride. But it's worth remembering that renal cell carcinoma patients are having a rather harder time of it than anyone else in this story, and they're the people who will be watching this most closely of all. . .

Comments (13) + TrackBacks (0) | Category: Cancer | Clinical Trials

August 6, 2012

Novartis Bankrolls T-Cell Cancer Therapies

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Posted by Derek

You may well recall the startling results of a modified T-cell therapy against leukemia that were reported one year ago. I'm happy to report that Novartis is investing in this technology and putting their own considerable amount of development expertise into making it work on a larger scale:

“I never thought this would happen, that the pharma industry would get into ultra-personalized therapy,” (Penn scientist Carl) June said in a telephone interview. “We had lots of venture capital interest, but it’s hard to be a new company and it takes time to get set up. The fastest route to widespread availability is to use an existing company.”

Novartis was one of three companies to negotiate with the university, according to June, who declined to name the other two. Novartis was selected in part because of its experience with Gleevac, a drug used to treat chronic myeloid leukemia. . .

. . .June’s group is now treating 1 patient a week, he said. The Novartis collaboration will help more people get treatment, said June, who is a professor of pathology and laboratory medicine at the University’s Abramson Cancer Center.
In addition to further trials in leukemia, the UPenn group has also engineered trials for lymphoma, mesothelioma, myeloma, and neuroblastoma.

Ah, but in oncology, it's probably going to be the case that every patient will be the subject of personalized therapy, to some degree. So the interest from the big companies makes a lot of sense. Good luck to Novartis and the Penn team - this work has tremendous potential, and I'm very glad to see the funding and manpower come in to investigate it.

Comments (2) + TrackBacks (0) | Category: Cancer

August 3, 2012

Finding Fast Fruit Fly Feasibility

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Posted by Derek

I'm an unabashed fan of phenotypic screening. (For those outside the field, that means screening for compounds by looking for their effects on living systems, rather than starting with a molecular target and working your way up). Done right, I don't think that there's a better platform for breakthrough drug discovery, mainly because there's so much we don't know about what really goes on in cells and in whole organisms.

Doing it right isn't easy, though, nor will you necessarily find anything even if you do. But there's a recent paper in Nature that is, I think, a model of the sort of thing that we should all be thinking about. A collaboration between the Shokat group at UCSF and the Cagan group at Mt. Sinai, this project is deliberately looking for one at the trickiest aspects of drug discovery: polypharmacology. "One target, one drug" is all very well, but what if your drugs hit more than one target (as they generally do?) Or what if your patients will only be served by hitting more than one target (as many diseases, especially cancer, call for)? The complexities get out of control very quickly, and model systems would be very helpful indeed.

This work goes all the way back to fruit flies, good ol' Drosophila, and the authors picked a well-characterized cancer pathway: multiple endocrine neoplasia type 2 (MEN2). This is known to be driven by gain-of-function mutations in the Ret pathway, and patients with such mutations show a greatly increased rate of endocrine tumors (thyroid, especially). Ret is a receptor tyrosine kinase, and the receptor is one that recognizes the GDNF family of signaling peptides. As oncology pathways go, this one is fairly well worked out, not that it's led to any selective Ret inhibitor drugs so far (although many have tried and are trying).

Using this Ret-driven fly model, the teams ran a wide variety of kinase inhibitor molecules past the insects, looking for their effects, while at the same time profiling the compounds across a long list of kinase enzymes. This gives you a chance to do something that you don't often get a chance to do: match one kind of fingerprint to another kind. And what they found was that you needed "balanced polypharmacology" to get optimal phenotypic effects. The compounds that inhibited the Drosophila equivalents of Ret, Raf, Src and S6K all at the same time made the flies survive the longest. That's quite a blunderbuss list. But some very similar compounds weren't as good, and that turned out to be due to the activity on Tor. Working these combinations out was not trivial - it took a lot of different strains of flies with different levels of kinase activity, and a lot of different compounds with varying profiles.

Now, these kinases cover an awful lot of ground, as you'll know if you've worked in the field, or if you just click on those links and look at some of the pathway diagrams. There is, I think it's fair to say, no way that anyone could have identified these particular combinations with certainly without running the experiment in a real system; there are just too many branching, intersecting, ramifications to get a clear picture of what would happen. Thus, phenotypic screening: let the real system tell you.

So, you may be thinking, fruit flies. Great. Does that tell us anything real? In this case, it looks like it does. The compound profiles that were seen in the model system translated to human cell lines, and to mouse xenograft models. And while neither of those is a perfect indicator (far from it), they're about the best we have, and many are the compounds that have gone into human trials with just such data.

I look forward to more applications of this technique, to see how far it can be pushed. Ret looks like a well-chosen test case - what happens when you go on to even trickier ones? It won't be easy, but being able to unravel some of the polypharmacology when you're still back at the fruit-fly stage will be worth the effort.

Comments (9) + TrackBacks (0) | Category: Cancer | Drug Assays

July 30, 2012

Cancer Drugs: Value for the Money?

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Posted by Derek

And while we're talking oncology, here's a piece from Luke Timmerman at Xconomy that brings up a lot of tough questions. We've talked about some of these before around here, but everyone who works in oncology drug discovery is going to hear them again: How much should a new cancer therapy cost? Who's going to pay for it? Are patients (and their insurance companies) getting value for their money?

I wouldn’t go so far as to say we need a draconian system to discourage drug developers from creating new products. Drug prices are rising fast, but there are a lot of other factors contributing to increased healthcare spending. Drug companies can, and should, be able to recoup the investments they make in the form of high drug prices. But if you’re going to charge a high price for a drug, I think a company needs to have a much stronger value proposition than “Hey, we shrank tumors in half for 20 percent of patients. Now hand over your $100,000.” It needs to be more like, “Hey, my drug has an 80 percent chance of helping people with this genetic profile, and those people can expect to live an extra year, with high quality of life.” Now you’re starting to really talk about $100,000 of value.

Sadly, drug companies tend to be more interested in satisfying the short-term profit desires of their investors than they are in truly delivering cost-effective care to patients. . .

Well, it's like this: we realize that people want inexpensive drugs that work great. But we have an awful time delivering anything like that. As I've said before here, we keep swinging for those fences and missing. That's why these drugs come out, the ones that only extend life span for a limited amount of time: every one of those are drugs that people had higher hopes for, but that's how they performed in the real world, so out they come onto the market to do as best they can. And if they're only going into a small patient population, then the pricing gets set accordingly.

So we have two trend lines that are trying to intersect: the amount of money one can hope to recoup from a new cancer medication, and the amount of money that it takes to find one. They haven't quite crossed, not yet, but they're on course to. If it were less costly to develop these things, or if they delivered more value in the end, we could push them back apart. Will either of those be realized in time to help?

Comments (31) + TrackBacks (0) | Category: Cancer | Drug Prices

Bert Vogelstein on Cancer Drugs and Cancer Screening

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Posted by Derek

Here's an interesting profile of Bert Vogelstein, who has had a major impact on oncology over the years, especially in the area of cancer-associated genetic mutations. Some of his recent work bears on the question of how useful some of the newer drugs are:

Vogelstein seems to enjoy pricking balloons. Recently, he has focused on a new target: exuberance over targeted cancer drugs. He says he got interested after seeing a paper last year on melanoma therapy. It included photos of the torso of a man with melanoma who had received a new drug aimed at a mutated gene called BRAF. Before treatment, the patient's skin was riddled with metastatic tumors; soon after treatment, the tumors vanished, and the man looked perfectly healthy. Five months later, the tumors reappeared in exactly the same locations. The photos “blew my mind,” Vogelstein says. “Why do the tumors all return at roughly the same time? It's almost as miraculous as when they disappear.”

Targeted drugs for other cancers usually stop working after about the same number of months, presumably because rare resistant cells in the tumors continue to grow and ultimately proliferate. To investigate, Luis Diaz and others in the Vogelstein-Kinzler lab drew on a sensitive technique they had developed for detecting mutations in the very small amount of tumor DNA present in a cancer patient's blood. They collected a series of these “liquid biopsy” measurements from patients with advanced colorectal cancer whose tumors had become resistant to a targeted cancer drug. With Harvard University computational biologist Martin Nowak, they devised a model showing that even before the patient begins treatment, some tumor cells always carry genes with random mutations that can support resistance to targeted drugs. This form of resistance, they wrote last month in Nature, is therefore “a fait accompli.”

But the modeling study also suggested that this resistance can be delayed by combining two drugs that target different pathways. Indeed, Vogelstein and colleagues suggest that once a targeted drug has passed initial safety trials, it's so clear that single-drug therapy will fail that they consider it unethical to give patients just one such drug. “Why shouldn't you design a large, very expensive trial to incorporate more than one agent?” Vogelstein asks.

There are a lot of labs working on this "liquid biopsy" idea, and it's the sort of thing that you could only imagine doing with modern DNA sequencing technology (and modern DNA sequencing costs). A big worry, as with any screening technology, is the false positive rate. As you make finer and finer distinctions among different tumor types, the incidence of any given one in the population gets lower and lower, and thus your test has to be more and more reliable in order to avoid overdiagnosing hordes of panicked patients.

Interestingly, when I talk to people outside of the medical research field, they seem less worried about overdiagnosis than underdiagnosis (false positives versus false negatives). Psychologically, I can see how that happens - they don't want to the test to miss anyone. But being told that you do have cancer, when you really don't, is not a good outcome, considering what the therapy will put you through. And this is what makes things like the PSA test recommendation (and mammograms in younger patients) so controversial. In the push to make sure that you find every patient, you can end up harming more people than you help. "But if you just save one life. . ." goes the phrase, at least goes the phrase from people who don't realize that they might be ending the sentence with ". . .it's worth killing off a few more".

I hope that the blood test idea works out; it would be a great advance. But a less-than-optimal one could be worse than having none at all. Look for plenty of arguments about this in the coming years - I'll fill in some of the talking points in advance: "The FDA is holding back medical progress by not approving this new test". "The FDA has given in to commercial pressures by approving this faulty new test". "This test will end up hurting more people than it helps". "How can you be against cancer screening? Isn't it always worth looking?". "This is all just a disguised cost-cutting effort; they're approving this test because it's cheaper than doing better screening". "This is all just a disguised cost-cutting effort; they're not approving this test because they're afraid that too many people will be diagnosed with cancer". And so on.

Comments (11) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

July 27, 2012

Antipsychotic Drugs Against Cancer?

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Posted by Derek

One of the hazards of medicinal chemistry - or should I say, one of the hazards of long experience in medicinal chemistry - is that you start to think that you know more than you do. Specifically, after a few years and a few projects, you've seen plenty of different compounds and their activities (or lack thereof). Human brains categorize things and seek patterns, so it's only natural that you develop a mental map of the chemical space you've encountered. Problem is, any such map has to be incomplete, grievously incomplete, and if you start making too many decisions based on it (rather than on actual data), you can miss out on some very useful things.

Here's a case in point: an assay against cancer stem cells, which have been a hot research area for some time now. It may well be that some classes of tumor are initiated and then driven by such cells, in which case killing them off or inactivating them would be a very good thing indeed. This was an interesting assay, because it included control stem cells to try to differentiate between compounds that would have an effect on the neoplasm-derived cells while leaving the normal ones alone.

And what did they find? Thioridiazine is what - an old-fashioned phenothiazine antipsychotic drug. For reasons unknown, it's active against these cancer stem cells. When the authors did follow-up screening, two other compounds of this class also showed up active: fluphenazine and prochlorperazine, so I'd certainly say that this is real.

And it appears that it might actually be the compounds' activity against dopamine receptors that drives this assay. The authors found that there's a range of dopamine receptor expression in such cells, and that this correlates with the activity of the phenothiazine compounds. That's quite interesting, but it complicates life quite a bit for running assays:

Our observations of differential DR expression between normal and neoplastic patient samples strongly suggest human CSCs are heterogeneous and drug targeting should be based on molecular pathways instead of surrogate phenotypic markers.

Working out molecular pathways is hard; a lot more progress might be made at this stage of the game by running phenotypic assays - but not if they're against a heterogeneous cell population. That way lies madness.

Interesting, the phenothiazines had been reported to show some anti-cancer effects, and schizophrenic patients receiving such drugs had been reported to show lower incidences of some forms of cancer. These latest observations might well be the link between all these things, and seem to represent the only tractable small-molecule approach (so far) targeting human cancer stem cells.

But you have to cast your net wide to find such things. Dopamine receptors aren't the most obvious thing to suspect here, and ancient antipsychotics aren't the most obvious chemical matter to screen. Drop your preconceptions at the door, is my advice.

Comments (22) + TrackBacks (0) | Category: Cancer | Drug Assays | The Central Nervous System

June 28, 2012

Effects of the Health Care Law on Pharma

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Posted by Derek

Over at Forbes, Matthew Herper has some thoughts now that the major parts of the Affordable Care Act have been upheld. Among them is this on its effect on the pharma business:

Will the law actually benefit some drug companies? Many in the drug business have expressed regret about the decision to back the Affordable Care Act, even blaming former Pfizer chief Jeffrey Kindler, a Democrat, for having pushed a deal through. I think that some of this opposition is based on outdated thinking that says that even though the government already pays for a lion’s share of health care spending through Medicare and Medicaid, giving it even more control will eventually create price controls like in Europe.

This made sense when the industry made all of its money selling mass market pills such as Lipitor and Plavix, both now off-patent. But the model for many new cancer drugs (the biggest category in drug company pipelines) and for drugs for rare diseases is that the companies charge a price no individual can pay, and then try to get insurers and governments to pay for them. This is the basic strategy taken by companies like Alexion, Biomarin, and the Genzyme division of Sanofi, all of which charge hundreds of thousands of dollars per patient per year for there medicines. Getting more people insured is good for these companies. Right now Alexion and Biomarin are down, which makes little sense. Fundamentally, the success of the drug industry depends on inventing new medicines; at most, the law is neutral. . .

We'll see. I think that the high-price/low-patient-population strategy that Herper refers to will be up for revision at some point, and perhaps sooner than we expect. One of the selling points of the ACA/Obamacare was that it would (somehow) contain costs, and I still have a lot of trouble believing that it will do anything of the kind. If (when?) we find that we're still spending piles of money on health care, one of the more politically popular ways to cut costs (or at least look as if you're cutting costs) will be to go after therapies that cost six figures a year.

And this could get tricky, because any cancer drugs that are actually effective are likely to be so only for small populations (the people who have tumors that are driven by one treatable mutation, as opposed to a swarm of genomically unstable cells that can mutate their way out of attempts to shut them down). The more we learn about which drugs to give to which patients, the smaller the treatable population gets for any individual drug, and the higher the price. These lines have been heading for an intersection for some time now, and I don't see how the health care law will keep things from getting messy.

Comments (27) + TrackBacks (0) | Category: Business and Markets | Cancer | Regulatory Affairs

June 25, 2012

A Kinase Inhibitor Learns Something New

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Posted by Derek

Here's another reminder that we don't know what a lot of existing drugs are doing on the side. This paper reports that the kinase inhibitor Nexavar (sorafenib) is actually a pretty good ligand at 5-HT (serotinergic) receptors, which is not something that you'd have guessed at all.

The authors worked up a binding model for the 5-HT2a receptor and ran through lists of known drugs. Sorafenib was flagged, and was (experimentally) a 2 micromolar antagonist. As it turns out, though, it's an even strong ligand for 5-HT2b (57 nM!) and 5-HT2c (417 nM), with weaker activity on a few other subtypes. This makes a person wonder about the other amine GPCR receptors, since there's often some cross-reactivity with small molecule ligands. (Those, though, often have good basic tertiary amines in them, carrying a positive charge under in vivo conditions. Sorafenib lacks any such thing, so it'll be interesting to see the results of further testing). It's also worth wondering if these serotinergic activities help or hurt the drug in oncology indications. In case you're wondering, the compound does get into the brain, although it's significantly effluxed by the BCRP transporter.

What I also find interesting is that this doesn't seem to have been picked up by some of the recent reports on attempts to predict and data-mine potential side effects. We still have a lot to learn, in case anyone had any doubts.

Comments (18) + TrackBacks (0) | Category: Cancer | Drug Assays | The Central Nervous System | Toxicology

June 13, 2012

Live By The Bricks, Die By The Bricks

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Posted by Derek

I wanted to highlight a couple of recent examples from the literature to show what happens (all too often) when you start to optimize med-chem compounds. The earlier phases of a project tend to drive on potency and selectivity, and the usual way to get these things is to add more stuff to your structures. Then as you start to produce compounds that make it past those important cutoffs, your focus turns more to pharmacokinetics and metabolism, and sometimes you find you've made your life rather difficult. It's an old trap, and a well-known one, but that doesn't stop people from sticking a leg into it.

Take a look at these two structures from ACS Chemical Biology. The starting structure is a pretty generic-looking kinase inhibitor, and as the graphic to its left shows, it does indeed hit a whole slew of kinases. These authors extended the structure out to another loop of the their desired target, c-Src, and as you can see, they now have a much more selective compound.
But at such a price! Four more aromatic rings, including the dread biphenyl, and only one sp3 carbon in the lot. The compound now tips the scales at MW 555, and looks about as soluble as the Chrysler building. To be fair, this is an academic group, which mean that they're presumably after a tool compound. That's a phrase that's used to excuse a lot of sins, but in this case they do have cellular assay data, which means that despite this compound's properties, it's managing to do something. Update: see this comment from the author on this very point. Be warned, though, if you're in drug discovery and you follow this strategy. Adding four flat rings and running up the molecular weight might work for you, but most of the time it will only lead to trouble - pharmacokinetics, metabolic clearance, toxicity, formulation.

My second example is from a drug discovery group (Janssen). They report work on a series of gamma-secretase modulators (GSMs) for Alzheimer's. You can tell from the paper that they had quite a wild ride with these things - for one, the activity in their mouse model didn't seem to correlate at all with the concentration of the compounds in the brain. Looking at those structures, though, you have to think that trouble is lurking, and so it is.

"In all chemical classes, the high potency was accompanied by high lipophilicity (in general, cLogP >5) and a TPSA [topological polar surface area] below 75 Å, explaining the good brain penetration. However, the majority of compounds also suffered from hERG binding with IC50s below 1 μM, CyP inhibition and low solubility, particularly at pH = 7.4 (data not shown). These unfavorable ADME properties can likely be attributed to the combination of high lipophilicity and low TPSA.

That they can. By the time they got to that compound 44, some of these problems had been solved (hERG, CyP). But it's still a very hard-to-dose compound (they seem to have gone with a pretty aggressive suspension formulation) and it's still a greasy brick, despite its impressive in vivo activity. And that's my point. Working this way exposes you to one thing after another. Making greasy bricks often leads to potent in vitro assay numbers, but they're harder to get going in vivo. And if you get them to work in the animals, you often face PK and metabolic problems. And if you manage to work your way around those, you run a much higher risk of nonspecific toxicity. So guess what happened here? You have to go to the very end of the paper to find out:

As many of the GSMs described to date, the series detailed in this paper, including 44a, is suffering from suboptimal physicochemical properties: low solubility, high lipophilicity, and high aromaticity. For 44a, this has translated into signs of liver toxicity after dosing in dog at 20 mg/kg. Further optimization of the drug-like properties of this series is ongoing.

Back to the drawing board, in other words. I wish them luck, but I wonder how much of this structure is going to have to be ripped up and redone in order to get something cleaner?

Comments (39) + TrackBacks (0) | Category: Alzheimer's Disease | Cancer | Drug Development | Pharmacokinetics | Toxicology

May 18, 2012

The Genetic Diversity of Cancer Cells

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Posted by Derek

For those of you interested in the recent work on the diversity of different cancer cell genotypes inside single tumors, there's a review out that covers the field well. The authors also go into some of the major unanswered questions: does having a tumor cell population with a lot of genetic diversity correlate with a poor prognosis for treatment? Can small populations of potentially troublesome cells be identified ahead treatments that might give them too free a field to work in? Can the huge genetic diversity be reduced to a more manageable set of practical phenotypes, to make therapeutic recommendations? This will keep everyone busy for a long time to come.

Comments (3) + TrackBacks (0) | Category: Cancer

May 4, 2012

Cytotoxic? You Bet!

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Posted by Derek

Now these are the funkiest structures I've seen in quite a while. I won't spoil the surprise; if you're an organic chemist, go ahead and click on the link. This is one of those "No one's made compounds like this, so let's see if they do anything" papers, and I'd say that if you're going to do that sort of thing, you should go pretty far off the beaten path. That they have.

These compounds are - not surprisingly - said to be cytotoxic, with activity against a range of cancer cell lines. A couple of passes through the paper, and I haven't found any normal cells used as controls for all that cytotoxicity. Sad to say, the betting would be that there's no window at all. But at least I've seen a class of compounds that I'll bet has never made it into J. Med. Chem. before.

Comments (28) + TrackBacks (0) | Category: Cancer | Chemical News

March 29, 2012

Sloppy Science

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Posted by Derek

Nature has a comment on the quality of recent publications in clinical oncology. And it's not a kind one:

Glenn Begley and Lee Ellis analyse the low number of cancer-research studies that have been converted into clinical success, and conclude that a major factor is the overall poor quality of published preclinical data. A warning sign, they say, should be the “shocking” number of research papers in the field for which the main findings could not be reproduced. To be clear, this is not fraud — and there can be legitimate technical reasons why basic research findings do not stand up in clinical work. But the overall impression the article leaves is of insufficient thoroughness in the way that too many researchers present their data.

The finding resonates with a growing sense of unease among specialist editors on this journal, and not just in the field of oncology. Across the life sciences, handling corrections that have arisen from avoidable errors in manuscripts has become an uncomfortable part of the publishing process.

I think that this problem has been with us for quite a while, and that there are a few factors making it more noticeable: more journals to publish in, for one thing, and increased publication pressure, for another. And the online availability of papers makes it easier to compare publications and to call them up quickly; things don't sit on the shelf in quite the way that they used to. But there's no doubt that a lot of putatively interesting results in the literature are not real. To go along with that link, the Nature article itself referred to in that commentary has some more data:

Over the past decade, before pursuing a particular line of research, scientists. . .in the haematology and oncology department at the biotechnology firm Amgen in Thousand Oaks, California, tried to confirm published findings related to that work. Fifty-three papers were deemed 'landmark' studies. . . It was acknowledged from the outset that some of the data might not hold up, because papers were deliberately selected that described something completely new, such as fresh approaches to targeting cancers or alternative clinical uses for existing therapeutics. Nevertheless, scientific findings were confirmed in only 6 (11%) cases. Even knowing the limitations of preclinical research, this was a shocking result.

Of course, the validation attempts may have failed because of technical differences or difficulties, despite efforts to ensure that this was not the case. Additional models were also used in the validation, because to drive a drug-development programme it is essential that findings are sufficiently robust and applicable beyond the one narrow experimental model that may have been enough for publication. To address these concerns, when findings could not be reproduced, an attempt was made to contact the original authors, discuss the discrepant findings, exchange reagents and repeat experiments under the authors' direction, occasionally even in the laboratory of the original investigator. These investigators were all competent, well-meaning scientists who truly wanted to make advances in cancer research.

So what leads to these things not working out? Often, it's trying to run with a hypothesis, and taking things faster than they can be taken:

In studies for which findings could be reproduced, authors had paid close attention to controls, reagents, investigator bias and describing the complete data set. For results that could not be reproduced, however, data were not routinely analysed by investigators blinded to the experimental versus control groups. Investigators frequently presented the results of one experiment, such as a single Western-blot analysis. They sometimes said they presented specific experiments that supported their underlying hypothesis, but that were not reflective of the entire data set. . .

This can rise, on occasion, to the level of fraud, but it's not fraud if you're fooling yourself, too. Science is done by humans, and it's always going to have a fair amount of slop in it. The same issue of Nature, as fate would have it has a good example of irreproducibility this week. Sanofi's PARP inhibitor iniparib already wiped out in Phase III clinical trials not long ago, after having looked good in Phase II. It now looks as if the compound was (earlier reports notwithstanding) never much of a PARP1 inhibitor at all. (Since one of these papers is from Abbott, you can see that doubts had already arisen elsewhere in the industry).

That's not the whole story with PARP - AstraZeneca had a real inhibitor, olaparib, fail on them recently, so there may well be a problem with the whole idea. But iniparib's mechanism-of-action problems certainly didn't help to clear anything up.

Begley and Ellis call for tightening up preclinical oncology research. There are plenty of cell experiments that will not support the claims made for them, for one thing, and we should stop pretending that they do. They also would like to see blinded protocols followed, even preclinically, to try to eliminate wishful thinking. That's a tall order, but it doesn't mean that we shouldn't try.

Update: here's more on the story. Try this quote:

Part way through his project to reproduce promising studies, Begley met for breakfast at a cancer conference with the lead scientist of one of the problematic studies.

"We went through the paper line by line, figure by figure," said Begley. "I explained that we re-did their experiment 50 times and never got their result. He said they'd done it six times and got this result once, but put it in the paper because it made the best story. It's very disillusioning."

Comments (38) + TrackBacks (0) | Category: Cancer | Drug Assays | The Scientific Literature

March 20, 2012

Personalized Medicine for Cancer? Try Every Cell.

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Posted by Derek

There's more news in the area of looking at what a cancer really is, cell by cell. This topic has come up here before, and the newer sequencing technologies are going to make it a bigger and bigger deal.

This latest paper (in the NEJM) looked at samples from four patients with metastatic renal cell carcinoma (RCC). (Here are a couple of summaries if you don't have access). In the first patient, they sampled the primary tumor and a metastatic tumor from the chest wall after surgery. These were then divided into zones, and deep sequencing was done on the samples. Consistent with earlier work, they found a lot of heterogeneity:

(We) classified the remaining 128 mutations into 40 ubiquitous mutations, 59 mutations shared by several but not all regions, and 29 mutations that were unique to specific regions (so-called private mutations) that were present in a single region. We subdivided shared mutations into 31 mutations shared by most of the primary tumor regions of the nephrectomy specimen (R1 to R3, R5, and R8 to R9), pretreatment biopsy samples of the primary tumor, and 28 mutations shared by most of the metastatic regions. The detection of private mutations suggested ongoing regional clonal evolution.

A tumor, in other words, is a war zone of mutated cells. It's not so much that a single cell goes rogue and spreads out everywhere. It's that the conditions that allow a cell to become cancerous are conducive to further genetic instability, leading to a competition of different branches and mutant families within what might appear to be a single tumor sample. A single biopsy is not enough to tell you what's going on. The metastatic tumors, as you'd expect, tended to be derived from particular lineages that were more likely to break loose and spread, and then they continued to evolve in their new locations. But the nastiest cells win, and sometimes they end up looking rather similar:

Despite genetic divergence during tumor progression, phenotypic convergent evolution occurs, indicating a high degree of mutational diversity, a substrate for Darwinian selection, and evolutionary adaptation.

This sort of thing is making the earlier attempts at finding cancer biomarkers look rather naive. Not only is cancer not a single disease, and not only is a single type of cancer not a single type of cancer, but individual patients contain a multitude of different cancerous cell lines, which vary by location. We're going to have to do a lot more work to understand what's going on in there - a lot more samples, a lot more sequencing, and a lot more thought about what it all means. Personalized medicine is getting a lot more personal than we thought: cell by cell.

Comments (28) + TrackBacks (0) | Category: Cancer

March 13, 2012

Verastem's Chances

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Posted by Derek

Last fall, when Verastem announced their initial public offering, I wondered about how such an early-stage company (in such a speculative area) could plausibly offer stock. Now Nate Sadeghi-Nejad at wonders the same thing:

Biotech companies with drugs in much later stages of clinical development find it difficult to go public today, yet here was Verastem, with nary a single patient exposed to any of its drugs, selling 5.5 million shares to the public at $10 per share.

Forty days later, the minimum time period allowed by law, sell-side analysts from all five of the investment banks which took Verastem public issued glowing reports with buy ratings and price targets 50% to 100% above the current share price.

Well, this sort of thing does happen. I mean, just because an investment bank makes money off an IPO doesn't mean that it isn't just a terrific place to put your money. Right? That's because they do lots of research on these things. Right? Well, as Sadeghi shows, that research assigned a Probability of Success of 30% to Verastem's plan of finding cancer-stem-cell specific therapeutics. This in an environment where the clinical failure rate is worse than 90%, and these guys haven't even been to the clinic yet. Their lead compound is salinomycin, an ionophore antibiotic which has been shown in vitro to target tumor stem cells.

Now, that's a perfectly respectable high-risk project to take on, because it has a lot of potential to go along with the risk. But a thirty per cent chance of success? There is no preclinical oncology program in the world with a thirty per cent chance of success. That figure is laughable.

I don't wish bad fortune to Verastem - I hope that their compound works. And I don't wish bad things for their investors, although I hope that they're braced for some. We need new modes of action in cancer drugs; we need for things to work. But we also need to be honest with ourselves and with investors. Investment banks are not going to do that for you, though.

Comments (23) + TrackBacks (0) | Category: Business and Markets | Cancer

February 23, 2012

Remember When We Were Going to Eliminate Deaths from Cancer?

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Posted by Derek

When I mentioned former FDA commissioner Andy Eschenbach the other day, I alluded to some other things about his approach that have bothered me. I thought I should follow up on that, because he's definitely not the only one. You may or may not remember this business from 2003, where Eschenbach wanted to set a goal for the National Cancer Institute to "eliminate death and suffering" from cancer by 2015. Here's what Science had to say at the time:

The nation's cancer chief, National Cancer Institute (NCI) director Andrew von Eschenbach, has announced a startling new goal in the battle against cancer. His institute intends to “eliminate death and suffering” from the disease by 2015. The cancer research community is abuzz over the announcement. Some say that however well intended, the goal is clearly impossible to reach and will undermine the director's credibility.

Von Eschenbach, who has headed the $4.6 billion NCI for a year, announced the 2015 target on 11 February to his National Cancer Advisory Board. He told board members that he did “not say that we could eliminate cancer.” Rather, he continued, his goal is to “eliminate suffering and death due to this disease.” NCI is working on a strategy to do that by discovering “all the relevant mechanisms” of cancer, developing interventions, and getting treatments to patients.

We have three years to go on that deadline, and it's safe to say that we're not going to make it. And that's not because we failed to follow Eschenbach's plan, because saying that you're going to figure out everything is not a plan.

Now, I'm actually kind of an optimistic person, or so I'm told. But I'm not optimistic enough to think that we can eliminate deaths from cancer any time soon, because, well, because I've worked on drugs that have attempted to do so. As has been detailed several times here (and many times elsewhere), cancer isn't one disease. It's a constellation of thousands of diseases, all of which end up by showing uncontrolled cell growth. Calling cancer a disease is like calling headache a disease.

But I'm operating on a different time scale from Eschenbach. Here he is in 2006, in The Lancet:

“Think of it”, von Eschenbach says, “for thousands of years we have dealt with cancer working only with what we could see with our eyes and feel with our fingers, then for a 100 years we've dealt with cancer with what we could see under a microscope. Now, we have gone in 10 years to a completely different level.” This new science “is going to change how we think, it's going to change how we approach things; it's going to change everything.”

. . .He points to the example of testicular cancer. The development of treatments for this cancer was a great success, von Eschenbach says, but one that “took decades of trial and error, one trial after another, after another, after another”. That hit-and-miss approach is no longer necessary, von Eschenbach says. Now, if 10% of patients responded to a treatment, he says, “you take the tools of genomics and go back, reverse engineer it, and ask: what was different about that 10%? Well, they had an EGF [epidermal growth factor] receptor mutation, ah ha!”

Ah ha, indeed. Here's more in a similar vein. The thing is, I don't disagree with this in principle. I disagree on the scale. No one, I think, knows how to eliminate deaths from cancer other than the way we're doing it now: detailed investigation of all sorts of cancers, all sorts of cellular pathways, and all sorts of therapies directed at them. Which is all a lot of work, and takes a lot of time (and a lot of money, too, of course). It also leads to a huge array of dead ends, disappointments, and a seemingly endless supply of "Hmm, that was more complicated than we thought" moments. I don't see that changing any time soon. I'm optimistic enough to think that there is a bottom to this ocean, that it's of finite size and everything in it is, in principle, comprehensible. But it's big. It's really, really big.

There are people who defend goal statements like Eschenbach's. Such things force us to aim high, they say, they focus attention on the problem and give us a sense of urgency. Taken too far, though, this point of view leads to the fallacy that what's important is to care a lot - or perhaps to be seen to care a lot. But the physical world doesn't care if we care. It yields up its secrets to those who are smart and persistent, not to the people with the best slogans.

Comments (32) + TrackBacks (0) | Category: Cancer

February 6, 2012

Academia and Industry, Suing Each Other

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Posted by Derek

This is not the sort of academic-industry interaction I had in mind. There's a gigantic lawsuit underway between Agios and the Abramson Institute at the University of Pennsylvania, alleging intellectual property theft. There are plenty more details at PatentBaristas:

According to the complaint filed in the US District Court Southern District Of New York, the Institute was created by an agreement between The Abramson Family Foundation and the Trustees of the University of Pennsylvania. The Foundation donated over $110 Million Dollars to the Institute with the condition that the money was to be used to explore new and different approaches to cancer treatment.

Dr. Thompson later created a for-profit corporation that he concealed from the Institute. After a name change, that entity became the Defendant Agios Pharmaceuticals, Inc. Dr. Thompson did not disclose to the Institute that at least $261 million had been obtained by Agios for what was described as its “innovative cancer metabolism research platform” – i.e., the description of Dr. Thompson’s work at the Institute. Dr. Thompson did not disclose that Agios was going to sell to Celgene Corporation an exclusive option to develop any drugs resulting from the cancer metabolism research platform.

Such are the accusations. There's more of Thompson's defense in this New York Times article:

Three people with knowledge of Dr. Thompson’s version of events, two of whom would speak only on condition of anonymity because of the litigation, said that the University of Pennsylvania knew about Dr. Thompson’s involvement with Agios and even discussed licensing patents to the company, though no agreement was reached.
“When you start a company like this, you want to try to dominate the field,” said Lewis C. Cantley, another founder of Agios and the director of the cancer center at the Beth Israel Deaconess Medical Center in Boston. “The goal was to get as many patents as possible, and it was frustrating that we weren’t able to get any from Penn.”

Michael J. Cleare, executive director of Penn’s Center for Technology Transfer, declined to discuss whether negotiations had been held but said, “Yes, Penn knew about Agios.”

So, as the lawyers over at PatentBaristas correctly note, this is all going to come down to what happened when. And that's going to be determined during the discovery process - emails, meeting minutes, memos, text messages, whatever can establish who told what to whom. If there's something definitive, the whole case could end up being dismissed (or settled) before anything close to a trial occurs - in fact, that would be my bet. But that's assuming that something definite was transferred at all:

A crucial question, some patent law and technology transfer specialists said, could be whether Dr. Thompson provided patented technology to Agios or merely insights.

“If somebody goes out and forms a company and doesn’t take patented intellectual property — only brings knowledge, know-how, that sort of thing — we wouldn’t make any claims to it,” said Lita Nelsen, director of the technology licensing office at the Massachusetts Institute of Technology.

In its complaint, the Abramson institute does not cite any specific patents. It says Penn did not pursue the matter because Dr. Thompson had told the university that his role in Agios did not involve anything subject to the university’s patent policies. The lawsuit says the institute did not find out about Dr. Thompson’s role in Agios until late 2011.

There will probably be room to argue about what was transferred, which could get expensive. That accusation of not finding out about Agios until 2011, though, can't be right, since he's mentioned all over their press releases and meeting presentations at least two years before that. But no matter how this comes out, this is not the way to build trust. Not quite.

Comments (6) + TrackBacks (0) | Category: Academia (vs. Industry) | Cancer | Patents and IP

January 30, 2012

(Un)stoppable Pixantrone

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Posted by Derek

This one mixes two categories on the blog: "Regulatory Affairs" with "How Not to Do It". A small company called Cell Therapeutics (catchy name) has been developing pixantrone for last-ditch non-Hodgkin's lymphoma. You'll note from that Wikipedia article that this compound has been knocking around for a long time, and it's had a very hard road towards any sort of approval.

In 2010, an FDA advisory committee voted it down 12-0, and from the sound of things, it wasn't even that close. But the company appealed and resubmitted, since hope springs eternal and all. They were heading towards an FDA decision next week, and the company's CEO was apparently been going around to investors telling them how confident he was of approval. You see, one of the drug's major critics at the FDA, he claimed, had been disciplined for his totally unfair review of the drug back in 2010. So how could they lose?

Like this. The company has announced that they're withdrawing their application, citing communication difficulties with the FDA. I'm sure they have some. The agency keeps trying to tell the company that the drug isn't approvable, and the company keeps on not hearing it.

Comments (18) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

January 20, 2012

Zelboraf: Treat One Cancer, Speed Up Another?

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Posted by Derek

You may well recall the excitement around the late-stage clinical data for Zelboraf (vermurafenib, PLX4032) in metastatic melanoma. The drug was approved late last summer, but (like all the other therapeutic options in oncology), it has its issues.

One of those appears to be speeding up the course of squamous cell carcinoma. (Here's the NEJM article and the accompanying editorial). A significant number of patients on Zelboraf have turned up with this other form of skin cancer. To be sure, they surely had these cancerous cells beforehand (which tend to feature RAS mutations), but the effects of the drug on the MAP-kinase pathway seem to kick up their activity. (The same effect is seen on melanoma cells that don't have the V600E mutation - if you give Zelboraf without genotyping the patient first, you risk making things much worse). One obvious fix would be to give a combination, something to target those squamous cells, and thus the idea of co-administering an MEK inhibitor. Squamous cell carcinomas can be removed, and are nowhere near as bad as melanoma (particularly metastatic melanoma), but this is still a problem.

A bigger problem is that (as mentioned in my older post on this drug) resistant melanoma crops up pretty quickly after initial treatment with Zelboraf. Virtually all of the people taking the drug will eventually die of metastatic melanoma; it's just going to take longer. But how much longer, we don't know. The numbers still aren't quite in on overall survival - it's going to be more than the previous standard of care, but it's probably not going to be overwhelmingly more. Of course, the definition of "more" and the value that an individual patient places on it (or an insurance company places on it), well, those are the very things that keep us arguing about health care. Maybe that MEK co-therapy will make it an easier call?

Comments (5) + TrackBacks (0) | Category: Cancer

January 18, 2012

Fun With Epigenetics

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Posted by Derek

If you've been looking around the literature over the last couple of years, you'll have seen an awful lot of excitement about epigenetic mechanisms. (Here's a whole book on that very subject, for the hard core). Just do a Google search with "epigenetic" and "drug discovery" in it, any combination you like, and then stand back. Articles, reviews, conferences, vendors, journals, startups - it's all there.

Epigenetics refers to the various paths - and there are a bunch of them - to modify gene expression downstream of just the plain ol' DNA sequence. A lot of these are, as you'd imagine, involved in the way that the DNA itself is wound (and unwound) for expression. So you see enzymes that add and remove various switches to the outside of various histone proteins. You have histone acyltransferases (HATs) and histone deacetylases (HDACs), methyltransferases and demethylases, and so on. Then there are bromodomains (the binding sites for those acetylated histones) and several other mechanisms, all of which add up to plenty o' drug targets.

Or do they? There are HDAC compounds out there in oncology, to be sure, and oncology is where a lot of these other mechanisms are being looked at most intensively. You've got a good chance of finding aberrant protein expression levels in cancer cells, you have a lot of unmet medical need, a lot of potential different patient populations, and a greater tolerance for side effects. All of that argues for cancer as a proving ground, although it's certainly not the last word. But in any therapeutic area, people are going to have to wrestle with a lot of other issues.

Just looking over the literature can make you both enthusiastic and wary. There's an awful lot of regulatory machinery in this area, and it's for sure that it isn't there for jollies. (You'd imagine that selection pressure would operate pretty ruthlessly at the level of gene expression). And there are, of course, an awful lot of different genes whose expression has to be regulated, at different levels, in different cell types, at different phases of their development, and in response to different environmental signals. We don't understand a whole heck of a lot of the details.

So I think that there will be epigenetic drugs coming out of this burst of effort, but I don't think that they're going to exactly be the most rationally designed things we've ever seen. That's fine - we'll take drug candidates where we can get them. But as for when we're actually going to understand all these gene regulation pathways, well. . .

Comments (15) + TrackBacks (0) | Category: Biological News | Cancer | Drug Development

December 21, 2011

AstraZeneca's Problems

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Posted by Derek

Not exactly a load of happy holiday news from AstraZeneca here - they're already facing one of the nastiest patent cliffs in the industry (second only, and arguably, to Eli Lilly), and now they've had still more development compounds crash out on them.

There's olaparib (AZN-), which is an inhibitor of the DNA repair pathway enzyme PARP, Poly-ADP ribose polymerase. There are a number of PARP inhibitors making their way through the clinic, but olaparib's performance can't be giving comfort to anyone else in the field. It looked promising a couple of years ago in an ovarian cancer trial, but that, folks, was only progression-free survival. As time went on, it became clear that there wasn't going to be any benefit in overall survival, and that's what the world cares about, as it should. The compound's still in trials against other forms of cancer, and who knows, it might have better effects there. Oncology is a crap shoot if ever there was one. But ovarian cancer was the big first hope for AZ, and that's been written off.

The other compound that's hit the skids recently was TC-5214, mecamylamine, a nicotinic antagonist, which would have been a new mechanism for depression. But not if it doesn't work, and the compound missed its primary endpoint in the clinic, as I wrote about here last month. That one came in from Targacept, as olaparib came in from KuDOS, and these results have people wondering in the press about what this says about AstraZeneca's whole inlicensing strategy.

The problem is, these are two fields (cancer and depression) that have very high failure rates no matter who's doing the inlicensing. And while it's true that AZ seems to have had a lot of bad luck, some of that might just be the normal course of events if you're targeting these conditions. Having it happen while your other patents are expiring is bad, of course, but being in a position to have to depend on these therapeutic areas is a tough place to be to start with. (Not that there are a lot of safe places to work, true, but these are especially tricky). And it leads to things like this:

“AstraZeneca seems to have had more than its fair share of misfortune when it comes to the development pipeline,” analysts at Barclays Capital in London wrote in a note to investors today. “Additional development failures increase the probability that management will reassess the likely return on investment from additional R&D investment and cut costs further.”

Well, that'll really make R&D more productive. . .

Comments (15) + TrackBacks (0) | Category: Business and Markets | Cancer | The Central Nervous System

December 14, 2011

Burzynski Revisited

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Posted by Derek

Here, courtesy of Science-Based Medicine, is a comprehensive look at the Burzynski cancer clinic's methods. If you have any interest at all in cancer quackery or semi-quackery, or especially if you know of anyone desperate enough to approach the Burzynski people themselves, here's everything you need to know from a med-chem point of view.

Comments (10) + TrackBacks (0) | Category: Cancer | Snake Oil

November 29, 2011

Podcast on Avastin

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Posted by Derek

As if hearing my voice on the page isn't enough, here's a podcast I did last week with Paul Howard of the Manhattan Institute on the FDA's Avastin decision. You might think that they'd be all worked up about this (a la the Wall Street Journal's editorial page), but you might be surprised. . .

Comments (4) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

The Burzynski Cancer Treatment

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Posted by Derek

There seems to have been a recent surge in interest in the Burzynski cancer therapy in the UK. A family publicly raised a good deal of money to have their daughter flown over to Texas for the treatment, and this seems to have raised the profile of the clinic quite a bit over there.

But Dr. Burzynski and his therapy have been around for decades, and not everyone has been pleased with their results. Orac over at Respectful Insolence has (as you'd expect!) taken up this topic before, and for background I definitely suggest reading his piece. Quackwatch also has background. Put together, it seems that no one has been able to replicate Burzynski's results, despite many attempts. This does not appear to have slowed down his acceptance of patients, nor his billing of them.

Perhaps the best single reference I can give for Burzynski and his associates, though, is this blog from Wales. Rhys Morgan, a high school student, wrote earlier this year about his misgivings about all the UK publicity and fund-raising to send patients to the clinic, and for his pains he was treated to some good old-fashioned legal scare tactics. I'm glad to see that he's standing up to these, and it appears to me as if he's been giving good legal advice in doing so. From his post, it seems that the same law firm is sending out such letters to other people who've written unfavorably about the Burzynski Clinic, and has this ever been a good sign?

It would appear that Dr. Burzynski has had a good deal of time, and numerous opportunities, to provide convincing data to back up his claims. Instead, he seems to have spent his efforts at expanding the definition of the phrase "clinical trial" in response to a court order - and in sending lawyers after people who point such things out. Personally, in my review of the literature, I have seen no reason to disagree with the American Cancer Society's opinion that the value, if any, of the Burzynski therapy has not been established, and I would add that this is still the state of affairs 35 years after his initial publications.

If anyone has anything that might change my mind about that - and I'd prefer data, not legal threats - I'd be glad to review it. But you'd think that the convincing evidence would already be out there by now. 1976!

Comments (16) + TrackBacks (0) | Category: Cancer | Snake Oil

November 22, 2011

The Mouse Trap

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Posted by Derek

If you haven't seen it, this series by Daniel Engber at Slate, on the use of the mouse as a laboratory workhorse, is excellent. (And I'm not just saying that because he references some of my disparaging comments about xenograft models, although that did give me a chance to teach my kids what the word "acerbic" means).

He has a lot of good points, which will resonate with people who do research (and inform those who don't). For example, writing on the ubiquity of C57 black mice, he asks:

So one dark-brown lab mouse came to stand in for every other lab mouse, just as the inbred lab mouse came to stand in for every other rodent, and the rodent came to stand in for dogs and cats and rabbits and rhesus monkeys, the standard models that themselves stood in for all Animalia. But where is Black-6 taking us? How much can we learn from a single mouse?

A lot - but enough? That's always the background question with animal models. My take has long been that they're tricky, not always reliable, and still, infuriatingly, essential. The problem is that even things like xenograft models are terrible only on the absolute scale. On the relative scale - compared to all the other animal models for new oncology drugs - they're pretty good. And compared to not putting your drugs into an animal at all before going to humans, well. . .

Comments (18) + TrackBacks (0) | Category: Animal Testing | Cancer

November 21, 2011

Avastin Coverage, Amended

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Posted by Derek

In response to the press coverage on the FDA's Avastin decision on Friday, a reader forwarded a revised and extended version of the New York TImes article that appeared soon afterwards. Here are some excerpts, which I think get across the thinking of many medicinal chemists and drug researchers. His contributions are bolded for emphasis, although it's not all that hard to see where the original ends and his revisions start.

"The commissioner of the Food and Drug Administration on Friday revoked the approval of the drug Avastin as a treatment for breast cancer, ruling in an emotional issue that pitted the hopes of some desperate patients against the statistics of clinical trials, two things that should never be compared, because that would be stupid.

The commissioner, Dr. Margaret A. Hamburg, said that the drug was not helping breast cancer patients to live longer or control their tumors, but did expose them to potentially serious side effects such as severe high blood pressure and hemorrhaging, making her decision very easy.

. . .The F.D.A. “recognizes how hard it is for patients and their families to cope with metastatic breast cancer and how great a need there is for more effective treatments. But patients must have confidence that the drugs they take are both safe and effective for their intended use.” Also, they shouldn’t take drugs that don’t work, so we thought that is was important that they stop eating 88 thousand dollar magic beans, and instead use drugs and medical procedures that work.

. . .Avastin will remain on the market as a treatment for other types of cancers, including forms of cancer that it actually treats, so doctors can use it off-label for breast cancer if they hate science. But some insurers might no longer pay for the drug, which would put it out of reach of many women because it costs about $88,000 a year.

Yet pressure came from the other direction as well the outcome was certain once the statistical analysis was done, so this could have been a much shorter article. The administration had pledged to make scientific decisions on the basis of science, which seems like a pretty good idea as well. That made it difficult for Dr. Hamburg to go against the pharmaceutical lobby, and easy to accept the conclusions of the F.D.A.’s own staff and the strong recommendations of the outside experts on its advisory committee.

. . .An initial clinical trial showed that Avastin, when combined with the drug (paclitaxel), delayed appeared to delay the progression of disease by about five and
a half months, compared to use of paclitaxel alone. However, the women who received
Avastin in the study did not live significantly longer and they suffered more side effects. As an example, high doses of sodium cyanide completely stops the progression of disease almost immediately and permanently, though women who receive this treatment don’t live as long and suffer more serious side effects from the control group.

. . .Many breast cancer specialists say that Avastin does appear to work very well for some patients, but that the effect gets drowned in a clinical trial that looks at overall results. Some doctors and patient advocates argued the drug should remain available for that reason. Representatives from large sugar companies also noted that their drug, placebo, works very well for some patients, but that effect is usually gets drowned in a clinical trial that looks at overall results. The FDA has yet to approve placebo for the treatment of breast cancer."

Comments (23) + TrackBacks (0) | Category: Cancer | Press Coverage | Regulatory Affairs

November 18, 2011

Avastin's Metastatic Breast Cancer Approval Revoked

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Posted by Derek

Here's the FDA's decision (70 page PDF). As I've said here many times, I think that this is the right decision. A key section:

. . .As noted, FDA may withdraw an accelerated approval when confirmatory trials fail to confirm clinical benefit, or when the evidence does not show that the drug is safe and effective. However, the agency also carefully considers the effect on current and future patients of such a decision, and there may be circumstances, in particular cases, that would lead the agency to conclude that it would be appropriate to exercise discretion and leave an approval in place pending further study. This is not such a case.

Accelerated approval was based on the results of E2100, which showed an effect on (progression-free survival) that would be large enough to constitute clinical benefit, despite the known risks of Avastin, which are serious. However, we now have five trials, and they have substantially changed our view of this drug. The current evidence no longer supports a determination that it has a strong effect in metastatic breast cancer, and it appears likely that its effects are very weak, while the risks associated with this drug remain serious and potentially life-threatening.

There's going to be a lot of commentary, not all of it very informed, to the effect that this decision is a price-driven attempt to bring down health care costs, an assault on medical progress, the opening salvo of Obamacare, and so on. Wrong.

Avastin doesn't work as well as we thought it did for this indication. If you're going to believe in medical progress at all, you have to believe in what multiple well-controlled clinical trials are telling you - trials carried out, keep in mind, by the drug company that has every interest in having them come out favorably. But they didn't. On medical grounds, on scientific grounds, this was the right decision.

Comments (12) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

November 17, 2011

Brain Cells: Different From Each Other, But Similar to Something Else?

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Posted by Derek

Just how different is one brain cell from another? I mean, every cell in our body has the same genome, so the differences in type (various neurons, glial cells) must be due to expression during development. And the differences between individual members of a class must be all due to local environment and growth - right?

Maybe not. I wasn't aware of this myself, but there's a growing body of evidence that suggests that neurons might actually differ more at the genomic level than you'd imagine. A lot of this work has come from the McConnell lab at the Salk Institute, where they've been showing that mouse precursor cells can develop into neurons with various chromosomal changes along the way. And instead of a defect (or an experimental artifact), he's hypothesized that this is a normal feature that helps to form the huge neuronal diversity seen in brain tissue.

His latest work used induced pluripotent cells transformed into neurons. Taking these cells from two different people, he found that the resulting neurons had highly variable sequences, with all sorts of insertions, deletions, and transpositions. (The precursor cells had some, too, but different ones, suggesting that the neural cell changes happened along the way). And this recent paper suggests that neurons have an unusual number of transposons in their DNA, which fits right in with McConnell's results.

The implication is that human brains are mosaics of mosaics, at the cell and sequence levels. And that immediately makes you wonder if these processes are involved in disease states (hard to imagine how they wouldn't be). The problem is, it's not too easy to get ahold of well-matched and well-controlled human brain tissue samples to check these ideas. But that's the obvious next step - take several similar-looking neurons and sequence them all the way. Obvious, but very difficult: single-cell sequencing is not so easy, to start with, and how exactly do you grab those single neurons out of the tangle of nerve tissue to sequence them? Someone's going to do this, but it's going to be a chore. (Note: McConnell's group was able to do the pluripotent-cell-derived stuff a bit more easily, since those come out clonal and give you more to work with).

Now, the idea that neurons are taking advantage of chromosomal instability to this degree is a little unnerving. That's because when you think of chromosomal instability, you think of cancer cells (See also the link in that last paragraph. It's interesting, as an aside, to see that those last two are to posts from this blog in 2002 - next year will mark ten years of this stuff! And I also enjoy seeing my remark from back then about "With headlines like this, I can't think why I'm not pulling in thousands of hits a day", since these days I'm running close to 20K/day as it is).

So, on some level, are our brains akin to tumor tissue? You really wonder why brain cancer isn't more common than it is, if these theories are correct. There may well be ways to get "controlled chromosomal instability", though, as opposed to the wild-and-woolly kind, but even the controlled kind is a bit scary. And all this makes me think of a passage from an old science fiction story by James Blish, "This Earth of Hours". The Earthmen have encountered a bizarre civilization that seems to involve many of the star systems toward the interior of the galaxy, and a captured human has informed them that these aliens apparently have no brains per se:

"No brains," the man from the Assam Dragon insisted. "Just lots of ganglia. I gather that's the way all of the races of the Central Empire are organized, regardless of other physical differences. That's what they mean when they say we're all sick - hadn't you realized that?"

"No," 12-Upjohn said in slowly dawning horror. "You had better spell it out."

"Why, they say that's why we get cancer. They say that the brain is the ultimate source of all tumors, and is itself a tumor. They call it 'hostile symbiosis.' "


"In the long run. Races that develop them kill themselves off. Something to do with solar radiation; animals on planets of Population II stars develop them, Population I planets don't."

The things you pick up reading 1950s science fiction. Blish, by the way, was an odd sort. He had a biology degree, and a liking for James Joyce, Oswald Spengler, and Richard Strauss. All of these things worked their ways into his stories, which were often much better and more complex than they strictly needed to be. Here's a PDF of "This Earth of Hours", if you're interested - it's not a perfect transcription, though; you'll have to take my word for it that the original has no grammatical errors. It's a good illustration of Blish's style - what appears at first to be a pulpy space-war story turns out to have a lot of odd background dropped into it, along with speculations like the above. And for someone who didn't always write a lot of descriptive prose, preferring to let philosophical points drive his plots, I find Blish's stories strangely vivid, particularly the relatively actionless ones like "Beep" or "Common Time". He's pretty thoroughly out of print these days, but you can find the paperbacks used, and in many cases as e-books. Now if you're looking for someone who always lets philosophical points drive his stores, then you'll be wanting some Borges. (As it happens, I've had occasion to discuss that particular translation with an Argentine co-worker. But this is not a literary blog, not for the most part, so I'll stop there!)

Comments (30) + TrackBacks (0) | Category: Biological News | Book Recommendations | Cancer | The Central Nervous System

November 15, 2011

Geron, Stem-Cell Pioneers, Drop Stem Cells

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Posted by Derek

Are stem cells overhyped? That topic has come up around here several times. But there have been headlines and more headlines, and breathless reports of advances, some of which might be working out, and many of which are never heard from again. (This review, just out today, attempts to separate reality from hype).

Today brings a bit of disturbing news. Geron, a company long associated with stem cell research, the company that started the first US trial of embryonic stem cell therapy, has announced that they're exiting the field. Now, a lot of of this is sheer finances. They have a couple of oncology drugs in the clinic, and they need all the cash they have to try to get them through. But still, you wonder - if their stem cell trial had been going really well, wouldn't the company have gotten a lot more favorable publicity and opportunities for financing by announcing that? As things stand, we don't know anything about the results at all; Geron is looking for someone to take over the whole program.

As it happens, there's another stem-cell report today, from a study in the Lancet of work that was just presented at the AHA. This one involves injecting heart attack patients with cultured doses of their own cardiac stem cells, and it does seem to have helped. It's a good result, done in a well-controlled study, and could lead to something very useful. But we still have to see if the gains continue, what the side effects might be, whether there's any advantage to doing this over other cell-based therapies, and so on. That'll take a while, although this looks to be on the right track. But the headlines, as usual, are way out in front of what's really happening.

No, I continue to think that stem cells are a very worthy subject of research. But years, quite a few years, are going to be needed before treatments using them can become a reality. Oh, and billions of dollars, too - let's not forget that. . .

Comments (12) + TrackBacks (0) | Category: Biological News | Business and Markets | Cancer | Cardiovascular Disease | Press Coverage

November 3, 2011

Verastem Goes Public: Why Not?

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Posted by Derek

Doesn't this seem just a bit. . .early. . .for an IPO? In this climate?

Chris Westphal, a founder of Sirtris and a fixture of Cambridge/Boston biotech startup culture, helped to launch a company called Verastem in the middle of 2010. They're concentrating on the role of stem cells in cancer, a very interesting field (and one that a lot of other oncology players are interested in as well). And rather to everyone's surprise, they've now announced that they're going public. No, there's no compound, nothing heading for the clinic in the foreseeable future. They're just going public, presumably because the equity markets are in such a placid, welcoming mood or something.

Their plan seems to be to develop assays based on stable populations of cancer stem cells, and then to find compounds that selectively target them and develop these into drug candidates. Each step of that process is very much an open question, and is most definitely not trivial. It's a very worthy area of research, don't get me wrong - but it does seem odd to be going public at this stage with it, when there's so little for potential investors to evaluate. And it's worth noting that Verastem raised $32 million in financing just back in July. Are they already plowing through that? The IPO looks to raise about another $50 million - is that a sum that just couldn't be brought in via private investors?

Those are other questions will get aired out extensively in the weeks to come. We'll see how smoothly this all goes - and a lot of other small companies will be watching as well. One first reaction hasn't been too favorable: over on Twitter, biotech watcher Adam Feuerstein says "Christoph Westphal is why the clubby, VC-back scratching world of private biotech is derided by public investors". They'll soon get their chance to deride in person!

Comments (21) + TrackBacks (0) | Category: Business and Markets | Cancer

Medivation Comes Through With MDV3100

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Posted by Derek

Remember Medivation? That's the small biotech that was trying to develop a Russian compound as an Alzheimer's drug, an effort which blew up completely in early 2010. The company did have one other compound in development, targeting prostate cancer, a ligand for the androgen receptor called MDV3100.

You'll note from that link that it's a rather odd-looking compound, a thiohydantoin, which is a heterocycle that you don't see very often. The discovery of the compound is detailed here, in a collaboration between Michael Jung's group at UCLA and Charles Sawyers' at Sloan-Kettering (here's an interview with him). It's been a long road. The starting point was another known ligand, RU 59063, which comes out of research in France in the early 1990s. The whole left-hand side of MDV3100 (including the thiohydantoin) comes from that scaffold, but it behaves differently on the androgen receptor. Taking advantage of the wild and often intractable complexity of nuclear receptor signaling, it binds in a different mode than other AR ligands, and in a way that the receptor loses its ability to further bind DNA in the nucleus.

Here's the J. Med. Chem. paper (in open-access form) on the development of the series. The compounds were pushed through relatively quickly in cellular assays and in an in vivo model in mice, which allowed MDV3100 and its close analogs to stand out not only for their superior activity on the androgen receptor (which many compounds in the series had), but for their pharmacokinetics. Interestingly, the lead compound for some time seems to have been a spiro-cyclobutyl analog (RD162), but the corresponding gem-dimethyl compound was just as active and a lot easier to make, so that one became the clinical candidate.

Medivation's Phase III trial of the compound came in with data yesterday, and it was startlingly good, so much so that the trial was stopped early and the placebo group switched to the drug. The company's stock is going through the top of the chart in pre-market trading as I write, which shows that the expectations weren't all that high. But MDV3100 certainly seems to have come through, and considering how much failure we live with in drug discovery, it's nice to see something actually outperform. Congratulations to the company, and to Jung and Sawyers as well - they've added another straight-out-of-academia drug to the list, and helped to considerably advance the standard of care in prostate cancer. Good news all around.

Oh, and by the way. . .you have to wonder if this guy stuck around for this result. It all depends on what price he was in at - after today's trading, Medivation's stock might even make it up past where it was back when everyone was hoping that they had an Alzheimer's drug. Expectations!

Comments (12) + TrackBacks (0) | Category: Cancer | Clinical Trials

November 1, 2011

Exelixis Fights City Hall, and City Hall Looks Like Winning

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Posted by Derek

So what happens when you and the FDA disagree on the clinical trials needed to show efficacy for your new drug? Well, this happens: your stock opens down 40%. That's what's going on with Exelixis today - here are the details. Basically, the company had a fast clinical path in mind, taking their prostate cancer candidate cabozantinib into late-stage patients and using pain reduction as an endpoint. But the FDA wasn't (and isn't) buying that as a marker.

I see their point. Survival is really what you're looking for, and there doesn't seem to be enough evidence that pain reduction is going to translate to that. As that Adam Feuerstein piece notes, all the other prostate drugs have had to show survival benefits. EXEL was planning to follow up with a second trial to show that, but hoped to jump-start things by getting approval just on the pain data. It appears that they're going to stick with their strategy and hope that the numbers are so dramatic that the agency will reverse course. But is that realistic - both for the chances of getting great data and the chances of persuading the FDA? The market doesn't think so. Neither do I.

Comments (17) + TrackBacks (0) | Category: Business and Markets | Cancer | Clinical Trials

October 14, 2011

Avastin: False Hope for Metastatic Breast Cancer

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Posted by Derek

There should be a decision soon on the controversial Avastin-for-metastatic-breast-cancer indication. I've written about that several times here, and my position is unchanged: the preliminary clinical data made it worth a provisional approval, but the follow-up data didn't back it up. This happens. The provisional approval should, I think, be withdrawn, because based on the best evidence we have (which is a lot more than we had when the approval was granted), Avastin is not effective for metastatic breast cancer, and carries notable risks all its own.

Now, via NPR's Scott Hensley, I see that one of the members of the FDA's committee on this issue has published a letter in the New England Journal of Medicine explaining his vote. Says Mikkael Sekeres of the Cleveland Clinic:

"The responsibility of ODAC is to carefully consider the scientific data presented as part of an FDA application for a cancer drug and weigh the benefits that the drug may provide to patients with cancer against the risks posed by the drug's side effects. We try to be dispassionate, but we always think about the person we face in clinic sitting a foot or two away from us in our cramped examination rooms, waiting to hear what treatment we can offer to get rid of her cancer. What kind of conversation would I have with such a patient if I were trying to convince her to take a treatment like this?

“Well, I can offer you a drug that will not make you live longer, won't make you feel better, and may have life-threatening side effects, but it will keep your cancer from worsening by an average of 1 to 2 months.”

Hope? Or false hope?"

Survival is the first thing you have to consider with a cancer therapy. And right next to it comes quality of life, because extending someone's life for a brief period at the cost of horrible side effects is no bargain, either. Should women with metastatic breast cancer take Avastin? It does not, as far as anyone can tell, extend their lives. And it does not improve their quality of life - if anything, it makes it worse. Avastin can be a good drug against other forms of cancer, but it's not for this one. I very much hope the FDA follows the recommendation of the advisory panel.

Comments (22) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

October 11, 2011

Too Many Cancer Drugs? Too Few? About Right?

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Posted by Derek

According to Bruce Booth (@LifeSciVC on Twitter), Ernst & Young have estimated the proportion of drugs in the clinic in the US that are targeting cancer. Anyone want to pause for a moment to make a mental estimate of their own?

Well, I can tell you that I was a bit low. The E&Y number is 44%. The first thought I have is that I'd like to see that in some historical perspective, because I'd guess that it's been climbing for at least ten years now. My second thought is to wonder if that number is too high - no, not whether the estimate is too high. Assuming that the estimate is correct, is that too high a proportion of drug research being spent in oncology, or not?

Several factors led to the rise in the first place - lots of potential targets, ability to charge a lot for anything effective, an overall shorter and more definitive clinical pathway, no need for huge expensive ad campaigns to reach the specialists. Have these caused us to overshoot?

Comments (22) + TrackBacks (0) | Category: Cancer | Clinical Trials | Drug Development | Drug Industry History

September 27, 2011

So, How Come You're So Darn Lucky, Eh?

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Posted by Derek

Now here is a fascinating piece of work for anyone who's invested in the small pharma/biotech sector. The authors looked over the stocks of companies developing cancer therapies, ones that have had critical Phase III results or regulatory decisions announced over the past ten years. And they looked at the trading in their stocks, for 120 days before and after the announcements. What, do you suppose, did they discover in this exercise?

Uh-huh. You have surely guessed correctly:

The mean stock price for the 120 trading days before a phase III clinical trial announcement increased by 13.7% for companies that reported positive trials and decreased by 0.7% for companies that reported negative trials. . .Trends in company stock prices before the first public announcement differ for companies that report positive vs negative trials. This finding has important legal and ethical implications for investigators, drug companies, and the investment industry.

Indeed it does. Interestingly, the authors did not find such a split around announcements of FDA regulatory decisions, suggesting that insider trading there is not as big a problem compared to what goes on from inside the industry.

But wait - there's more, as they say in the infomercials. In a follow-up commentary on the article, Mark Ratain of Chicago and Adam Feuerstein of (who certainly has seen his share of market shenanigans) find another striking disparity in the data:

This analysis demonstrated a remarkable difference between companies that had positive and negative announcements. Specifically, the median market capitalization was approximately 80-fold greater for the companies with positive trials vs companies with negative trials. . .Furthermore, there were no positive trials among the 21 micro-cap companies (ie, companies with less than $300 million market capitalization, whereas 21 of 27 studies reported by the larger companies analyzed (greater than $1 billion capitalization) were positive.

That makes sense, as they point out: these small-cap stocks had such low valuations for a reason: because investors thought that the drugs weren't going to work, and in most cases, no larger companies had been willing to put up money on them, either. The oncology Phase III success rate for larger companies is comparable to therapeutics areas in the rest of the industry; the Phase III success rate for micro-cap oncology companies is catastrophic.

Comments (7) + TrackBacks (0) | Category: Business and Markets | Cancer | The Dark Side

September 15, 2011

Terra Slightly Less Incognita

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Posted by Derek

Back last year I did a brief post about how much not-so-exotic druglike chemical matter has never been explored. My example was substituting heteroatoms into the steroid nucleus - hard to get much more medicinally active than those, but most of the possible variations have never been made. Structurally they're right next door to things that have been known for decades, but they're largely unexplored (which is many cases is because they're not all that easy to make).
The RSC/SCI symposium called my attention to something in this exact class, abiraterone, a CYP17 inhibitor. This was discovered at the Institute for Cancer Research in London, and after several steps through the development world has ended up with J&J. It was approved by the FDA earlier this year for some varieties of prostate cancer.

So there's an example of a sorta-steroid making it all the way through. If intelligent (and oddly motivated) aliens landed tomorrow and forced me to use their advanced organic synthesis techniques to generate a library of unique structures with high hit rates in drug screens, I think I might ask them if they knew how to scatter basic amines, ethers, sulfonamides and so on in and around the steroid nucleus. I offer that advice free of charge to any readers who might find themselves in a similar situation.

Update: as per the comments, compare Cortistatin A for another, more highly modified steroid nucleus with an aromatic heterocycle hanging off it.

Comments (16) + TrackBacks (0) | Category: Cancer | Chemical News

August 12, 2011

A Startlingly Good Leukemia Trial

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Posted by Derek

You've probably seen the headlines about a new experimental treatment for leukemia. For once, the excitement seems justified - this is a remarkable and very promising result, and it's worth taking a close look at it.

As reported in the New England Journal of Medicine, a patient in this study had been diagnosed with chronic lymphoid leukemia (CLL) since 1996. In this condition, B cells proliferate uncontrollably, piling up in the bone marrow and the lymph nodes. This patient had run through several courses of chemotherapy over the years. He would go for periods with no signs of disease, but it would always come back (in harder-to-treat form, naturally). By the time of this study, he was in bad shape and running out of options. Those, frankly, are the patients who are appropriate to enroll in a trial like this one - you want to treat cancer with what we know can treat it before going to something that might well not work at all (or might even make things worse).

And this particular idea had not shown as much promise in the past as everyone had hoped, despite being immunologically reasonable. The idea is to take T-cells from the patient and modify them to express a new antigen receptor, then infuse them back in and let them go to work on the tumor cells. But previous attempts to do this (against lymphoma, ovarian cancer, and neuroblastoma) hadn't had much effect, since the modified T cells had apparently not proliferated once back in the patient. Without the cells taking off on their own, it really doesn't seem feasible to infuse enough of them from outside to show a significant effect.

In this case, the chimeric antigen receptor (CAR) was designed to go after CD19, a surface protein found on all B-cells. That's as solid a target as you could find for treating CLL, but without something new, trying to have engineered T cells clear them out would very likely fall short in this case as well. But this time, the T-cells were outfitted (via a lentivirus vector) not only with the anti-CD19 CAR, but with signaling domains from CD3-zeta and CD137. These are known to be involved with (respectively) coupling surface antigen recognition to intracellular processes and with T-cell proliferation in general. Animal studies had suggested that this combination could deliver a more robust response from the T-cells after being sent back.

And a robust response is what happened. Before treatment, the patient was given a drug regiment to deplete his lymphocytes (in order to give the new T cells a clear field to work in), and at that point his bone marrow was found to be widely infiltrated by cancerous B cells. He then went through three consecutive days of infusions with his own T cells, 5% of which had been modified. Nothing untoward happened during this stage. And in fact, it doesn't appear as if much at all happened for a couple of weeks, which must have had everyone wondering.

But on day 14, the patient started experiencing chills and fever, followed by nausea and enough severe flu-like symptoms to send him into the hospital. Blood work showed no evidence of infection, but large increases in uric acid, lactate dehydrogenase, and other factors, with signs of kidney damage as well. But this was actually good news. Because at this same time, more than20% of his circulating lymphocytes turned out to be the engineered T cells, which had indeed proliferated and were vigorously going after the B cells of the leukemia. (At this point, it wouldn't surprise me if the folks running the study were beginning to wonder what they'd turned loose). The patient's kidneys were, in fact, having a hard time keeping up with the amount of cellular debris that they were being asked to sweep out of the blood stream; he lost over a kilo of cancerous cells.

On day 23, there was no evidence of CLL in the patient's bone marrow. The swollen lymph glands had resolved, and a CT scan confirmed that the masses seen before treatment had disappeared. None of the cancerous B-cell types that were present before the therapy (two clones, both with mutations in p53) could be detected. Ten months later, they still can't. As far as can be told, this case of refractory leukemia has been completely cured.

Two of the three patients treated in this fashion showed this effect - the third still shows signs of leukemia in the bone marrow, but appears to be asymptomatic. Most interestingly, it appears that the T-cell effect is persistent, and may continue as a "surveillance" mechanism in the treated patients.

Now, this is all excellent news, because this sort of therapy can be adapted to a wide variety of tumors. The main requirement is that there is some sort of surface antigen that's specific to the tumor type, but that still leaves you with a wide field to work in. It's important to note, though, that in one way this experiment did something quite strange: it worked much better than anyone expected. The dose of engineered T cells was much smaller than used in previous trials, and was deliberately chosen to be on the low side because no one was quite sure what to expect. Given the response, that was certainly a good move. I've no idea what would have happened if the therapy had been more aggressive, but it couldn't have been good.

I hope, though, that everyone involved is enjoying this as much as possible, because this is a rare event indeed. Having things go suddenly, crazily right in a clinical trial is a once-in-a-career thing, if ever. The field of immunological cancer therapy has been given a huge boost, and now all the other groups working in the area have a huge motivation to spur them on. This is potentially some of the best oncology news in years, so let's hope that it continues to work out.

Comments (43) + TrackBacks (0) | Category: Cancer

August 8, 2011

More On Cancer Drug Shortages

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Posted by Derek

I wrote here back in June about the growing problem of shortages of oncology drugs. The blog post I linked to then (at Marginal Revolution) blamed regulatory factors and price controls as two major contributors to the shortages, but pointed out that you can't point your finger at just one factor. A pile of them, taken together, can gum up the system enough to cause trouble.

Now Ezekiel Emanuel in the New York Times has weighed in with a good editorial on the situation, and it blames. . .price controls and regulatory factors. For those who thought I was engaging in dangerous FDA-bashing in my last post, here's another factor to consider:

Historically, this “buy and bill” system was quite lucrative; drug companies charged Medicare and insurance companies inflated, essentially made-up “average wholesale prices.” The Medicare Prescription Drug, Improvement and Modernization Act of 2003, signed by President George W. Bush, put an end to this arrangement. It required Medicare to pay the physicians who prescribed the drugs based on a drug’s actual average selling price, plus 6 percent for handling. And indirectly — because of the time it takes drug companies to compile actual sales data and the government to revise the average selling price — it restricted the price from increasing by more than 6 percent every six months.

The act had an unintended consequence. In the first two or three years after a cancer drug goes generic, its price can drop by as much as 90 percent as manufacturers compete for market share. But if a shortage develops, the drug’s price should be able to increase again to attract more manufacturers. Because the 2003 act effectively limits drug price increases, it prevents this from happening. The low profit margins mean that manufacturers face a hard choice: lose money producing a lifesaving drug or switch limited production capacity to a more lucrative drug. . .You don’t have to be a cynical capitalist to see that the long-term solution is to make the production of generic cancer drugs more profitable.

What many people don't realize is that the US has some of the cheaper generic medicines in the world, on average. But a solution that involves allowing drug companies (even the generic ones) to make more money is going to be politically difficult to implement. . .

Comments (14) + TrackBacks (0) | Category: Cancer | Drug Prices

August 4, 2011

Dendreon: Watch the Cost Curve Being Bent

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Posted by Derek

Dendreon has made a lot of news over the last few years with its Provenge prostate cancer therapy. This is the immunological "cancer vaccine" treatment that had such a wild ride through the FDA (and gave DNDR and its investors such a wild ride in the stock market, including some weirdness that I'm not sure ever was explained).

Well, the company is back in the news, and not in a good way. They've been selling Provenge for a while now, but have had all kinds of manufacturing woes (as you might expect from something as complex as personalized immunology). But they've apparently been working through all that, so investors were very much anticipating the company's earnings report yesterday. Unfortunately, they got one.

The company missed all the earnings forecast by an ugly margin, which has really caught everyone by surprise. Worse for them, the reason for the miss is reimbursement. Health insurance companies, in other words, are balking at paying Dendreon's price. And you know, they have a right to. The tug-of-war between drug companies and insurance is the closest thing we have to a free market in the whole drug business, and we might as well get what benefits from it we can.

You can fill in the arguing points: "I'm a prostate cancer patient, and I want to be treated with Provenge" "Fine, but as your insurance carrier, I'm telling you that it's too expensive for what it does. We're not paying for it - if you want it, buy some yourself." "But I can't - you know that - and should my own health be held hostage to how much I can afford to pay?" "Should we be held hostage to how much you want us to spend on you?" "Fine, let's get the government involved - don't I have a right to health care?" "Not seeing that in so many words in the Constitution - but even so, would it give you the right to the most expensive health care there is? Who pays for that? If you want to get the government involved, make them whack the company until they lower their price." And so on.

No, this is what bending the infamous cost curve really looks like. If a company finally prices its products over what the market will bear (and remember, the market in this case is made up of insurance providers), its sales will fall, and it'll either have to persuade its customers that the price is worth it, or it'll have to find a way to offer its good more cheaply (most likely by accepting lower profits). No one wants to give in, no one's particularly happy. But it's probably the only way to arrive at something approaching a right answer.

Update: There's also a theory on Wall Street that the real problem is that demand for Provenge isn't strong enough, and that the company is spinning this as a reimbursement problem. Here's Adam Feuerstein with that take - it'll be interesting to see if that's right. Has the price point at which insurance will balk still not been hit?

Comments (16) + TrackBacks (0) | Category: Business and Markets | Cancer | Drug Prices

July 8, 2011

The Duke Cancer Scandal and Personalized Medicine

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Posted by Derek

Here's a good overview from the New York Times of the Duke scandal. Basically, a team there spent several years publishing high-profile papers, and getting high-profile funding, and treating cancer patients based on their own tumor-profiling biomarker work. Which was shoddy, as it turns out, and useless, and wasted everyone's time, money, and (in some cases) the last weeks or months of people's lives. I think that about sums it up. It was Keith Baggerly at M. D. Anderson who really helped catch what was going on, and Retraction Watch has a good link to his presentation on the whole subject.

The lead investigator in this sordid business, Anil Potti, ended up retracting four papers on the work and left Duke last fall (although he's since resurfaced at a cancer treatment center in South Carolina). That's an interesting hiring decision. Looking over the case (and such details of it as Potti lying about having a Rhodes Scholarship), I don't think I'd consider hiring him to mow my yard. Perhaps that statement will be something for his online reputation management outfit to deal with.

But enough about Dr. Potti himself; I hope I never hear about him again. What this case illustrates are several very important problems with the whole field of personalized medicine, and with its public perception. First off, for some years now, everyone has been hearing about the stuff: the coming age of individual cancer treatment, biomarkers, zeroing in on the right drugs for the right patient, and so on. You'd almost get the impression that this age is already here. But it isn't, not yet. It's just barely, barely begun. By one estimate, no major new cancer biomarker has been approved for clinical use in 25 years. Update: changed the language here to reflect differences of opinion!)

Why is that? What's holding things up? We can read off DNA so quickly these days - what's to stop us from just ripping through every cancer sample there is, matching those up with who responded to which treatment regime and which cancer targets are (over)expressed, and there you have it. That's what all these computers are for, right?

Well, that sort of protocol has, in fact, occurred to many researchers. And it's been tried, over and over, without a whole lot of success. Now, there are some good correlations, here and there - but the best ones tend to be in relatively rare tumor types. There's nowhere near as much overlap as we'd like between the cancers that present the most serious public health problems and the ones that we have good biomarker-driven treatment data for. Breast cancer may be one of the fields where things have moved along the most - treatment really is affected by checking for things like Her-2. But it's not enough, nowhere near enough.

So why, then, is that the case? Several reasons - for one, tumor biology is clearly a lot more complex than we'd like it to be. Many common forms of cancer present as a host of mutated cells, each with a host of mutations (see this breast cancer work for an example). And they're genetically unstable, constantly changing. That's why so many cancers relapse after initially successful treatment - you kill off the tumor cells that can be killed off, but that may just give the ones that are left a free field.

Given this state of affairs, and the huge need (and demand) for something that works, the field is primed for just the sort of trouble that occurred at Duke. Someone unscrupulous would have no problem convincing people that a hot new biomarker was worthwhile - any patients that survived would praise it to the skies, while the ones that didn't would not be around to add their perspective. And even without criminal behavior, it's all too easy for researchers to honestly believe that they're on to something, even what that isn't true. The statistical workup needed to go through data sets like these is not trivial; you really have to know what you're doing. Adding to the problem, a number of judgment calls can be made along the way about what to allow, what to emphasize, and what to ignore.

The other problem is that cancer is such an emotional issue. It's very easy for anyone with a drum to beat to join in at full volume. Do you think that the FDA is letting all sorts of toxic junk through? Or do you think that the FDA is killing people by being stupidly cautious? Are drug companies ignoring dying patients, or ruthlessly profiteering off them? Are there too few good ideas for people to work on, or too many? Come to oncology; you can find plenty of support for whatever position you like. They can't all be right, but when did that ever slow anyone down? Besides, that means that there will invariably be Wrong-Thinking Evil People on the other side of any topic, and that's always stimulating, too.

It is, in fact, a mess. Nor are we out of it. But our only hope to is to keep hacking away. Wish us luck!

Comments (22) + TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs | The Dark Side

July 1, 2011

Avastin and Medicare

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Posted by Derek

So, the FDA's advisors voted unanimously to remove Avastin's indication for metastatic breast cancer. Fine. But Medicare is saying that they'll continue to cover it? Really?

Now, as opposed to the other day, we're starting to talk about cost. Avastin is (famously) not cheap, and insurance companies often don't want to reimburse for off-label use of drugs. But if Medicare, well, doesn't care, then what? A number of insurance companies take their policies into account for their own coverage recommendations.

So this makes a person wonder what all the arguing over this issue has accomplished. Perhaps fewer oncologists will be willing to write off-label prescriptions after the FDA makes its call - there is that. But (on the one hand) this isn't looking quite like the consigning-people-to-death outcome that patient advocates were warning about. It also gives you an insight into health care costs, doesn't it? The FDA says "We don't recommend you use this. The clinical trial data don't support it." And Medicare says "Well, yeah, sure, but we'll pay for it, so what the hey". What, indeed, the hey?

Comments (13) + TrackBacks (0) | Category: Cancer | Drug Prices | Regulatory Affairs

June 29, 2011

Avastin At the FDA Today: Passion Should Lose

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Posted by Derek

Today is Day Two of the FDA's hearings on Avastin for metastatic breast cancer. Note: if you want to follow things in near real time, I'd suggest a Twitter search for #Avastin. I can particularly recommend Len Lichtenfeld's feed. This has been a very contentious issue - as most of you know, Avastin was provisionally approved for these patients, then pulled when more trial data came in showing no benefit. Roche/Genentech's team is now appealing that decision, and the questions are:

1. Should Avastin be approved for metastatic breast cancer patients? The answer to this one is "depends on the evidence for it". So. . .

2. Is there enough evidence to decide one way or another? Both the FDA and Roche seem to think that there is. The problem's that they come to opposite conclusions. So. . .

3. What's the risk/benefit ratio for Avastin in these patients? Now the serious arguing starts. Avastin is not without its serious side effects - but metastatic breast cancer is a terrible disease. The initial reports were promising - but none of the larger follow-up trials have really confirmed those results. Genentech is proposing still another confirmatory trial, with the drug to stay approved during that period, but the FDA seems to be arguing that leaving the drug approved for this indication will hurt more people than it helps. There you have it.

And all of this is being done against a backdrop of emotional cancer patient testimony. The problem with that is summed up by one of the most fervent advocates, Patricia Howard, who told the FDA "I’m not just a statistic; it is in your hands to ensure that I don’t become one."

She is wrong. It pains me to say this, but she's wrong. If we're ever going to get anywhere with cancer (or any other disease), we're going to need all the statistics we can get our hands on, and no amount of passionate testimony should be allowed to move one number in them. I've had family members with cancer; I've seen good friends and plenty of good people die from cancer. But cancer cells do not care about how strong your feelings are. The growth factor receptors, the checkpoint kinases, the apoptosis regulators, the metabolic enzymes and cell adhesion proteins: they don't give a damn. They have no damn to give. We have to fight them on those terms, on that battlefield, because that's the only one that matters and the only one where they can be defeated.

As it stands, I agree with the FDA's position: I don't think that Avastin has been shown to offer enough benefit. The 2008 provisional approval was already arguable - the agency went against its own advisory committee just to do that much - and the subsequent data have made it even less tenable. If we're going to have provisional approvals, then they have to be able to be taken back. And if we're going to evaluate drugs by their risks versus their benefits, then Avastin - for this indication, in these patients - doesn't (to my eyes) seem to make the cut.

If, on the other hand, you disagree with the provisional approval process, fine. Propose something more useful. If you disagree with the risk/benefit analysis in this case, then you should bring some new numbers or some new arguments (which is what Genentech is trying to do right now, as I write this, and I hope that they don't slip over the line while doing it). If you disagree with the whole idea of risk/benefit analysis, then. . .well, you'd better have something more useful to offer. And you'd better be sure that it doesn't end with the decisions going to whoever is the most passionate and tearful in making their case. That won't end well.

One more side issue: you'll note that I've done this whole blog post without talking about the price of Avastin at all. That's because I don't think that the price is the issue at all here. This is not a health-care-rationing issue, no matter how much some people would like for it to be. Roche gets to charge what they think Avastin can bring - they and Genentech have put the time, effort, and money into the drug. But for metastatic breast cancer, as I said here, Avastin doesn't seem like a good idea even if it were free.

Comments (63) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

June 27, 2011

The Evolution of Resistance: Are We Doing It Wrong?

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Posted by Derek

Here's a paper in PNAS that says that we're probably treating infectious disease the wrong way - and perhaps cancer as well. The authors go over the currently accepted doctrines: multiple-mechanism therapies, when possible, and restricted use to patients who really need antibiotics. But there's a third assumption that they say is causing trouble:

A third practice thought to be an effective resistant management strategy is the use of drugs to clear all target pathogens from a patient as fast as possible. We hereafter refer to this practice as “radical pathogen cure.” For a wide variety of infectious diseases, recommended drug doses, interdose intervals, and treatment durations (which together constitute “patient treatment regimens”) are designed to achieve complete pathogen elimination as fast as possible. This is often the basis for physicians exhorting their patients to finish a drug course long after they feel better (long-course chemotherapy). Our claim is that aggressive chemotherapy cannot be assumed to be an effective resistance management strategy a priori. This is because radical pathogen cure necessarily confers the strongest possible evolutionary advantage on the very pathogens that cause drugs to fail.

The harder you hit a population of infectious disease organisms, the harder you're selecting for resistance. The key, they say, is that in many cases there's genetic diversity among these organisms even inside single patients. So you can start off with a population of bacteria, say, that could be managed by less aggressive therapy and the patient's own immune system. But then aggressive treatment ends up killing off the great majority of the bacterial population, which you'd think would be a step forward. But what you're left with are the genotypes that are hardest to kill with antibiotics. They were in a minority, and might well have died out under competition from their less-genetically-burdened cohorts. But killing those off gives the resistant organisms an open field to work in.

The other problem here is a public-heath one. You want to cure the individual patient, and you want to keep their disease from spreading, and you want to keep from encouraging resistance among the infectious organisms. Optimizing for all three at once is probably not possible.

The paper goes into detail with the example of malaria, pointing out that it may well be the norm for people to be infected with several different lineages of malaria parasites at the same time. They seem to be in there competing for nutrients and for red blood cells, and some of them appear to be keeping the others in check. Antimalarial drugs alter the cost/benefit ratio (for the parasites) of carrying resistance genes.

So what should we do? The problem is, they say, that there are probably no general rules that can be recommended:

Thus, aggressive chemotherapy is a double-edged sword for resistance management. It can reduce the chances of high-level resistance arising de novo in an infection. But when an infection does contain resistant parasites, either from de novo mutation or acquired by transmission from other hosts, it gives those parasites the greatest possible evolutionary advantage both within individual hosts and in the population as a whole. How do the opposing evolutionary pressures generated by radical cure combine in different circumstances to determine the useful life span of a drug? There will be circumstances when overwhelming chemical force retards evolution and other times when it drives things very rapidly. We contend that for no infectious disease do we have sufficient theory and empiricism to determine which outcome is more important. It seems unlikely that any general rule will apply even for a single disease, let alone across disease systems.

For more on such ideas as applied to bacterial infections, see here and here. But near the end of this paper, the authors apply similar reasoning to cancer. (That analogy has come up around here before, I should note).

An analogous situation also occurs in cancer therapy, where cell lineages within a tumor compete for access to space and nutrients. There, the argument has recently been made that less aggressive chemotherapy might sustain life better than overwhelming drug treatment, which simply removes the competitively more able susceptible cell lineages, allowing drug-resistant lineages to kill the host. Mouse experiments support this: Conventionally treated mice died of drug-resistant tumors, but less aggressively treated mice survived (95).

So maybe too many of us have been thinking about these questions the wrong way. If we switch over to favoring whatever strategy minimizes resistance, both in individual patients and thus across the population, we could be in better shape. . .

Comments (21) + TrackBacks (0) | Category: Cancer | Infectious Diseases

June 14, 2011

A Shortage of Cancer Drugs?

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Posted by Derek

There have been several headlines about a shortage of classic chemotherapy drugs recently. How do these things happen? This post at Marginal Revolution is the best short overall look at the problem that I've seen so far:

Currently there are about 246 drugs that are in short supply, a record high. These shortages are not just a result of accident, error or unusual circumstance, the number of drugs in short supply has risen steadily since 2006. The shortages arise from a combination of systematic factors, among them the policies of the FDA. The FDA has inadvertently caused drugs long-used in the United States to be withdrawn from the market and its “Good Manufacturing Practice” rules have gummed up the drug production process and raised costs.

As Alex Tabarrok says there, one pebble, or a few, won't dam up a stream. But if you keep throwing them in, something's going to happen, and I think that we've reached that point here. . .

Comments (19) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

May 27, 2011

The Ethics of Avastin

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Posted by Derek

When we last spoke about the Avastin-and-breast-cancer story here, the FDA had rescinded its provisional approval for that indication, and a number of people were shouting that here it was, health care rationing based on price, right in front of us. As I said at the time, I think that those worries were misplaced: the reason Avastin was approved for metastatic breast cancer was that it seemed to work (a little). But when the numbers were firmed up with more studies, it turned out that it didn't. The whole point of a provisional approval is that it can be rolled back if things don't work out they way that they looked at first.

Now Genentech is coming back to the FDA next month asking for approval again. Here's an op-ed in the New York Times that I think does a good job of laying out the case against the whole idea:

Genentech presented progression-free survival as a surrogate for better quality of life, but the quality-of-life data were incomplete, sketchy and, in some cases, non-existent. The best that one Genentech spokesman could say was that “health-related quality of life was not worsened when Avastin was added.” Patients didn’t live longer, and they didn’t live better.

It was this lack of demonstrated clinical benefit, combined with the potentially severe side effects of the drug, that led the F.D.A. last year to reject the use of Avastin with Taxol or with the other chemotherapies for breast cancer.

In its appeal Genentech is changing its interpretation of its own data to pursue the case. Last year Genentech argued that the decrease in progression-free survival in its supplementary studies was not due to the pairing of Avastin with drugs other than Taxol. This year, however, in its brief supporting the appeal, Genentech argues that the degree of benefit may indeed vary with “the particular chemotherapy used with Avastin.” In other words, different chemotherapies suddenly do yield different results, with Taxol being superior. The same data now generate the opposite conclusion.

Another problem, as the piece says, is that the whole cancer drug approval process has a tendency to slip into ancedotal form: tearful patients testify that the drug saved their lives. But the plural of anecdote is still not data, and never will be. In oncology, there's really not much way of being sure about any individual patient's response. There are so many different types of cancer, and they occur in so many different kinds of people. The only way to say anything useful is in a well-designed clinical trial setting.

Now, that doesn't mean that you just have to round up thousands of people with all kinds of cancer and let things rip. It's perfectly acceptable - in fact, very useful - to screen the patients that go into the trials so that you're sure that they, as far as can be told, all have the same sort of disease. But you have to do that up front to really trust the conclusions. Data-mining, running things in reverse, is tricky, and if you're going to do it, it should be used to tell you how to run your next trial, not to argue for approval. Only when you've run these kinds of experiments can you say with any certainly that a cancer therapy is useful.

But that's a hard sell, compared to someone who is convinced that they're alive because of cancer drug X (or is convinced that a loved one would be alive, if they'd only been able to get it). If you're trying to persuade a crowd (or a mob), that would be the way to go: Aristotle's appeal to pathos. But keep in mind that Aristotle (and the rest of the Greeks) looked down on that technique, and they were right. Logos, used properly, is what we're after here, mixed in with the ethos of a disinterested observer who's trying to find the truth.

And this gets to the moral dilemma at the heart of the modern drug industry: are we trying to find drugs that work? Or are we trying to sell drugs, whether they work or not? Roche/Genentech has every right to make its case and to petition the FDA for whatever decision they want. But they (and every other drug company out there) owe the rest of us, and the rest of the world, something while they're doing it: to present all the solid data they have, and to let the numbers speak for themselves. But if the numbers can't persuade, then a company should go back and get some more before trying again.

Comments (23) + TrackBacks (0) | Category: Cancer | Clinical Trials | Why Everyone Loves Us

April 27, 2011

Off the Beaten Track. Way, Way, Off.

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Posted by Derek

Now here's a structure that you don't see every day. A company called RadioRx is developing compounds as radiotherapy sensitizers for oncology, designed to release reactive free radicals and intensify the cell-killing effects of ionizing radiation. And these compounds are not from the usual sources. As they put it:

In collaboration with a major defense contractor, RadioRx is developing its first lead candidate, RRx-001, a best-in-class small molecule, adapted from an energetic solid rocket propellant. The development candidate is scheduled to enter first-in-man phase 1 clinical studies by Q1 2011.

I've been forwarded a report that this is the structure of their compound, which would make their defense-contractor partner Thiokol (the assignee where that compound appears in the patent literature). (Here's one of RadioRx's own patents in this area). And I truly have to salute these guys for going forward with such an out-there structure. Can anyone doubt that this is the first gem-dinitroazetidine to reach the clinic? And with a bromoamide on the other end of it, yet?
It's easy to look at something like this and mutter "Only in oncology", but at the same time, it takes some nerve and imagination to go forward with compounds this odd. I hope that they work - and I hope that everyone else looks at their own chemical matter and decides that hey, maybe there's more to life than Suzuki couplings and benzo-fused heterocycles.

Comments (28) + TrackBacks (0) | Category: Cancer | Drug Development

April 7, 2011

More Zeroing In On Breast Cancer Cells

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Posted by Derek

While we're on the what's-going-on-inside-cancer-cells topic, there's another new Nature paper that makes interesting reading on the subject. This one also confirms some earlier work, but does a pretty thorough job of it, and sheds some new light as well on that breast cancer mutation work that I blogged about the other day.

This group has taken around 100 cells at a time from tumor samples, and applied single-nucleus sequencing techniques to them. After correcting for a number of factors (see the paper, of course, if you're really into this stuff), they can use this technique to get a good read on the genomic copy number of the cells, which is of particular interest for unstable things like tumor samples. (Comparison of single-cell data versus the averages from samples of millions of cells were also made; the correlations are quite good).

The cells were taken from a breast cancer sample ("triple negative" ductal carcinoma) and from an associated metastatic liver tumor from the same patient. (Given that situation, I'm guessing that these were post-mortem). Each sample was dissected into physical zones, and the cells were then flow-sorted and subjected to sequencing. This revealed a number of interesting patterns.

For one thing, the original tumor sample showed different cell populations across its diameter. There were standard diploid cells in the entire sample, but one population type (less than diploid) was found only one end of the sample, fading out gradually towards the middle, with two other varieties (near-tetraploid) showing up at the other end. On closer inspection, almost all of those garden-variety diploids were normal cells, and most of those were white blood cells, immunocytes that had infiltrated the tumor.

Of the cancer cells themselves, half of them sorted out into three distinct clonal populations, and the metastatic tumor was found to be purely derived one of these. Looking these over, it appears that these three groups emerged very early in the process, and the various mutations (and there were many) still traced back to these early branch points. One of them (arising much later in the process) was clearly more like to break loose and resettle than the others, a pattern that has been seen in other studies. Trying the same thing with another set of tumors from a different patient, they found in this case that the tumor had emerged from a clonal expansion of a single aneuploid cell line, and the metastatic tumor was from one of the later resulting mutants (and had hardly evolved since).

But what about the rest of the tumor cells in these samples? Those turned out to be the pseudodiploid population that they'd seen in the initial sorting, and these were all over the place genetically. No family-tree relationship could be drawn between them (in contrast to aneuploids), indicating that they hadn't been doing the clonal-exapansion thing. They seem to be the result of some ongoing genetic instability in the tumor population, generating a steady stream of one-of-a-kind messed-up cells with missing chunks of chromosomes. You have to wonder if a lot of the 1700 mutations that the full-genome sequencing work picked up were from these cells, and that the other clonally-similar lines showed less variation.

If that's true, it would probably be good news - perhaps all these mutations aren't as evenly spread across the worrisome cells types as you might fear, and especially among the ones that go metastatic. It's a pity that we can't yet do whole-genome sequencing on single nuclei - combining the population breakdown this copy-number technique gives with the hardcore sequence data would really tell the story, and tell us which cells we have to try to kill off first. And finding the root causes of all the genomic instability would be a big advance, too - I wrote about this back in 2002, and it's still relevant and still not well worked out.

Comments (8) + TrackBacks (0) | Category: Cancer

April 5, 2011

So, You Thought Breast Cancer Was Complicated?

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Posted by Derek

You may have detected, here and there, a certain amount of skepticism on this blog about the direct application of genomic information to complex human diseases. And several times I've beaten the drum for the position that there is no such disease as "cancer" - just a lot of conditions that all result in the phenotype of uncontrolled cellular growth.

Well, here's some pretty dramatic evidence in favor of both of those positions. A new study, one of those things that could only be done with modern sequencing techniques, has given us the hardest data yet on the genomic basis of cancerous cells. This massive effort completely sequenced the tumors from 50 different breast cancer patients, along with nearby healthy cells as controls for each case.

Over 1700 mutations were found - but only three of them showed up in as many as 10% of the patients. The great majority were unique to each patient, and they were all over the place: deletions, frame shifts, translocations, what have you. The lead author of the study told Nature News that the results were "complex and somewhat alarming", and I second that, only pausing to drop the "somewhat". I add that qualification because these patients were already more homogeneous than the normal run of breast cancer cases - they were all estrogen-receptor positive, picked for trials of an aromatase inhibitor.

Half the tumors were estrogen-sensitive, and half weren't, and one of the goals of the study was to see if any genetic signatures could be found that would distinguish these patients. There was an association with the MAP3K1 gene, but hardly a powerfully predictive one, since that one only showed up in 10% of the samples to start with. (Mind you, that still makes it one of the top three mutations).

The Nature piece contains some brave-face material about how this study has uncovered a whole list of new therapeutic targets, but sheesh. What are the odds that any of these will prove to be crucial, even for the low percentage of women who turn out to have them? No, instead of making me yearn for ever-more-personalized targeted therapies, this makes me think that early detection and powerful, walloping chemotherapy (and surgery) must be the way to go for now. I mean, this was still only fifty patients, and uncovered this much complexity: how tangled must the real world be?

We'll get a chance to start finding out - the same team is now moving ahead to expand this effort to 1,000 patients. These are also, I believe, from clinical trials, so we'll be able to correlate outcomes with exact genetic sequences. If there are any correlations that we can understand, that is. . .that's the next thing that I'm really looking forward to seeing. If the whole personalized-medicine idea is ever to work, this is just the sort of thing that's going to have to be done. But we shouldn't be surprised if the results, for some time to come, are that the whole era of personalized medicine is a lot further away than we might have thought.

Comments (33) + TrackBacks (0) | Category: Cancer

February 22, 2011

Oncology Follow-Up Trials

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Posted by Derek

During the most recent Avastin controversy (with its conditional approval for metastatic breast cancer being pulled by the FDA), the role of follow-up studies in oncology became a big point of discussion.

Now there are reports that some companies aren't exactly following up in the way that they're supposed to. This isn't good. Conditional approvals are granted under the banner of "better to help people now than wait for more data", but eventually the numbers have to show up. After all, not all of these treatments are going to confirm when they're looked at more closely.

Not all of this can be put down to foot-dragging on the part of the companies. In some cases, it's proven hard to round up enough patients for further trials, and in others, the trial protocols themselves have become outdated. But there needs to be some way to review these things more regularly (as seems to be the case in the EU) to keep the process from getting tangled up.

You'll note from the article that opinions are all over the place on how lenient the FDA's approval process really is. You have people who say that the agency is dragging its feet on life-saving treatments, and people (looking at the same data set) who say that they're letting too much stuff through on the flimsiest grounds. We're not going to resolve that argument any time soon. But can we at least agree that we're going to require evidence at some point?

Comments (11) + TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs

February 14, 2011

New Cures! Faster! Faster!

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Posted by Derek

I wrote here the other day about the NIH's new translational medicine plans. The New York Times article that brought this to wide attention didn't go over well with director Francis Collins, who ended up trying to disabuse people of the idea that the NIH was going to set up its own drug company.

But there's been an overwhelming negative response from the academic research community, largely driven (it seems) by worries about funding. Given the state of the budget, flat funding would be seen as a victory by NIH, so this isn't the best environment to be talking about putting together a great new institute. The money for it will, after all, have to come out of someone else's pile. Collins spends most of that statement linked above denying this, but it's hard to see how there won't be problems.

I think, though, that there's an even more fundamental problem here. In the latest BioCentury, there's an interesting sidelight on all this:

In comments submitted to NIH, Joseph Zaia, associate director of the Center for Biomedical Mass Spectrometry at the Boston University School of Medicine, argued against setting timetables for research results. “I do not believe that running medical science on a short sighted business time schedule will produce more cures faster. It will, however, deplete NIH resources very rapidly and possibly tear down an infrastructure of knowledge that took decades to create.”

Zaia complained that the NCATS “process seems to be driven by the FasterCures movement sponsored by Michael Milken,” which he said has “been masterful in manipulating the political system for their purposes, and forcing NIH into this reorganization.”

FasterCures’ Margaret Anderson, executive director of the non-profit group that advocates for accelerating medical innovation, submitted a letter strongly endorsing NCATS, which she said “will provide a significant stimulus to moving ideas out of the lab and into the clinic.”

And that's the problem. Over the last few years, an idea has taken hold that there are all kinds of great ideas for all kinds of diseases that no one is doing anything with. Now, I'm not going to claim that everyone is trying every single thing that could possibly be tried, but I really don't see how there's this treasure chest of great discoveries that aren't being followed up on. Drug companies of all sizes are always watching for such opportunities - I've been a part of many such efforts to jump on these as they show up.

My guess is that many of these advocates have a different definition of what a "great discovery" is than I do. There are all kinds of things that come out in the literature, often with breathless press releases from the university PR office, that make it sound like the latest JBC paper has the cure for cancer in it. But the huge majority of these things don't pan out, generally because they're just part of a much, much larger (and more complicated) story. And that's why things tend to fail on the way to (and through) the clinic.

Am I exaggerating? Well, many advocates in this area have taken to using the phrase "valley of death" to describe the gap between basic research and success in the clinic. Here's Amy Rick of the Parkinson's Action Network:

Rick said patient groups are concerned that the valley of
death is growing, and they want government to help bridge it. The prospect that there are “good discoveries that are basically collecting dust” is “terrifying to patients,” she said.

“What we are finding from a patient perspective is that discoveries that are being made in very exciting basic research are not being acted upon,” Rick told BioCentury This Week. “They are not moving through the pipeline. So the patient community is pushing very hard — if private money isn’t filling that space, the government should be moving some of its funding into that space.”

I have a great deal of sympathy for the patient population - they're our customers in this business, after all, and any one of us could join their ranks at any time. (Drug company researchers come down with all the maladies that everyone else does). But the patient population is not the group of people discovering and developing drugs. What looks like agonizingly slow progress from outside is often just the best that can be done. It can be hard to imagine how crazy, complex, and frustrating medical research can be unless you've tried doing it. Nothing else quite compares.

I worry that some of these people have an unrealistic view of how things work (or should work). This all reminds me of Andrew Grove, ex-Intel, and his complaints that the drug research business wasn't moving as fast as the semiconductor industry. It sure isn't. That's because it's a lot harder.

The Biocentury article is right in line with my thinking here:

FASEB’s Talman argues that patient groups and the public are overly optimistic about the breakthroughs that could be made by shifting resources to translational science. He believes basic scientists are partly to blame because “there is too much of a tendency for basic or clinical scientists to sell our work.” In the process, he said, “we can come across as saying that the newest discovery can lead to a cure.”

Senior NIH officials have contributed to the belief that cures are around the corner by dangling the prospect of quick payoffs in front of congressional appropriators. For example, in 1999, Gerald Fischbach, then director of the National Institute of Neurological Diseases and Stroke, told a Senate committee that with sufficient funding it was reasonable to expect a cure for Parkinson’s disease within five years. The NINDS budget has increased from $902 million in FY99 to $1.6 billion in FY10, but PD hasn’t been cured.

Starting in 2004, National Cancer Institute Director Andrew von Eschenbach claimed in numerous public speeches that it would be possible to “end suffering and death from cancer by 2015,” a claim that current NCI Director Harold Varmus has repudiated.

When he led the human genome sequencing effort, NIH Director Collins himself made comments that the press, public and politicians interpreted as promising that it would directly and quickly lead to new medicines for common diseases.

“There is a real danger of over-promising,” Keith Yamamoto, executive vice dean of the University of California San Francisco School of Medicine, told BioCentury. “Scientists too often take an intellectual short cut. They think they will not be able to explain the nuances of why basic discovery takes so long, so they just say if you give me the money we are about to cure the disease.”

He added: “That’s thin ice — it is our responsibility to explain why things are as difficult as they are.”

It sure is. I know that patients and the general public get tired of hearing about how it's hard, how discoveries take time, all that sort of thing, while the diseases just keep marching on and on. But it's all true. I honestly don't think that most people realize, despite that huge amounts of knowledge we've managed to accumulate, just how little we know about what we're doing.

Comments (39) + TrackBacks (0) | Category: Academia (vs. Industry) | Cancer | Drug Development | The Central Nervous System

January 31, 2011

Sanofi's PARP1 Inhibitor Misses

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Posted by Derek

Past results, they tell you, are no guarantee of future performance. Sanofi-Aventis is ready to tell you all about that after the results of a Phase III trial of their recently acquired oncology drug, iniparib (BSI-201). This had shown very strong results in Phase II against "triple-negative" breast cancer, but it appears to have missed two survival endpoints in a larger trial. Sanofi bought BiPar, the company that had been developing the drug, a little less than two years ago.

Iniparib's a small molecule indeed - small enough that its systematic name can be immediately parsed by any sophomore chemistry student. It's 4-iodo-3-nitrobenzamide; it's the sort of thing you can order out of a catalog. But it's also an inhibitor of poly-(ADP-ribose) polymerase I (PARP1), and it's the first compound of that class to get this far in the clinic. PARP1 is part of a DNA repair pathway, although it's not on the front line. That would be homologous recombination, which is the pathway that needs the well-known BRCA to function. The idea has been that since so many aggressive breast cancers are deficient in BRCA, that they'd be especially sensitive to something that targeted PARP as well - they should accumulate so many DNA breaks that they'd be unable to replicate.

That's a perfectly reasonable theory. But it doesn't seem to have yielded perfectly reasonable results in this case. Problem is, PARP1 has a lot of functions in the cell, and inhibiting the lot of them all at once may not be such a good idea. One possibility is that effects on the Akt pathway might boomerang and reduce the effectiveness of therapy.

More broadly, this is yet another illustration of the perils of Phase II data. And it does make a person think about the idea of tightening up the endpoints of such trials even more. Problem is, you often don't get good survival numbers until Phase III, anyway, by which time you've spent the money. Like Sanofi-Aventis is spending it now. Let's hope that one of the other indications for the drug works out better.

Update: here's a rundown on competition in this field. The next round of clinical data will be quite interesting. . .

Comments (10) + TrackBacks (0) | Category: Cancer | Clinical Trials

January 24, 2011

Not Enough Progress Against Cancer?

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Posted by Derek

Here's a topic that's come up here before: for a new cancer drug, how much benefit is worthwhile? As it stands, we approve things when they show a statistically meaningful difference versus standard of care (with consideration of toxicology and side effects). But should our standards be higher?

That's what this paper in the Journal of the National Cancer Institute is proposing. The authors look at a number of recent Phase III trials for metastatic solid tumors. It's a tricky business:

When designing a randomized phase III clinical trial, the investigators must specify in the protocol the difference (δ) in the primary endpoint between experimental and control groups that they aim to detect or exclude (24). The number of patients to be recruited and the duration of the study will depend on the value of δ; increasing the sample size will allow the detection or exclusion of smaller values of δ. Ideally, trials should be designed such that δ represents the minimum clinically important difference, taking into account the tolerability and toxicity of the new treatment, that would persuade oncologists to adopt the new treatment in place of the standard treatment. Of course, the opinions of oncologists as to what constitutes a minimal important value of δ will vary, but a reasonable consensus can be reached by seeking the opinions of oncologists who manage a given type of cancer. For example, an increase in median survival by less than 1 month for patients with advanced-stage cancer would not be regarded by most as clinically important, unless the new agent had less toxicity than standard treatment, whereas an improvement of median survival by greater than 3 months for a drug that was reasonably well tolerated would usually be accepted as clinically important.

And the problem is, given the costs of some of these drugs versus their benefits, you run the risk of, finally, paying too much for too little. I know that people say that you can't put a cost on a human life, but that's probably not true, when you're talking about an entire economy. As the article points out, the rough estimate is that the developed world can support expenditures of up to roughly US $100,000 per year of life gained, but past that, we're into arguable territory. (If someone wants to spend more out of their own pocket, that's another matter, naturally, but at these levels, we're usually talking public and private insurance).

The benefits can indeed be marginal, and you have to look at the statistics carefully so as not to be misled:

. . .several trials showed a statistically significant difference in a major outcome measure between the experimental and control groups, but the difference in outcome was of lower magnitude (eg, hazard ratio was closer to one) than that specified in the protocol. For example, the clinical trial that led to approval of erlotinib for treatment of pancreatic cancer was designed to detect a relative risk reduction of 25% (HR ≤ 0.75), but the best estimate of hazard ratio from the trial showed a relative risk reduction of 18% (HR = 0.82, 95% confidence interval = 0.69 to 0.99). The difference was statistically significant (P = .038), but the median survival differed by only 10 days.

What happens is that the trials are (understandably enough) designed to detect the minimum difference that regulatory authorities are likely to find convincing enough for approval of the drug. And the FDA has generally set the bar at "anything that's statistically significant for overall survival". These authors (and others) would like to see that raised. They're calling for trials not to go for a statistically significant P value, so much as to show some sort of meaningful clinical benefit - because it's become clear that you can have the first without really achieving the second.

I think that might be a good idea, whether or not you buy into that cost-per-year-of-life figure or not. At this point, I think it's fair to say that we can come up with drugs that provide some statistical measure of efficacy, given enough effort in the clinic, for many kinds of cancer (although certainly not all of them). But how many add-a-month-maybe therapies do we need? Not everyone's convinced, though:

Wyndham Wilson, a lymphoma researcher at the National Cancer Institute in Bethesda, Maryland, argues that the proposed clinical endpoints are somewhat arbitrary. “What constitutes a clinically meaningful difference? Six months is obvious, but where do you cut the line?” What's more, he adds, simply focusing on median responses often ignores important outlier effects that could merit approval for an experimental drug. “The difference in overall survival may not be great, but it may be driven by a great benefit to a small group,” he says.

Problem is, it's often quite difficult to figure out who that small group might be, and just treat them, instead of treating everyone and hoping for the best. And there's always the argument that these therapies are stepping stones to more significant improvements, but I wonder about that. My impression of oncology research has always been more like "OK, this looks reasonable. Lots of these tumors have UVW upregulated; let's make an UVW inhibitor. (Years later): Hmm, that's disappointing. Our UVW inhibitor doesn't seem to do as much as you'd think it should. But now it's been found that XYZ looks like it's necessary for tumor growth; let's see if we can inhibit it. (Years later): Hmm, that's not as big an effect as you would have thought, either, is it? Seems to help a few people, but it's hard to say who they'll be up front. How's the JKL antagonist coming along? No one's tried that yet; looks like a good cell-division target. . ."

It's just sort of one thing after another - that one didn't work so well, neither did that one, this other one and these three together seem to be a bit better, but not always, and so on. Would we learn as much, or nearly so, just from the earlier clinical work on such compounds as opposed to taking them to market? And although you can't deny that there's been incremental progress, I'm not sure what form it's taking. It's very likely that the answer isn't to keep turning over mechanistic ideas until we find The One That Really Truly Works - cancer is a tough enough (and varied enough) disease that there probably isn't going to be one of those.

My guess is that meaningful cancer success will come from combinations of therapies that we mostly don't even have yet. I think that we'll need to hit several different mechanisms at the same time, but that some of what we'll need to hit hasn't even been discovered. And on top of that, each patient presents a slightly different problem, and ideally would receive a more customized blend of therapies (not that we know how to do that, either, in most cases).

What I'm saying is that we'll probably need combinations of things that already work better than most of what we have already, and that these will stand out enough in clinical trials that we'll know that they're worth developing. As it stands, though, companies see hints here and there in the clinic, enough to run a Phase III trial, and if it's large enough and tightly controlled enough, they see enough efficacy to get things through the FDA and onto the market. Would we be better off to not proceed with the marginal stuff, and put the significant amounts of money into things that stand out more? Or would that choke off the market too much, since we mostly end up making marginal things anyway (damn it all), leaving no one able to keep going long enough to find the good stuff? It's a hard business.

Comments (32) + TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs

January 4, 2011

Detecting Single Cancer Cells

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Posted by Derek

This story on a new diagnostic method in oncology is getting a lot of attention in the press. It's a collaboration between J&J, a small company they've bought called Veridex, and several oncology centers to see if very sensitive monitoring of circulating tumor cells could be a more useful biomarker.

The press coverage has some hype in it - for one thing, all the stuff about detecting one single cancer cell in the whole body isn't too helpful. The cells have to be circulating in the blood, and they have to display the markers you're looking for, to start with. But I can't deny that this is an interesting and potentially exciting field. There's some evidence to suggest that circulating tumor cells could be a strongly predictive marker can in several kinds of cancer.

These studies are looking at the sorts of endpoints that clinicians (and patients, and the FDA) all respect: overall survival, and progression-free survival. As discussed around here before, it's widely felt in oncology that these are where the field should really be spending its time, rather than on tumor size and so on. (You'd think that tumor size or number of detectable tumors would correlate with survival, but in many cases it's a strikingly poor predictor - which is a shame, since those are easier and faster numbers to get). A blood test, on the other hand, that strongly correlates with survival would be a real advance.

The value would not just be in telling (some) patients that they're showing better chances for survival, although I'm sure that'll be greatly appreciated. It's the patients whose numbers come back worse that may well be helped out the most, because that indicates that the current therapy isn't doing the job, and that it's time to switch to something else (assuming that there is something else, of course). The more quickly and confidently you can make that call, the better.

And from a drug development perspective, the uses of such assays in clinical trials are immediately obvious. Additionally, I'd think that these would be a real help to rolling-enrollment Bayesian trial designs, since you could assign patients to (and move them between) the different study groups with more confidence.

The Veridex/J&J assay (called CellSearch) uses an ingenious magnetic immunochemical approach. Blood samples are treated with antibody-coated iron nanoparticles that recognize a common adhesion protein. The cells that get bound are separated magnetically on a diagnostic chip for further immunostaining and imaging. There are other techniques out there as well - here's an article from Technology Review on a competing one that's said to be more sensitive, and here's a San Diego company trying to enter the market with an assay that's supposed to be broader-based). The key for all of these things will be bringing the costs down (and the speed of production up, in some cases). These are tests that ideally would be run early and often, so the cheaper and faster the assay can be made, the better.

Now, of course, we just need some more therapies that work, so that when people find out that their current regimen isn't working, then they have something else to try. If these circulating-cell assays help us sort things out faster in the clinic, maybe we'll be able to make better use of our time and money to that end.

Comments (14) + TrackBacks (0) | Category: Analytical Chemistry | Cancer | Clinical Trials

December 17, 2010

The Avastin Decision: A Reality Check

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Posted by Derek

So the FDA did indeed rescind their conditional approval for Avastin in metastatic breast cancer. I think that this was the right thing to do, given that the weight of the evidence now says that it doesn't do any good in that situation. Problem is, there are a lot of people trying to make political points off this decision, saying "See? We told that Obama's health care plan would lead to this. Life-saving medical breakthroughs, pulled because some bureaucrat says that they're too expensive".

Wrong. And I say this as someone who still thinks that the health care plan is a bad idea, poorly implemented. It would be good if other people opposed to it could resist the any-weapon-to-hand temptation in this case, but that's politics for you. (I'd hoped back in August that we could avoid this stuff, but that was always a long shot). The FDA is not in the business of considering costs, just safety and efficacy. And the balance between those two, in the case of hard-to-treat metastatic breast cancer, is not in Avastin's favor. If we're going to speed things up with conditional approvals, we're going to have to be able to take them back when they don't work out. This one didn't.

Here's some good background from WebMD on this decision, and more from Science-Based Medicine on the clinical evidence. That's the evidence we have, and that's why I think this was the right decision.

Comments (9) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

December 1, 2010

Resveratrol (SRT501): Development Halted

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Posted by Derek

Back in May, GlaxoSmithKline halted a trial of SRT501, which is a formulation of resveratrol, in myeloma. Now the folks at the Myeloma Beacon site are the first with the news that the company has halted all further development:

According to a GlaxoSmithKline spokesperson, an internal analysis of the kidney failure cases has concluded that they “most likely were due to the underlying disease … However, the formulation of SRT501 was not well tolerated, and side effects of nausea / vomiting / diarrhea may have indirectly led to dehydration, which exacerbated the development of the acute [kidney] failure.”

For this reason, the company decided to halt further development of SRT501 in multiple myeloma. The SRT501 formulation of resveratrol “may only offer minimal efficacy,” explained the Glaxo spokesperson, while increasing the chances of kidney failure. . .

. . .In a separate statement to The Myeloma Beacon, a Glaxo spokesperson explained the rationale for the company’s decision to halt all development of SRT501. Ending all work on SRT501, the spokesperson said, will allow Glaxo to focus its resources on the development of drugs that act similarly to SRT501, but have more favorable properties. The spokesperson mentioned, in particular, SRT2104 and SRT2379 as drugs similar to SRT501 that the company is developing.

These compounds are still a bit of a mystery - they've been in the clinical trial registry for a while, and are certainly the subject of active investigation, but we don't know how they fit into the whole activation-of-SIRT1 brouhaha. They haven't been challenged by the critics of the work, nor specifically defended by GSK, so we're just going to have to see how they perform out there in the real world (which was always going to be the final word, anyway).

But this would appear to be it for resveratrol itself in the real world, as far as GSK's concerned. Hey, does this mean that they'll let their two former Sirtris execs start selling it again on the side, now that they have no interest in the parent compound? One doubts it. But why not?

Comments (27) + TrackBacks (0) | Category: Aging and Lifespan | Cancer | Clinical Trials

November 18, 2010

Halaven: Holder of the Record

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Posted by Derek

The FDA has approved Eisai's Halaven (eribulin) for late-stage breast cancer. As far as I can tell, this is now the most synthetically complex non-peptide drug ever marketed. Some news stories on it are saying that it's from a marine sponge, but that was just the beginning. This structure has to be made from the ground up; there's no way you're going to get enough material from marine sponges to market a drug.
If anyone has another candidate, please note it in the comments - but I'll be surprised if there's anything that can surpass this one. There have been long syntheses in the industry before, of course, although we do everything we can to avoid them. Back when hydrocortisone was first marketed by Merck, it had a brutal synthetic path for its time. (That's where a famous story about Max Tishler came from - one of the intermediates was a brightly colored dinitrophenylhydrazone. Tishler, it's said, came into the labs one day, saw some of the red solution spilled on the floor, and growled "That better be blood") And Roche's Fuzeon is a very complicated synthesis indeed, but much of that is repetitive (and automated) peptide coupling. It took a lot of work to get right, but I'd still give the nod to eribulin. Can anyone beat it?

Comments (44) + TrackBacks (0) | Category: Cancer | Chemical News | Drug Industry History

October 20, 2010

Is Cancer A Disease of the Modern World?

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Posted by Derek

This paper in Nature Reviews Cancer is getting more attention in the popular press than most papers in that journal manage. Titled "Cancer: an old disease, a new disease or something in between?", it goes over the archaeological evidence for cancer rates in ancient populations, and goes on to speculate whether the incidence of the disease is higher under modern conditions.

I'd be interested in knowing that, too, but the problem seems to be that there's not much evidence one way or another. The authors concentrate on the evidence that can be found in bone samples, since these are naturally the most numerous, but it seems to be quite hard to get any meaningful histology data from ancient bone tissue. As for other tissue, the Egyptian record is probably the most statistically robust, thanks to deliberate mummification and the desert conditions, but even that isn't too definitive. The Greeks definitely described metastatic tumors, though (and in fact, gave us our name for the disease).

Still, they believe that the archaeological record indicates a smaller incidence of cancer than you'd expect, although given the long list of confounding factors they present, I'm not sure how sturdy that result is. One of the biggest of those is the shorter life expectancies in ancient populations, and it's not easy to get around that one. As the authors themselves point out, working-class ancient Egyptians seem to have mostly died at ages between 25 and 30 (!), and there aren't many forms of cancer that would be expected to show up well under those demographic conditions. (Osteosarcoma is the main tumor type the authors look for as being not so age-dependent).

The paper itself is fairly calm about its conclusions:

Despite the fact that other explanations, such as inadequate techniques of disease diagnosis, cannot be ruled out, the rarity of malignancies in antiquity is strongly suggested by the available palaeopathological and literary evidence. This might be related to the prevalence of carcinogens in modern societies.

But the press reports (based, I think, partly on further statements from the authors) haven't been. "Cancer Is A Modern Disease", "No Cancer In Ancient Times" go the headlines. (Go tell that last one to the ancient Greeks). And it's impossible to deny the environmental causes of some cancers - I'll bet that lung cancer rates prior to the introduction of tobacco into the Old World were pretty low, for example. Repeated exposure to some industrial chemicals (benzene and benzidine, right off the top of my head) are most definitely linked to increased risk of particular tumor types.

So in that way, modern cancer incidence probably is higher, at least for specific forms of the disease. But (as mentioned above) the single biggest factor is surely our longer lives. Eventually, some cells are going to hit on the wrong combination of mutations if you just give them enough time. And the widely reported statement from Professor Davids, one of the paper's authors, that "There is nothing in the natural environment that causes cancer", is flat-out wrong. What about UV light from the sun? Aflatoxins from molds? Phorbol esters in traditional herbal recipes?

That statement strongly suggests a habit of mind that I think has to be guarded against: the "Garden of Eden" effect. That's the belief, widely held in one form or another, that there was a time - long ago - when people were in harmony with nature, ate pure, wholesome natural foods (the kind that we were meant to eat), and didn't have all the horrible problems that we have in these degenerate modern times. (You can see a lot of Rousseau in there, too, what with all that Noble Savage, corrupted-by-modern-society stuff).

This 1990 article (PDF) by Bruce Ames and Lois Gold, "Misconceptions on Pollution and the Causes of Cancer" is a useful corrective to the idea that modern environments cause all cancers. You'll have to guard yourselves, though, against the prelapsarian Golden Age fallacy. It's everywhere.

Comments (31) + TrackBacks (0) | Category: Cancer | General Scientific News

October 11, 2010

Princeton's New Chemistry Building

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Posted by Derek

So I believe that they're moving into the new chemistry building at Princeton, which is a mighty glass whopper. In light of some of the past discussions we've had around here about lab design, I'd be interested in hearing from anyone with personal experience of the building. I can't really get a good sense of the layout from the pictures I've seen, just that there sure seem to be a lot of glass walls. And those aren't necessarily bad; it's the way the labs are put together and their relationship the desks and offices.

Interestingly, much of the money for its construction seems to have come from the university's royalties on Alimta (pemetrexed), a folate anticancer drug discovered by Ted Taylor's group there in the early 1990s and developed by Lilly. (Taylor, a heterocyclic chemistry legend, worked on antifolates for many, many years, and contributed a huge amount to the field).

Here's more on the building, and here are some photos, and here are some architectural renderings, for what those are worth. Any comments from folks on the ground?

Comments (29) + TrackBacks (0) | Category: Cancer | Chemical News | Drug Industry History

September 9, 2010

PLX4032: The Good News and the Bad News

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Posted by Derek

There's been a lot of excitement about PLX4032, which has shown some dramatic effects against late-stage melanoma. Very few therapies have done anything at all in that patient population, so on that level, the excitement is justified.

The compound is an azaindole targeting a mutated form (V600E, that is, glutamate for valine at amino acid 600) of B-RAF, a well-known cancer kinase target. The compound seems to be very selective indeed for this form, with no significant activity at wild-type RAF or other kinases (That glutamic acid makes all the difference). Update - that's overstating the case; see the comments section). A significant proportion of melanoma cases show this mutation, as it turns out.

Testing it out in the clinic has not been easy. As this Nature News piece details, one key was to come up with a better formulation than the original one. I can well believe it - azaindole kinase inhibitors are not the most tractable molecules on the planet, and PLX4032 doesn't look any less like a brick than the rest of 'em. (Update: fixed link to structure). The initial trials were done with crystalline material, which I'll bet doesn't dissolve worth a hoot, but the later runs were done with some sort of microprecipitated powder, which seems to behave better. They managed to get up to 720mg b.i.d., which is the sort of load you associate with antibiotics and similar horse pills, before dose-limiting tox set in.

Most of the patients in the study had the V600E mutation; the few that didn't showed no effects whatsoever. (And yes, this is an ethical study, because the standard of care for late-stage melanoma consists of everyone standing around wringing their hands). But of the group with the mutation, about 4/5ths of them showed partial or complete regression, which is unheard of.

Here's the bad news: that regression doesn't last. Of the people who responded to the drug, that response lasted from 2 to around 18 months. (And keep in mind, there were people with the mutation who also showed no response at all, for reasons that are totally unclear). What seems to be happening is either the tumor cells are mutating around the effect of PLX4032, coming up with yet another B-RAF variation, or there could be some cells around from the start that escape its effects (and then take over). We don't have survival data yet, but the best guess is that the drug will add a few months to the lives of these patients. It's not a cure, and that's the bad news.

But on the other hand, it's the first time anything has done much of anything for such patients. If we can find out why some of the V600E tumors don't respond, or better characterize the ones that re-occur after treatment, that could point the way to something more significant. That's not going to be easy - but it's not impossible, either. It's a start, for sure.

Comments (25) + TrackBacks (0) | Category: Cancer

September 3, 2010

Metformin Against Cancer?

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Posted by Derek

It's always good to hear about an older compound that may be doing good things that we didn't realize. The current example is metformin, the diabetes drug known to many by its brand name Glucophage, but a generic compound for some years now. Evidence has recently been accumulating that patients taking it over the long term may well have lower incidence of several types of cancer, which is a refreshing change from the usual creeping realizations in this business. (There's a reason for that - the opportunities to mess something up inside a cell, something you probably didn't even know was there, are far, far, more numerous than the opportunities to make something work the way you want).

A new paper may well have tracked down a mechanism for this effect, which adds to the sense that it's real. Here's a summary of the work - it looks like an mTOR-driven process, which is plausible. Specifically, it seems to inhibit the TORC1 pathway, though at least two different mechanisms. That's an important player in nutrient sensing and cellular growth, among a bewildering variety of other things, and the whole mTOR area has been the subject of oncology research for quite a long time now.

Metformin (and related biguanides) might be acting on it in a very useful way. Mice exposed to a known lung-cancer agent were substantially protected by pretreatment with the drug. What's not clear yet is if that direct TORC1 effect is the reason, or if it's a more general downstream effect having to do with metformin's effects on glucose levels and insulin signaling. If it's the latter, there are tumor lines that should (unfortunately) be able to evade the problem, specifically ones that have their PI3K signaling cranked up already, so it's going to be quite interesting to see how metformin does protecting against those. As has been noted many times, nutrient sensing, insulin signaling pathways, carcinogenesis, and mechanisms of aging are tangled together in ways that it's very much in our interest to unravel. (mTOR specifically is right in the middle of it, apparently).

These results (both the new mechanistic study in mice and the retrospective clinical observations) would seem to strongly suggest trying metformin out in patients with a high risk of developing various sorts of cancer. It also suggests that, other things being equal, Type II diabetics might want to use metformin to take advantage of its apparent side benefits. A protective effect would be very welcome news indeed - it's terribly difficult to do anything about most tumors once they've occurred, and the best thing would be for them not to appear in the first place.

Oh, and one more thing. If everyone had followed Sidney Wolfe's advice when metformin first came out - not to use it - we wouldn't have found out about these effects at all. Would we?

Comments (23) + TrackBacks (0) | Category: Cancer

August 30, 2010

Avastin For Metastatic Breast Cancer: The Whole Story

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Posted by Derek

Here's an excellent roundup of the Avastin story, referenced in an earlier post here.

I have to say, I've been disappointed in some of the commentary on this issue (which that article goes into as well). Too many people have jumped right to the conclusion that yep, here's what the new health care plan is going to do to us, yank life-saving medicines out of our hands because they cost too much. Well, I think that the health care bill was a disastrous idea, myself, and at the same time I still think that Avastin doesn't deserve approval for metastatic breast cancer.

The best evidence we have is that Avastin doesn't help these patients and may well even hurt them. That would be true even if it were free. And remember, off-label use is still perfectly legal. Anyone who wishes to spend their own money on something that does not appear to work - and that Wall Street Journal editorial aside, Avastin really doesn't, here - is free to do so. Getting everyone else to pay for it is quite another thing, and you'd think that conservatives and libertarians would find that argument more appealing than they seem to.

The FDA meets to discuss this issue on September 17. I wish everyone who's gearing up to write editorials about the decision would get up to speed on the facts before then.

Comments (7) + TrackBacks (0) | Category: Cancer | Drug Prices | Regulatory Affairs

August 17, 2010

Avastin: Taking It Back

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Posted by Derek

As if one were needed, here's an example of how rough the state of current oncology therapy is today. Avastin, the antibody-based therapy from Genentech/Roche, had been approved (conditionally) for advanced breast cancer, based on a study showing about a five-month benefit in tumor growth. (Everyone should already know that such numbers, for many types of cancer, are indeed enough to get an indication approved, and everyone has, I'm sure, already decided what they think about that.)

But the approval came with a requirement to follow up on those results. For one thing, the study that led to conditional approval didn't show much of a survival benefit, making the approval itself controversial at the time.. The follow-up work has shown that those initial results were right on target. For metastatic breast cancer, Avastin has something like a month-and-a-half survival benefit. That probably doesn't outweigh the risks, and the FDA is seriously thinking about revoking that earlier approval.

Based on these numbers, I think that they should go ahead and do that. The whole point of conditional or accelerated approval is that it can go either way when the harder numbers come in, and in this case, it seems pretty clear that the benefit isn't there. No one cares about tumor growth if it doesn't affect survival or (at the very least) quality of life. And in this case, the later studies have suggested that even the earlier tumor growth numbers were too optimistic. You have to be willing to abide by the evidence.

Because of Avastin's high cost, this is probably going to turn into a rationing-health-care argument - in fact, it probably has already. But I'm not even talking cost here. Avastin, by the evidence we have, does not seem to help advanced breast cancer patients. It wouldn't help them even if it were free.

Comments (30) + TrackBacks (0) | Category: Cancer | Clinical Trials

August 16, 2010

Cancer Cells: Too Unstable For Fine Targeting?

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Posted by Derek

The topic of new drugs for cancer has come up repeatedly around here - and naturally enough, considering how big a focus it is for the industry. Most forms of cancer are the very definition of "unmet medical need", and the field has plenty of possible drug targets to address.

But we've been addressing many of them in recent years, with incremental (but only rarely dramatic) progress. It's quite possible that this is what we're going to see - small improvements that gradually add up, with no big leaps. If the alternative is no improvement at all, I'll gladly take that. But some other therapeutic areas have perhaps made us expect more. Infectious disease, for example: the early antibiotics looked like magic, as patients that everyone fully expected to die started asking when dinner was and when they could go home. That's what everyone wants to see, in every disease, and having seen it (even fleetingly), we all want to have it happen again.

And it has happened for a few tumor types, most notably childhood leukemia. But we definitely need to add more to the list, and it's been a frustrating business. Believe me, it's not like we in the business aiming for incremental improvements, a few weeks or months here and there. Every time we go after a new target in oncology, we hope that this one is going to be - for some sort of cancer - the thing that completely knocks it down.

We may be thinking about this the wrong way, though. For many years now, there have been people looking at genetic instability in tumor cells. (See this post from 2002 - yes, this blog has been around that long!) If this is a major component of the cancerous phenotype, it means that we could well have trouble with a target-by-target approach. (See this post by Robert Langreth at Forbes for a more recent take). And here's a PubMed search - as you can see, there's a lot of literature in this field, and a fair amount of controversy, too.

That would, in fact, mean that cancer shares something with infectious disease, and not, unfortunately, the era of the 1940s when the bacteria hadn't figured out what we could do to them yet. No, what it might mean is that many tumors might be made of such heterogeneous, constantly mutating cells that no one targeted approach will have a good chance of knocking them down sufficiently. Since that's exactly what we see, this is a hypothesis worth taking seriously.

There are other implications for drug discovery. Anyone who's worked in oncology knows that the animal tumor models we tend to use - xenografts of human cell lines - are not particularly predictive of success. "Necessary but nowhere near sufficient" is about as far as I'd be willing to go. Could that be because these cells, however vigorously they grow, have lost (or never had) that rogue instability that makes the wild-type tumors so hard to fight? I haven't seen a study of genetic instability in these tumor lines, but it would be worth checking.

What we might need, then, are better animal models to start with - here's a review on some efforts to find them. From a drug discovery perspective, we might want to spend more time on oncology targets that work outside the cancer cells themselves. And clinically, we might want to spend more time studying combinations of agents right from the start, and less on single-drug-versus-standard-of-care studies. The disadvantage there is that it can be hard to know where to start - but we need to weigh that against the chances of a single agent actually working

Comments (52) + TrackBacks (0) | Category: Animal Testing | Cancer | Clinical Trials | Drug Development

June 23, 2010

Exelixis Gets a Compound Back

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Posted by Derek

Exelixis has long been a bit of a puzzle to outside observers. The company has developed a number of clinical candidates in oncology (many of them kinase inhibitors, I believe). In fact, for a while there, they seemed to have developed more clinical candidates than a company that size should have been able to manage. It was a bit alarming to employees of larger companies in the area.

And figuring out what the structures of these things were wasn't so easy, either. I once had the unenviable assignment of trying to break down a stack of their patent applications to see if I could find the lead structure for one of their compounds, and after a week or so I had to concede. None of my usual tricks worked - untangling and charting out the synthetic pathways from the experimental section to see the common threads, looking for sudden upticks in the amounts of intermediates or final compounds being prepared, looking to see if some compounds had been more completely characterized than others, and so on. No, these folks had done a fine job of sweeping up after themselves, and over the years I've run into other people who came to the same conclusion.

The company has had a long relationship with Bristol-Myers Squibb. There have been many twists and turns, but in 2008 the companies agreed to develop a compound called XL-139. (You won't quite be able to figure it out from that Exelixis page, but that announcement also marked the end of one of the broader agreements that the two companies had signed). Later that year came an announcement (also on that link above) about two more kinase inhibitors, XL-184 and XL-281, whose status hadn't been resolved earlier.

Now comes word that XL-184 has been returned to Exelixis. The press release, as press releases will, makes it seem as if the problem was that the compound was just too darn good:

"Given the recent progress of BMS' wholly-owned oncology pipeline and positive data generated by XL184, Exelixis and BMS were not able to align on the scope, breadth and pace of the ongoing clinical development of XL184."

They say that they're pleased to have the chance to develop the compound outside the meddling influence of BMS (well, not quite in those words naturally). But I'll bet they're not pleased to have to do it without BMS cash. Having the drug sent back makes you think that the larger company put it in the category of "Nothing we can't live without", although it's true that XL-184 is surely worth more to Exelixis. (Development of the other compound, XL-281, is apparently continuing).

My guess is that kinase inhibitors of this sort just look a lot less attractive than they did a few years ago. Several of them have made it to market, and while they can be profitable, the field is getting crowded. Mind you, they're all different from each other, but sorting out what works in the clinic is a long process. None of them seem (so far) to do anything dramatic against the most common tumor types. (Here's a recent article on just that problem). What Exelixis will make of XL-184 remains a mystery, probably to them just as much as to anyone else.

Comments (12) + TrackBacks (0) | Category: Cancer | Drug Development

June 22, 2010

Mylotarg and the FDA

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Posted by Derek

Someone completely outside the industry asked me the other day what I thought about the FDA. I replied that I had a lot of sympathy for them, actually. There's almost no way that they can avoid being yelled at by one group or another. You know - they're a bunch of foot-dragging nitpickers who are keeping effective medicines (things used in other industrialized countries, yet!) off the market here. Oh, hold it, it's Tuesday already - they're actually a bunch of incompetent industry shills who let all kinds of useless, toxic stuff through because they can't be bothered to do their jobs.

That's the sort of thing. If you want a good example of this, take a look at Mylotarg. Wyeth developed this oncology agent years ago for some forms of leukemia. It's a monoclonal antibody to CD33 (a cell-surface receptor found on leukocytes), conjugated to ozogamicin, a fairly aggressive chemotherapy agent. It was approved back in 2000 under "accelerated approval" rules, which are supposed to bring drugs for life-threatening conditions to market more quickly. The requirement is that companies continue to study such drugs after they're marketed, though.

Well, the studies have been completed on Mylotarg. It's not a very widely used drug, since it's only indicated for people 60 and older with particular forms of leukemia who aren't candidates for the more common therapies. But the numbers are in. . .and it turns out that people die more quickly while taking it than while taking the standard of care. Oh, dear. The drug has now been pulled from the market.

And there you have the FDA's dilemma: if they had sat on Mylotarg longer and required more studies, this probably wouldn't have happened. On the other hand, Wyeth might have decided to abandon it at that point - and not everything that gets accelerated approval is a Mylotarg. Some compounds that could actually help people could get lost that way. It's a real tightrope, and the rope is set up completely differently for every new drug. There's no way to get all these decisions right, but for life-threatening diseases, letting through more iffy compounds is still probably the right way to do it, I think.

Update: fixed all sorts of formatting and spelling issues, after taking a break from my real job to have a look (!)

Comments (10) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

June 14, 2010

Angiotensin Receptor Blockers and Cancer: For Real?

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Posted by Derek

Well, this could be nothing, or it could be big trouble: there's a report out that taking the angiotensin antagonists (the various "sartans") might be linked to increase risk of cancer. A meta-analysis of several large trials, reported in Lancet Oncology, patients in the treatment groups showed a 7.2% incidence of new cancer diagnoses, versus 6% for the control groups. These are large sample sizes, so that difference has a p-value of 0.016.

The authors wisely refuse to take the data any further, and call for more investigation, which certainly seems warranted. The whole renin-angiotensin system is certainly involved in angiogenesis, and thus could very plausibly have effects in oncology. But the surprising thing is that there's evidence that blockade of the receptors could actually cut down on tumor formation, too. If you'd taken a survey last week, you'd probably have gotten a lot of people to bet that these drugs would actually have a protective effect.

So what's going on? It's going to be quite a while before we find out. But an awful lot of people take these drugs, and now they're all wondering what to do. . .

Comments (9) + TrackBacks (0) | Category: Cancer | Cardiovascular Disease

June 8, 2010

Ipilimumab (And Progress Against Cancer)

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Posted by Derek

This time last year, Medarex made all sorts of headlines with their antibody ipilimumab. A press release from the Mayo Clinic made it sound like a miracle cure for prostate cancer; the company's stock soared, and they were acquired not long afterwards by Bristol-Myers Squibb. I wrote about ipilimumab once, and I still get email from people asking me if I know how they can possibly get some for their relatives with cancer.

As Jim Edwards points out at Bnet, though, this week's ASCO meeting has results for the drug that are more in keeping with what we've come to expect. The antibody had real effects in metastatic melanoma patients, and that's a good thing, because that's a particularly hard situation to show anything useful. (And all too many melanoma patients present after the disease has already gone metastatic, for that matter). From the data that BMS presented, there appears to be no doubt that ipilimumab extended survival.

But it did so by three or four months, on average, with some serious adverse events in the treatment group. As I said yesterday, this is the sort of progress that we generally make in oncology, not the oh-my-God-the-cancer-disappeared sort that last year's press release had people thinking about. And again, you can look at this news in two different ways. On the one hand, showing real statistical efficacy against metastatic melanoma is impressive: pretty much everything else we've got does nothing at all. But on the other hand, well. . .three and a half months.

For some people, that's definitely going to be worth it, while for others, they (and their heirs) would be better off not spending the money. That's a very hard decision, one of the hardest, but it is a decision. And either people will make it for themselves, or someone will make it for them. Given the continued emphasis on bringing down the costs of modern medical care - which doesn't look to be going away any time soon - you have to expect that there will be times that governments and/or insurance carriers will say "No, not for that price." Expect? It already happens. But it'll happen more.

This does present a problem for drug discovery. As many commenters noted yesterday, these are the sorts of incremental improvements that can add up in oncology. We're unlikely to hit many miracle-cure home runs, so we have to add a few months here and a few months there, learning as we go, and coming back around with better ideas next time. This takes money - big stacks of it - and we in the industry are expecting people (and their insurance companies, and their governments) to pay up. What if they don't, or not so much?

One thing we could see is companies finding themselves caught out, developing drugs in anticipation of a pricing structure that won't materialize. And it's true that strong pricing pressure will likely slow down progress in the whole field - after all, we don't have any other cheaper ways to develop drugs yet. But that doesn't mean that it couldn't happen. If we want to forestall it, I think we should make clear how incremental and expensive most oncology work is likely to be, and to point out that if there are miracle cures out there, that we're probably not going to find any of them without going through a lot of not-so-miraculous ones first.

Comments (21) + TrackBacks (0) | Category: Cancer | Drug Prices

June 7, 2010

Again, What's It Worth to You?

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Posted by Derek

Let's open up a painful subject here. This is prompted, partly, by the news the other day about Erbulin. The main reason I posted about that compound was because of its chemical complexity and total-synthesis heritage, both of which are unusual. But it's an oncology drug. As such, it looks like an awful lot of other drugs in that space.

And that's not good. Because we should face up to the fact that most of the newer anticancer compounds aren't so good, not in any absolute sense. (Most of the old ones, too, but those are rather cheaper, aren't they?) Too often, what we're looking at is an extension of a few weeks or months of life - life as a terminal cancer patient, mind you, but life nonetheless. The price you put on that will vary according to your circumstances, but in many cases we're asking a lot. Is it worth it?

Increasingly, that's not a question that's going to be answered by the patient alone, but by some combination of the patient and his or her insurance company. In other cases, it will have been answered well before by a country's national health service, when it did a cost/benefit analysis of the drug and decided whether it would even be included in a national formulary. That's the whole point of the UK NICE, and although their execution has not been trouble-free, the idea behind it is not going to go away.

Nor should it. Now, I think people should be able to spend their own money on what they want to spend it on. True, cancer patients are known for spending some of it, out of sheer desperation, on bizarre and worthless stuff. Taking advantage of these people by selling them Wonder Water or Miracle Mixture is a crime, as far as I'm concerned, and should be prosecuted. But I'm not advocating force to keep people from exercising their choice to buy the stuff, if it's out there, although I'd certainly like to talk them out of doing that. I'll reserve the force for the ones selling it, so that the crap is not out there for purchase in the first place.

But when it's other people's money being spent - an insurance company's, or tax money - those others should get a say. And here's where things get messy. Because while there's a difference between Wonder Water and the latest angiogenesis inhibitor or cell-cycle interrupter, it's not a meaningful a difference as anyone would like. True, one is likely to do nothing, and the other is likely to do something. But when "something" is "keeping you from dying in November, in order that you should die in March", well. . .you'd want something more, wouldn't you?

Let me say here that it's not for lack of trying. We in the business keep throwing our best punches in oncology. Here, here's a target that makes perfect sense - this thing should kill a cancer cell. Shouldn't it? I mean, cutting off the blood supply to a solid tumor is a good idea. Messing up mitosis, re-establishing programmed cell death: good ideas. But they just don't work as well as we'd hope that they would. We're not there yet.

And so we get these add-a-few-months-of-life drugs, because in most cases, that's all we're capable of delivering at the moment. But we're asking a lot of money for these things, and increasingly, the people who are really paying for them are asking whether anyone's getting a good deal.

I wrote about this situation a few years ago on this site, and I have to say, not much has changed - other than the pricing pressure, of course. I'll have some more to say about this issue this week, but I wanted to start people thinking - about where we are, and whether there are any ways out.

Comments (51) + TrackBacks (0) | Category: Cancer | Drug Prices

June 3, 2010

Eribulin Gets Reviewed, Finally

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Posted by Derek

So it looks like the FDA is giving reviewing Eisai's oncology drug Eribulin (E7389) a priority review. The company had hoped to get it reviewed three years ago, but the FDA told them to get back into the clinic and collect more data.
The compound is being reviewed for advanced breast cancer, and the earlier clinical data looked pretty good. (Head and neck tumors, on the other hand, didn't show much of a response). It binds to yet another site on tubulin (a popular site for various oncology agents), but in a rather complicated fashion that differs from the other agents in this category.

The compound is remarkable mainly for its brutal structural complexity, and for the fact that it's being made synthetically. It looks like a natural product, for sure, but it's actually a modified version of the right-hand side of halichondrin B, whose structure is still more horrific. Kishi's group at Harvard synthesized that beast back in 1992, and that work was the foundation of the synthesis of Eribulin. I don't think this is necessarily going to spark a renaissance of Big Natural Product Analog Synthesis inside the pharma labs, but it's quite a story. Here's hoping it has a good ending - we should know in September.

Comments (23) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

June 2, 2010

The Power of Photons, You Say?

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Posted by Derek

A longtime reader sends me word of a new company out in La Jolla, Nativis Pharmaceuticals, whose technology is most certainly eyebrow-raising. I think that the only way that I can do it justice is to quote directly from their web site; I wouldn't want to get anything wrong:

Nativis has developed and patented a breakthrough technology that captures the unique photon field (signal) of active pharmaceutical ingredients (API), or drugs. . .Every drug molecule in a solution is surrounded by a photon field that contains information unique to the molecule. With Nativis’ technology, the photon field, or “drug signal” can be recorded and then replicated for medical treatment. Nativis has proven in preliminary trials that the drug signal – or photonic signature – mimics the original chemical molecule and can unlock the same biological processes as the original to treat diseases, such as brain tumors. With the technology, the drug signal can be reproduced rapidly and flawlessly, each time containing all relevant biochemical information encoded into the new therapeutic signal to drive a biologic reaction. . .

There now, tell me that your eyebrows didn't get some exercise when you read that. I'm baffled. According to this story from the North County Times, Nativis has investors and advisors who are neither scam artists nor saffron-robed gurus, and unfortunately, the only other appropriate category I can think of is "victim". Am I wrong?

I say that because there have been ripoffs beyond number that claim to use some sort of strangely energized or structured water, which is what seems to be going on here (see below). Honestly, you could easily fill a 500-page book with them, in fine print, and there are more every day. And if the Nativis folks don't want to be taken for another member of that crowd, then they should do more to differentiate themselves from the scam artists (and no, linking to videos of Feynman explaining the basics of quantum electrodynamics is not enough). Here's why I say that - this is the company's explanation of their process:

MIDS (Molecular Interrogation and Data Systems) captures the photon field surrounding the solvation shell of a molecule in solution.

Captured photons are then imprinted into Coherence Domains in dipole (water-based) solution for delivery to patients; following administration, the photon payload chemically activates a non-water molecule for therapeutic effect.

The questions come tumbling out: what, exactly, is a "photon field"? And how do you capture one? Isn't a solvation shell a rather dynamic thing, which depends on (among other things) concentration, ionic strength, and pH? How do you imprint captured photons into something? And "Coherence Domains?" That sounds like optical coherence tomography or the like, but only vaguely. How do you imprint into one? And this creates a "photon payload"? How does that, whatever it is, not dissipate?

And that "chemically activates a non-water molecule", does it? By that, I presume that they mean a drug target. But my understanding of how a drug works on its target is that the drug has to be physically present, because it's interacting, on an atom-by-atom basis, with said target. Drugs engage in a complex dance of attraction and repulsion with their binding sites (with attraction winning out!), and this process is affected by electron density (charge), hydrogen bonding, van der Waals forces, and more besides. The drug molecule physically occupies that binding site, which forces the rest of its target into a different shape. And in many cases, it physically displaces water molecules while doing so, and while it's there, it keeps other molecules from coming in.

I don't see how a "photon payload" can do these things. If it's some real assembly of water molecules, I don't see how it holds together at room temperature. Besides, the water solvation shell of a drug molecule isn't what comes in and binds to a target; it's the molecule itself. Shedding those waters is a key energetic part of the whole process. And if it's not a real, physical assembly of water molecules, then what the heck is it? And here's another objection: either way, it sound as if they're taking this "drug signal" while the original drug is out there in solution. But the shape that most drugs have in solution isn't the one that most drug have when they bind to their targets; adopting that new shape is another key process.

No, I have a weakness for wild ideas, but not this wild. Nativis has a lot to prove: can they take the "drug signal" from a fluoroquinolone antibiotic and kill bacteria with it? Can they use the signal from a receptor agonist and see calcium or cAMP changes in a cell assay? Will the "drug signal" displace a reference compound in a radioligand binding assay? Can you do Michaelis-Menten kinetics with one of an enzyme inhibitor? Will it affect a protein's NMR spectrum? Can you determine its on- and off-rates in an SPR assay? Can you see a thermodynamic signature in a calorimeter?

And most importantly, will it help anyone who's sick? Well. . .Nativis says that they've shown efficacy in a mouse model of glioblastoma with the "drug signal" of taxol. They say that they hope to file an IND later this year, and to publish more details in the literature within the next few months. I cannot wait. If they really have data sufficient for an IND, then I will enjoy, most thoroughly, being proved wrong. And if this stuff works, we can all take the opportunity to learn some physics while glory, prizes, and huge amounts of money rain down on the Nativis folks, to a backdrop of cheering cancer patients.

I am, as this post shows, intensely skeptical. But these are issues that can be answered, completely answered, by experiment. Bring on the data, guys. I'm sticking with the blog category shown until then.

Update: John Butters, CEO of Nativis, has sent along some more information about his company's technology. Much of it seems to be based on work by del Giudice and Preparata on the properties of water. Those names rang a faint bell for me - turns out that their work pops up in all sorts of discussions of odd water effects: cold fusion, homeopathy, theories on the origins of life and of consciousness, and so very much on. I must confess that much of the physics is beyond my competence.

However, this all reminds me very much of homeopathy, and of the Benveniste affair and its aftermath, with many phrases ("digital biology") in common. I have to conclude, for now, that this is what's going on. In which case, I wish everyone involved - particularly the investors - the best of luck, because I have grave doubts that anything useful will come out of it. I will be delighted and amazed if I am proven wrong.

Comments (83) + TrackBacks (0) | Category: Cancer | Snake Oil

May 14, 2010

DCA And Cancer: More Results

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Posted by Derek

In early 2007 there was quite a stir caused by reports of dichloroacetate (DCA) salts as possible cancer therapies. I didn't cover it as well as I should have here, partly because I was in the final stages of getting laid off from my previous job at the time, but here's a good roundup from Orac while the story was going on. It appeared that dichloroacetate was quite active in a number of cancer cell lines, where it worked by some sort of metabolic disruption pathway, quite possibly involving the Warburg effect through inhibition of mitochondrial PDHK. In short form, what that means is that some of these tumors stop using glucose exclusively as an energy source, and divert more of it into other pathways where it's used as a feedstock for the synthesis of other biomolecules. That allows the cells to get by on less oxygen (since the traditional glucose pathways use up a fair amount), which is particularly important in a solid tumor. This is also tied with with a resistance to apoptosis (programmed cell death), so it makes a pretty good package, if you're a tumor cell. But it does leave them metabolically vulnerable, and there have been attempts over the years to target this. (The latest idea in the area is a kinase called PKM2, a good candidate for the key switch that turns on the whole Warburg effect).

The news sent a lot of people searching for their own sources of dichloroacetic acid, and also was the occasion for a lot of "Unpatentable Cancer Wonder Drug Ignored By Big Pharma" commentary, which is always enjoyable. A new paper is now out in Science Translational Medicine looking at DCA in glioblastoma. That's a good place to look, because aggressive solid tumors of that sort are probably the most vulnerable to a Warburg-effect strategy. The authors found that mitochondia from glioblastoma tissue isolated from a number of patients do indeed show the signs of altered metabolism, which DCA reversed in cell culture. And they present the results of treating 5 patients over a period of months with oral DCA therapy.

How'd it work? They were able to compare pre- and post-therapy tissue samples in only three of the patients, but all three showed signs that more cells were undergoing apoptosis, slowing the growth of the tumors. So this wasn't an amazing cancer-disappears result, but it definitely keeps the story going. Three patients is not enough to draw robust conclusions from, of course, and they did see some (reversible) neuropathy as a side effect, but I'd say that DCA is still worth looking into on a larger scale.

Should cancer patients just up and take it themselves? It's really hard to recommend that, since we still don't know a lot about what's going on with the stuff. But it's also hard to tell someone with a refractory solid tumor not to try whatever they can get their hands on.

Update: more from Orac, including details of all five patients treated in this study.

Comments (43) + TrackBacks (0) | Category: Cancer | Clinical Trials

May 10, 2010

Malcolm Gladwell on Synta and Oncology

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Posted by Derek

The folks at the New Yorker sent along this link to a new article by Malcolm Gladwell about Synta and their attempts to get elesclomol (STA-4783) to work as a melanoma therapy. (If you don't know how this one turns out, you might want to read the article before clicking on that second link).

Update: didn't realize that the full article was subscriber-only at the New Yorker site. Not sure if there's anything to be done about that, but I've dropped them a line. . .

Gladwell (an occasional reader of this blog) often takes some hits from experts in the fields he writes about, but after reading the article this morning, I think he's done a fine job of showing what drug discovery is like. His division between screening and rational drug design is a bit too sharply defined, to my eyes, but he gets all the important stuff right - namely, just how hard a business this is, how much luck is involved, and how much we don't know. Those are messages that a lot of people need to hear, and I hope that this piece helps get them out to a wide audience.

Comments (8) + TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History | Press Coverage

May 7, 2010

Environmental Cancer?

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Posted by Derek

I find the President's Cancer Panel report -at least, the general tone of it - hard to believe. Most of the headlines yesterday focused on the "grievous harm", "bombarding", and "grossly underestimated" statements, and suggested that there was an epidemic of environmentally-caused cancer. Since most age-adjusted cancer incidence rates have, in fact, been dropping, I find this a bit hard to believe.

Here's the whole report (whopping PDF). Update: that link may be bad - try here. It actually does mention that cancer rate data, but (as far as I can see) just sort of blows right past it. And while I take the point that endocrine disruptors and the like need to be watched (and that we really do need to study these things more), I don't see why the alarm bells need to be rung quite this loudly.

I see that the American Cancer Society seems to agree. My own views are closer to those of Bruce Ames (PDF) than to the President's panel. We should always be alert to possible environmental causes of cancer, but we should also realize that (as far as we can tell) they seem to be relatively minor.

Comments (35) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

May 6, 2010

Perverse Incentives In Clinical Trials

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Posted by Derek

I came across an article from 2007 that I'd missed, and I'm willing to bet others have, too. It's on the sometimes perverse incentives in developing oncology drugs (although the points in it apply to many other fields as well. The author (Tony Fiorino) is an investor, not a researcher, and seems to be an exceptionally clear-headed one.

He notes that larger profitable companies have more of an incentive to be careful about what drug candidates they take into the clinic, since they're spending their own profits when they do so. Start-up companies, on the other hand, tend to get valued according to how many clinical candidates they have going, so their incentive is to push things along rather more. . .briskly. This will be a familiar phenomenon to many readers here - the topic has come up whenever we talk about some compound wiping out in Phase III after what looked like promising data:

"This factor often leads development-stage companies to make very poor assessments with their own product candidates and to radically misjudge their likelihood of success. Indeed, if the fortunes of the entire company depend on the fate of a single phase II compound, and the interests of those deciding whether or not to enter phase III are tied entirely to the ongoing viability of the company, it would hardly seem surprising that companies push forward with the development of drugs when to objective outside observers further development seems futile. Indeed the market is likely to punish correct decision making by development-stage biotechnology companies. Given a set of questionable phase II data, the stock price of a company would suffer far more if management concluded it would be improper to expend shareholder capital on a phase III program likely to fail than if management decided to forge ahead into phase III on the basis of some dubious, post hoc subgroup analyses."

Of course, when this article was written, the funding environment was more permissive than it is today - but it will surely go that way again, and anyway, when the money is tight, the pressures to fight for it are even stronger.

"Thus, market forces do not produce efficient drug development; at least for the biotechnology industry, they may actually hinder it. This is particularly true in oncology drug development, where a set of unique circumstances conspire to make drug development more difficult and increase the likelihood that drug candidates are advanced too quickly. Zia et al1 documented a high rate of phase III failures in oncology, even when the phase III protocol uses a regimen identical to what was used in phase II. In particular, the lack of reliable surrogate markers and the common practice of looking for response rates in single arm trials make phase II oncology trials unreliable.

Most troubling, in my view (which is admittedly the view of a battle-scarred skeptic), oncology clinical development programs often appear to be designed specifically not to provide insight into the likelihood of success in phase III. . ."

Remind you of any events of the last few years? Fiorino's only answer to these problems is to call for the oncology clinical community to be more skeptical when it comes to enrolling patients in Phase III trials. And that might help a bit, but in a better world, we'd be running better Phase IIs.

Comments (19) + TrackBacks (0) | Category: Business and Markets | Cancer | Clinical Trials | Drug Development

May 3, 2010

SRT501 - A Trial Suspended

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Posted by Derek

A comment to this post on the Sirtris compound saga just had me checking And indeed the commenter is correct: a trial against myeloma of a combination of Velcade (bortezomib) and SRT501, which I believe is reformulated resveratrol itself, was suspended as of April 22 for "unexpected safety concerns".

There's no way of knowing what those are, and it's worth keeping in mind that a number of other studies have been completed with SRT501. But since there's been (as far as I can tell) no mention of this trial's halt anywhere, I thought it worth noting.

Comments (35) + TrackBacks (0) | Category: Aging and Lifespan | Cancer | Clinical Trials

April 27, 2010

Masses of Data, In Every Sample

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Posted by Derek

I've said several times that I think that mass spectrometry is taking over the analytical world, and there's more evidence of that in Angewandte Chemie. A group at Justus Liebig University in Giessen has built what has to be the finest imaging mass spec I've ever seen. It's a MALDI-type machine, which means that a small laser beam does the work of zapping ions off the surface of the sample. But this one has better spatial resolution than anything reported so far, and they've hooked it up to a very nice mass spec system on the back end. The combination looks to me like something that could totally change the way people do histology.

For the non-specialist readers in the audience, mass spec is a tremendous workhorse of analytical chemistry. Basically, you use any of a whole range of techniques (lasers, beams of ions, electric charges, etc.) to blast individual molecules (or their broken parts!) down through a chamber and determine how heavy each one is. Because molecular weights are so precise, this lets you identify a lot of molecules by both their whole weights - their "molecular ions" - and by their various fragments. Imagine some sort of crazy disassembler machine that rips things - household electronic gear, for example - up into pieces and weighs every chunk, occasionally letting a whole untouched unit through. You'd see the readouts and say "Ah-hah! Big one! That was a plasma TV, nothing else is up in that weight range. . .let's see, that mix of parts coming off it means that it must have been a Phillips model so-and-so; they always break up like that, and this one has the heavier speakers on it." But mass spec isn't so wasteful, fortunately: it doesn't take much sample, since there are such gigantic numbers of molecules in anything large enough to see or weigh.
Take a look at this image. That's a section of a mouse pituitary gland - on the right is a standard toluidine-blue stain, and on the left is the same tissue slice as imaged (before staining) by the mass spec. The green and blue colors are two different mass peaks (826.5723 and 848.5566, respectively), which correspond to different types of phospholipid from the cell membranes. (For more on such profiling, see here). The red corresponds to a mass peak for the hormone vasopressin. Note that the difference in phospholipid peaks completely shows the difference between the two lobes of the gland (and also shows an unnamed zone of tissue around the posterior lobe, which you can barely pick up in the stained preparation). The vasopressin is right where it's supposed to be, in the center of the posterior lobe.

One of the most interesting things about this technique is that you don't have to know any biomarkers up front. The mass spec blasts away at each pixel's worth of data in the tissue sample and collects whatever pile of varied molecular-weight fragments that it can collect. Then the operator is free to choose ions that show useful contrasts and patterns (I can imagine software algorithms that would do the job for you - pick two parts of an image and have the machine search for whatever differentiates them). For instance, it's not at all clear (yet) why those two different phospholipid ions do such a good job at differentiating out the pituitary lobes - what particular phospholipids they correspond to, why the different tissues have this different profile, and so on. But they do, clearly, and you can use that to your advantage.

As this technique catches on, I expect to see large databases of mass-based "contrast settings" develop as histologists find particularly useful readouts. (Another nice feature is that one can go back to previously collected data and re-process for whatever interesting things are discovered later on). And each of these suggests a line of research all its own, to understand why the contrast exists in the first place.
The second image shows ductal carcinoma in situ. On the left is an optical image, and about all you can say is that the darker tissue is the carcinoma. The right-hand image is colored by green (mass of 529.3998) and red (mass of 896.6006), which correspond to healthy and cancerous tissue, respectively (and again, we don't know why, yet). But look closely and you can see that some of the dark tissue in the optical image doesn't actually appear to be cancer - and some of dark spots in the lighter tissue are indeed small red cells of trouble. We may be able to use this technology to diagnose cancer subtypes more accurately than ever before - the next step will be to try this on a number of samples from different patients to see how much these markers vary. I also wonder if it's possible to go back to stored tissue samples and try to correlate mass-based markers with the known clinical outcomes and sensitivities to various therapies.

I'd also be interested in knowing if this technique is sensitive enough to find small-molecule drugs after dosing. Could we end up doing pharmacokinetic measurements on a histology-slide scale? Ex vivo, could we possibly see uptake of our compounds once they're applied to a layer of cells in tissue culture? Oh, mass spec imaging has always been a favorite of mine, and seeing this level of resolution just brings on dozens of potential ideas. I've always had a fondness for label-free detection techniques, and for methods that don't require you to know too much about the system before being able to collect useful data. We'll be hearing a lot more about this, for sure.

Update: I should note that drug imaging has certainly been accomplished through mass spec, although it's often been quite the pain in the rear. It's clearly a technology that's coming on, though.

Comments (9) + TrackBacks (0) | Category: Analytical Chemistry | Biological News | Cancer | Drug Assays

March 30, 2010

GeneVec's Pancreatic Cancer Therapy Crashes

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Posted by Derek

Another promising Phase II oncology idea goes into the trench in Phase III: GenVec has been working on a gene-therapy approach ("TNFerade") to induce TNF-alpha expression in tumors. That's not a crazy idea, by any means, although (as with all attempts at gene therapy) getting it to work is extremely tricky.

And so it has proved in this case. It's been a long, hard process finding that out, too. Over the years, the company has looked at TNFerade for metastatic melanoma, soft tissue sarcoma, and other cancers. They announced positive data back in 2001, and had some more encouraging news on pancreatic cancer in 2006 (here's the ASCO abstract on that one). But last night, the company announced that an interim review of the Phase III trial data showed that the therapy was not going to make any endpoint, and the trial was discontinued. Reports are that TNFerade is being abandoned entirely.

This is bad news, of course. I'd very much like gene therapy to turn into a workable mode of treatment, and I'd very much like for people with advanced pancreatic cancer to have something to turn to. (It's truly one of the worst diagnoses in oncology, with a five-year survival rate of around 5%). A lot of new therapeutic ideas have come up short against this disease, and as of yesterday, we can add another one to the list. And we can add another Promising in Phase II / Nothing in Phase III drug to the list, too, the second one this week. . .

Comments (8) + TrackBacks (0) | Category: Biological News | Cancer | Clinical Trials

March 29, 2010

Antisoma's Phase III Disaster

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Posted by Derek

We get reminded again and again that interesting Phase II results are only that: interesting, and no guarantee of anything. Antisoma (and their partner Novartis) are the latest company to illustrate that painful reality - their drug AS404 (vadimezan) looked in Phase II as if it might be a useful addition to oncology treatments, but has completely missed its endpoints in the bigger, more realistic world of Phase III. The trial was halted after an interim analysis showed basically no hope of it showing benefit if things continued.

There are many reasons for why these things happen. Phase II trials are typically smaller, and their patient populations are more carefully selected. And they're quite susceptible to wishful thinking. They're designed to keep things going, to show some reason to proceed, and they often do. If your drug candidate makes it through Phase II, that may say more about how you designed the trial than it says about the compound.

That's not to say that getting past Phase II is meaningless. Compared to having no efficacy data at all, it's a big step. But Phase III, when a compound goes out to a larger and more diverse patient population, is a much bigger one. And plenty of candidates aren't up to it.

Comments (28) + TrackBacks (0) | Category: Cancer | Clinical Trials

March 26, 2010

Diminishing Returns

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Posted by Derek

As we slowly attack the major causes of disease, and necessarily pick the low-lying fruit in doing so, it can get harder and harder to see the effects of the latest advances. Nowhere, I'd say, is that more true than for cardiovascular disease, which is now arguably the most well-served therapeutic area of them all. It's not that there aren't things to do (or do better) - it's that showing the benefit of them is no easy task.

Robert Fortner has a good overview of the problem here. The size of the trials needed in this area is daunting, but they have to be that size to show the incremental improvements that we're down to now. He also talks about oncology, but that one's a bit of a different situation, to my mind. There's plenty of room to show a dramatic effect in a lot of oncology trials, it's just that we don't know how to cause one. In cardiovascular, on the other hand, the space in which to show something amazing has flat-out decreased. This is a feature, by the way, not a bug. . .

Comments (40) + TrackBacks (0) | Category: Cancer | Cardiovascular Disease | Clinical Trials | Drug Industry History

March 25, 2010

The Problem With Research on Aging

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Posted by Derek

Nature has a review of a new book on the anti-aging field, Eternity Soup by Greg Critser, and I found this part very instructive. The same things apply to several other therapeutic areas where people see fast money to be made:

Critser's methodical portrayal of a host of anti-ageing practitioners reveals some fascinating people who seek to convince others that they can purchase longer and healthier lives like any other commodity. He makes clear that many anti-ageing treatments are based more on faith healing than on science, and that the industry defends them and presents them to the public with evangelical zeal. Scientific gerontologists who point out the lack of empirical evidence behind the claims are shouted down, sued for libel or made fun of as lab technicians or statisticians with no experience in treating patients.

Critser became aware during his research of why the ridiculed scientific gerontologists find the anti-ageing industry so aggravating. The industry closely monitors the field for any advances, and when it spots something that might be turned into a commercial enterprise, the product is repackaged, branded and sold to the public as the next great breakthrough of its own invention. . .

It's interesting, though, that the cancer-cure quacks tend not to ride so much on the current research. A lot of that stuff seems just to be completely made up, without even a connection to something in the scientific literature. Perhaps that's because there are occasional spontaneous remissions from cancer, but none from old age. . .

Comments (9) + TrackBacks (0) | Category: Aging and Lifespan | Cancer | Snake Oil

Nanoparticles and RNA: Now In Humans

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Posted by Derek

In recent years, readers of the top-tier journals have been bombarded with papers on nanotechnology as a possible means of drug delivery. At the same time, there's been a tremendous amount of time and money put into RNA-derived therapies, trying to realize the promise of RNA interference for human therapies. Now we have what I believe is the first human data combining both approaches.

Nature has a paper from CalTech, UCLA, and several other groups with the first data on a human trial of siRNA delivered through targeted nanoparticles. This is only the second time siRNA has been tried systemically on humans at all. Most of the previous clinical work has been involved direct injection of various RNA therapies into the eye (which is a much less hostile environment than the bloodstream), but in 2007, a single Gleevec-resistant leukaemia patient was dosed in a nontargeted fashion.

In this study, metastatic melanoma patients, a population that is understandably often willing to put themselves out at the edge of clinical research, were injected with engineered nanoparticles from Calando Pharmaceuticals, containing siRNA against the ribonucleotide reductase M2 (RRM2) target, which is known to be involved in malignancy. The outside of the particles contained a protein ligand to target the transferrin receptor, an active transport system known to be upregulated in tumor cells. And this was to be the passport to deliver the RNA.

A highly engineered system like this addresses several problems at once: how do you keep the RNA you're dosing from being degraded in vivo? (Wrap it up in a polymer - actually, two different ones in spherical layers). How do you deliver it selectively to the tissue of interest? (Coat the outside with something that tumor cells are more likely to recognize). How do you get the RNA into the cells once it's arrived? (Make that recognition protein is something that gets actively imported across the cell membrane, dragging everything else along with it). This system had been tried out in models all the way up to monkeys, and in each case the nanoparticles could be seen inside the targeted cells.

And that was the case here. The authors report biopsies from three patients, pre- and post-dosing, that show uptake into the tumor cells (and not into the surrounding tissue) in two of the three cases. What's more, they show that a tissue sample has decreased amounts of both the targeted messenger RNA and the subsequent RRM2 protein. Messenger RNA fragments showed that this reduction really does seem to be taking place through the desired siRNA pathway (there's been a lot of argument over this point in the eye therapy clinical trials).

It should be noted, though, that this was only shown for one of the patients, in which the pre- and post-dosing samples were collected ten days apart. In the other responding patient, the two samples were separated by many months (making comparison difficult), and the patient that showed no evidence of nanoparticle uptake also showed, as you'd figure, no differences in their RRM2. Why Patient A didn't take up the nanoparticles is as yet unknown, and since we only have these three patients' biopsies, we don't know how widespread this problem is. In the end, the really solid evidence is again down to a single human.

But that brings up another big question: is this therapy doing the patients any good? Unfortunately, the trial results themselves are not out yet, so we don't know. That two-out-of-three uptake rate, although a pretty small sample, could well be a concern. The only between-the-lines inference I can get is this: the best data in this paper is from patient C, who was the only one to do two cycles of nanoparticle therapy. Patient A (who did not show uptake) and patient B (who did) had only one cycle of treatment, and there's probably a very good reason why. These people are, of course, very sick indeed, so any improvement will be an advance. But I very much look forward to seeing the numbers.

Comments (8) + TrackBacks (0) | Category: Biological News | Cancer | Clinical Trials | Pharmacokinetics

March 12, 2010

The PSA Test for Prostate Cancer: Useless

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Posted by Derek

The discoverer of the prostate-specific antigen (Richard Ablin) has a most interesting Op-Ed in the New York Times. He's pointing out what people should already know: that using PSA as a screen for prostate cancer is not only useless, but actually harmful.

The numbers just aren't there, and Ablin is right to call it a "hugely expensive public health disaster". Some readers will recall the discussion here of a potential Alzheimer's test, which illustrates some of the problems that diagnostic screens can have. But that was for a case where a test seemed as if it might be fairly accurate (just not accurate enough). In the case of PSA, the link between the test and the disease hardly exists at all, at least for the general population. The test appears to have very little use in detecting prostate cancer, and early detection itself is notoriously unreliable as a predictor of outcomes in this disease.

The last time I had blood work done, I made a point of telling the nurse that she could check the PSA box if she wanted to, but I would pay no attention to the results. (I'd already come across Donald Berry's views on the test, and he's someone whose word I trust on biostatistics). I'd urge other male readers to do the same.

Comments (22) + TrackBacks (0) | Category: Biological News | Cancer

February 26, 2010

HER2 Confusion

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Posted by Derek

For years now, drug companies and journalists have been touted the new era of personalized medicine. This is one of those things that always seems to be arriving, but is taking its time getting here. The industry has sunk a huge pile of money into biomarker research, and it's safe to say that it hasn't paid off yet - although, at the same time, one still has to think that it should, eventually.

Nature Biotechnology has a good article that shows how tricky the whole business can be. HER2 is one of the more validated cancer biomarkers, and there's a drug (Herceptin) that's targeted specifically for breast cancer patients that express it. So how's that going? Not so well:

A recent study from the University of California, San Francisco, reveals that one in five HER2 tests gives the wrong answer1. Furthermore, the article, which reviews the medical literature, reports that as many as two-thirds of breast cancer patients who should be tested for HER2 are not, and consequently a significant fraction of women treated with Genentech's Herceptin (trastuzumab) have never been tested for HER2 overexpression.

The health benefit provider Wellpoint, of Indianapolis, might dispute that finding. According to Genentech staff scientist Mark Sliwkowski, the insurer has data showing that 98% of its breast cancer patients are tested. However, doctors differ in their views on testing before prescribing Herceptin. “Some doctors don't know how to interpret test results, they prefer just to prescribe it and assess the patient's progress,” says Michael Liebman of the patient stratification company Strategic Medicine of Kennett Square, Pennsylvania.

More than a decade after the drug received US Food and Drug Administration (FDA) approval, the personalized medicine paradigm clearly has holes. . .

That it does. As the article goes on to explain, there are doubts about how good many of the existing HER2 tests are, worries about how they don't always agree, questions about whether some HER2-negative patients might be benefiting from Herceptin anyway, and more questions about those results due to uncertainties about the tests. That's the state of the art right there, folks, and it's clear that we have a long way to go. I don't see any reason why biomarkers (of various kinds, not just genetic) won't help us figure out which patients should be getting which drugs, but don't let anyone tell you that we're there yet.

Comments (15) + TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs

February 22, 2010

The Front Lines of Cancer Treatment

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Posted by Derek

The New York Times is starting a series of articles on the clinical trials of a recent B-Raf inhibitor (from Plexxikon and Roche, PLX4032). The first installment is an excellent look at what early-stage clinical research is like in this field. For example:

Typically, Phase 1 trials are limited to a few dozen patients and end when the dose reaches the point where side effects like rashes and diarrhea make patients too uncomfortable.

Dr. Flaherty and Dr. Chapman started the first three patients on 200 milligrams per day. After two months with no side effects — and no response — they doubled it.

Two more months passed, still nothing. They gave three more patients 800 milligrams, the equivalent of the dose that made tumors stop growing in mice. Even shrinking tumors, the doctors knew, would not mean the cancer had been cured but might at least offer a reprieve.

Dr. Flaherty pounced on the scans when they arrived. In some patients, tumors had remained the same size. “Maybe we’re starting to see something,” he could not help thinking. But at the next set of scans, the disease had progressed. On conference calls, Dr. Nolop sometimes referred to those patients as “responders.”

“They’re not responders,” Dr. Flaherty gently corrected him: under the accepted definition, tumors had to shrink to qualify patients as responders.

By the time they had doubled the dose four times, Dr. Flaherty could not help wondering if the targeted therapy skeptics were right. Dr. Chapman, crisp and businesslike on the weekly calls, supplied no comfort. He pointed out new research that B-RAF was mutated even in benign moles, and therefore could not be the key driver in melanoma. . .

What everyone involved in this work has to deal with is living between two very different mental states: you have to see people who are dying, and who you will probably not be able to help, even with your best efforts. But it's also possible that the next new thing you try might be the thing that keeps some of them alive. It's a hard place to work.

Back here in early research we don't see the patients, of course (which is good, since I'm pretty sure I couldn't take it). But we also have the same narrow path to walk: most of the compounds we make aren't drug candidates. Most of the drug candidates we send on for development fail. But the answer to that is not to stop making drug candidates, because every so often, something works.

Comments (17) + TrackBacks (0) | Category: Cancer | Clinical Trials

January 11, 2010

MAGL: A New Cancer Target

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Posted by Derek

I do enjoy some good chemical biology, and the latest Cell has another good example from the Cravatt group at Scripps (working with a team at Brigham and Women's Hospital over here on this coast). What they've done is profile various types of tumor cells using an activity-based probe to search for changes in serine hydrolase enzymes. Those are a large and diverse class (with quite a few known drug targets in them already), and there had already been reports that activity in this area was altered as cancer cell lines became more aggressive.

What they tracked down was an enzyme called MAGL (monoacylglyceride lipase). That's an interesting finding. Cancer cells have long been known to have different ideas about lipid handling, and several enzymes in that metabolic area have been proposed over the years as drug targets. (The first one I can think of is fatty acid synthase (FAS), whose elevated presence has been correlated with poor outcome in several tumor types). In general, aggressive tumor cells seem to run with higher levels of free fatty acids, for reasons that aren't quite clear. Some of the downstream products are signaling molecule, and some of these lipids may just be needed for elevated levels of cell membrane synthesis.

But it looks from this paper as if MAGL could be the real lipid-handling target that oncology people have been looking for, though. The teams inhibited the enzyme with a known small molecule (well, relatively small), and also via RNA knockdown, and in both cases they were able to disrupt growth of tumor cell lines. The fiercer the cells, the more they were affected, which tracked with the MAGL activity they had initially. On the other hand, inducing higher expression of MAGL in relatively tame tumor cells turned them aggressive and hardy. They have a number of lines of evidence in this paper, and they all point the same way.

One of those might be important for other reasons. The teams took the cell lines with impaired MAGL activity, and wondered if this could be rescued by providing them with the expected products that the enzyme would deliver. Stearic and palmitic acid are two of the fatty acids whose levels seem to be heavily regulated by MAGL, and sure enough, providing the MAGL-deficient cells with these restored their growth and mobility. As the paper points out specifically, this could have implications for a relationship between obesity and tumorigenesis. (I'd add a recommendation to look with suspicion at other conditions that lead to higher-than-usual levels of circulating free fatty acids, such as type II diabetes, or even fasting).

It may be that I particularly enjoyed this paper because I have a lipase-inhibiting past. As anyone who's run my name through SciFinder or Google Scholar has noticed, I helped lead a team some years ago that developed a series of inhibitors for hormone-sensitive lipase, a potential diabetes target. We were scuppered, though, by the fact that this enzyme does (at least) two different things in two totally different kinds of tissue. Out in fat and muscle, it helps hydrolyze glycerides (in fact, it's right in the same metabolic line as MAGL), and that's the activity we were targeting. But in steroidogenic tissues, it's known as neutral cholesteryl ester hydrolase, and it breaks those down to provide cholesterol for steroid biosynthesis. Unfortunately, when you inhibit HSL, you also do nasty things to the adrenals and a few other tissues. There's no market for a drug that gives you Addison's disease, I can tell you.

So I wondered when I saw this paper if MAGL has a dual life as well. If I'd ever worked in analgesia or cannabinoid receptor pharmacology, though, I'd have already known the answer. MAGL also regulates the levels of several compounds that signal through the endocannabinoid pathway, and has been looked at as a target in those areas. None of this seems to have an affect on the oncology side of things, though - this latest paper also looked at CB receptor effects on their cell lines that were deficient in MAGL, and found no connection there.

So, what we have from this paper is a very interesting cancer target (whose crystal structure was recently reported, to boot), a new appreciation of lipid handling in tumors, and a possible rationale for the connections seen between lipid levels and cancer in general. Not bad!

Special bonus: thanks to Cell's video abstracts, you can hear Ben Cravatt and his co-worker Dan Nomura explain their paper on YouTube. The journal has recently enhanced the way their papers are presented online, actually, and I plan to do a whole separate blog entry on that (and on video abstracts and the like).

Comments (9) + TrackBacks (0) | Category: Biological News | Cancer | Diabetes and Obesity

January 7, 2010

Is XMRV the Cause of Chronic Fatigue Syndrome? Or Anything?

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Posted by Derek

Last fall it was reported that a large proportion of patients suffering from chronic fatigue syndrome also showed positive for a little-understood retrovirus (XMRV). This created a lot of understandable excitement for sufferers of a conditions that (although often ill-defined) seems to have some puzzling biology buried in it somewhere.

Well, let the fighting begin: a new paper in PLoS One has challenged this correlation. Groups from Imperial College and King's College have failed to detect any XMRV in a similar patient population:

. . .Unlike the study of Lombardi et al., we have failed to detect XMRV or closely related MRV proviral DNA sequences in any sample from CFS cases. . .Based on our molecular data, we do not share the conviction that XMRV may be a contributory factor in the pathogenesis of CFS, at least in the U.K.

Interestingly, XMRV has also been reported in tissue from prostate cancer patients, but recent studies in Germany and Ireland failed to replicate these results. Could we be looking at a geographic coincidence, a retroviral infection that's found in North America but not in Europe, and one whose connection with these diseases is either complex or nonexistent?

Note: as per a comment on this post, the Whittemore Peterson Institute is firing back, claiming that their original work is valid and that the London study has many significant differences. PDF of their release here.

Comments (94) + TrackBacks (0) | Category: Biological News | Cancer | Infectious Diseases

October 5, 2009

A Nobel for Telomerase

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Posted by Derek

As many had expected, a Nobel Prize has been awarded to Elizabeth Blackburn (of UCSF), Carol Greider (of Johns Hopkins), and Jack Szostak (of Harvard Medical School/Howard Hughes Inst.) for their work on telomerase. Blackburn had been studying telomeres since her postdoc days in the late 1970s, and she and Szostak worked together in the field in the early 1980s, collarborating from two different angles. Greider (then a graduate student in Blackburn's lab) discovered the telomerase enzyme in 1984. She's continued to work in the area, as well she might, since it's been an extremely interesting and important one.

Telomeres, as many readers will know, are repeating DNA stretches found on the end of chromosomes. It was realized in the 1970s that something of this kind needed to be there, since otherwise replication of the chromosomes would inevitably clip off a bit from the end each time (the enzymes involved can't go all the way to the ends of the strands). Telomeres are the disposable buffer regions, which distinguish the natural end of a chromosome from a plain double-stranded DNA break.

What became apparent, though was that the telomerase complex often didn't quite compensate for telomere shortening. This provides a mechanism for limiting the number of cell divisions - when the telomeres get below a certain length, further replication is shut down. Telomerase activity is higher in stem cells and a few other specialized lines. This means that the whole area must be a key part of both cellular aging and the biology of cancer. In a later post, I'll talk about telomerase as a drug target, a tricky endeavour that straddles both of those topics.

It's no wonder that this work has attracted the amount of attention it has, and it's no wonder either that it's the subject of a well deserved Nobel. Congratulations to the recipients!

Comments (20) + TrackBacks (0) | Category: Aging and Lifespan | Biological News | Cancer | Current Events

September 11, 2009

Antioxidants and Cancer: Backwards?

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Posted by Derek

Readers may remember a study from earlier this year that suggested that taking antioxidants canceled out some of the benefits of exercise. It seems that the reactive oxygen species themselves, which everyone's been assuming have to be fought, are actually being used to signal the body's metabolic changes.

Now there's another disturbing paper on a possible unintended effect of antioxidant therapy. Joan Brugge and her group at Harvard published last month on what happens to cells when they're detached from their normal environment. What's supposed to happen, everyone thought, is apoptosis, programmed cell death. Apoptosis, in fact, is supposed to be triggered most of the time when a cell detects that something has gone seriously wrong with its normal processes, and being detached from its normal signaling environment (and its normal blood supply) definitely qualifies. But cancer cells manage to dodge that difficulty, and since it's known that they also get around other apoptosis signals, it made sense that this was happening here, too.

But there have been some recent reports that cast doubt on apoptosis being the only route for detached cell death. This latest study confirms that, but goes on to a surprise. When this team blocked apoptotic processes, detached cells died anyway. A closer look suggested that the reason was, basically, starvation. The cells were deprived of nutrients after being dislocated, ran out of glucose, and that was that. This process could be stopped, though, if a known oncogene involved in glucose uptake (ERBB2) was activated, which suggests that one way a cancer cells survive their travels is by keeping their fuel supply going.

So far, so good - this all fits in well with what we already know about tumor cells. But this study found that there was another way to keep detached cells from dying: give them antioxidants. (They used either N-acetylcysteine or a water-soluble Vitamin E derivative). It appears that oxidative stress is one thing that's helping to kill off wandering cells. On top of this effect, reactive oxygen species also seem to be inhibiting another possible energy source, fatty acid oxidation. Take away the reactive oxygen species, and the cells are suddenly under less pressure and have access to a new food source. (Here's a commentary in Nature that goes over all this in more detail, and here's one from The Scientist).

They went on to use some good fluorescence microscopy techniques to show that these differences in reactive oxygen species are found in tumor cell cultures. There are notable metabolic differences between the outer cells of a cultured tumor growth and its inner cells (the ones that can't get so much glucose), but that difference can be smoothed out by. . .antioxidants. The normal process is for the central cells in such growths to eventually die off (luminal clearance), but antioxidant treatment kept this from happening. Even more alarmingly, they showed that tumor cells expressing various oncogenes colonized an in vitro cell growth matrix much more effectively in the presence of antioxidants as well.

This looks like a very strong paper to me; there's a lot of work in it and a lot of information. Taken together, these results suggest a number of immediate questions. Is there something that shuts down normal glucose uptake when a cell is detached, and is this another general cell-suicide mechanism? How exactly does oxidative stress keep these cells from using their fatty acid oxidation pathway? (And how does that relate to normally positioned cells, in which fatty acid oxidation is actually supposed to kick in when glucose supplies go down?)

The biggest questions, though, are the most immediate: first, does it make any sense at all to give antioxidants to cancer patients? Right now, I'd very much have to wonder. And second, could taking antioxidants actually have a long-term cancer-promoting effect under normal conditions? I'd very much like to know that one, and so would a lot of other people.

After this and that exercise study, I'm honestly starting to think that oxidative stress has been getting an undeserved bad press over the years. Have we had things totally turned around?

Comments (43) + TrackBacks (0) | Category: Biological News | Cancer

August 26, 2009

Thalidomide for Myeloma: Whose Idea Was It?

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Posted by Derek

So, if you're a patient with a rare disease (or a relative of a patient with one), and you have an idea for repurposing an old drug for treatment. . .and you get a company interested, and it actually works. . .works to the point that the company takes in a billion or two dollars a year. . .what then?

Some readers will have guessed that I'm talking about thalidomide and Celgene, and right they are. Beth Jacobsen is the person involved - her husband died of multiple myeloma, but her medical sleuthing had turned up the idea of using thalidomide as a therapy for the disease, and she kept up the pressure to have the idea tried out. Celgene's mentioned her in annual reports, and she's been thanked by name in a publication on the clinical results.

But now she's suing Celgene, saying that they misappropriated her idea. Complicating the issue is the question of whether the late Judah Folkman was really the source of the inspiration, in a phone conversation with Jacobsen (earlier versions of the story have it that way, but the lawsuit apparently tells it differently). Which way did it happen? Is Jacobsen indeed owed compensation? And whether she is or not, will she be able to convince a court? Matt Herper has the story at Forbes.

I'll defer my own comments until I know a bit more about the case, but this is definitely an interesting one. I can add something that might be of relevance, though: a search in PubMed for "thalidomide myeloma" turns up 64 pages of references, almost all of them post-1999. But there is this one, from Italy in 1963. Has the idea been around for that long? Someone who can track down that journal can tell us. . .

Comments (21) + TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History | Patents and IP

August 4, 2009

Wasted Money, Wasted Time?

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Posted by Derek

Now, while we've been talking about how much basic research is done in industry, or how much clinical research gets done in academia, here's something that might bear on the discussion. Too much of what looks like useful clinical research on the academic side is actually wasted effort. The New York Times has been running a series called "The Forty Year War", looking at the history of the "War on Cancer", and the latest installment is on clinical trials.

It's been a problem for some time now that there aren't enough patients to go around for many cancer trials. Breast cancer is an especially problematic area, last I heard. It's high-profile, fairly high-incidence, and a lot of investigational anticancer agents are lined up to take a whack at it. So many, in fact, that there aren't enough breast cancer patients available in the US, nowhere near, and the same situation obtains in a number of other areas.

Much of this problem comes from low recruitment rates. As the Times article makes clear, only three per cent of adult cancer patients are enrolled in any kind of trial at all. Many cancer patients want to stick with the best therapy that's currently known, and don't want to add any uncertainty to what they're already dealing with. It's hard to blame them, but that does make the state of the art advance more slowly.

Another factor that may come as a surprise is that many oncology practices find that they lose money by participating in trials. The reimbursement-to-paperwork ratio doesn't always come out very well, especially for centers that don't do a lot of clinical research and haven't been able to streamline the process as much as possible. When they look at the number of patients that they can serve, given the time that's taken up, the trials start to make less sense.

Finally, and this is the least excusable factor on the list, there are many trials that really shouldn't be run at all. The Times does work in a line about how some studies by drug companies are just "designed to persuade doctors to use their drugs." My take on that is that these studies usually are designed to do that by showing that their drug actually works better, which is not such a bad thing. But note this other problem:

There are more than 6,500 cancer clinical trials seeking adult patients, according to, a trials registry. But many will be abandoned along the way. More than one trial in five sponsored by the National Cancer Institute failed to enroll a single subject, and only half reached the minimum needed for a meaningful result, Dr. Ramsey and his colleague John Scoggins reported in a recent review in The Oncologist.

Even worse, many that do get under way are pretty much useless, even as they suck up the few patients willing to participate. These trials tend to be small ones, at single medical centers. They may be aimed at polishing a doctor’s résumé or making a center seem at the vanguard of cancer care. But they are designed only to be “exploratory,” meaning that there are too few patients to draw conclusions or that their design is less than rigorous.

“Unfortunately, many patients who are well intentioned are in trials that really don’t advance the field very much,” said Dr. Richard Schilsky, an oncologist at the University of Chicago and immediate past president of the American Society of Clinical Oncology.

I don't want to dump a bucket of tar on all academic and publicly funded clinical research, because there's a lot of good stuff that goes on as well. (And remember, the publicly basic research is very valuable indeed). But the next time someone tells you about the number of clinical trials run outside of the drug industry, you might want to keep those above figures in mind.

Not all trials are created equal, not by a long shot. But the ones that we run in industry, from what I can see, tend to have a better chance of relevance. That's partly because we're spending our own money on them, and with a goal of finding drugs that people will spend money on in turn. It focuses one's efforts. It's not like we never waste money in this business, but I'm very much willing to bet that we waste it less often than happens with public funds. Companies trying to get an agent through the clinic tend not to set up meaningless trials just to make everyone's resume look better. That I can tell you.

Comments (24) + TrackBacks (0) | Category: Academia (vs. Industry) | Cancer | Clinical Trials

June 9, 2009

Avastin's Numbers

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Posted by Derek

Here's a fascinating (and alarming) look at the clinical data from the recent trial of Avastin (bevacizumab) in adjuvant colorectal cancer (that is, post-surgical therapy). This was an issue in the recent Roche/Genentech takeover, since it could significantly enlarge the market for the drug. According to the In Vivo Blog, the one-year interim look at the data (adding Avastin to the standard chemotherapy regimen) was nearly good enough to stop the trial early. There were 2,710 patients enrolled, and an additional six events would have pushed things over the top, statistically.

The trial went on, though, with two more years of standard therapy as follow-up. But by the (pre-set) three-year endpoint it turned out that there was no eventual real benefit to adding Avastin back in that first year. So what's the story? Is it that you need to keep giving the combination regime? Would those-one year results have held up? Or is this just a case of real long-term survival numbers wiping out what seems to be a promising short-term result?

It looks like Genentech may be gearing up to put that first theory to a test, and I wish them luck. Long-term tolerability will be an issue, and long-term cost will be a big one, too. They're going to have to show some pretty impressive numbers to overcome those two concerns. . .as impressive as, well, as those first-year interim ones they had. Will that effect dissipate or not?

Time and money will answer that little question. But for now, consider what would have happened if a few more patients had shown disease-free survival in time for that interim analysis. The trial would have been stopped early, all kinds of people would have gone on Avastin for their first year of adjuvant therapy. . .and this year we would have seen that it was apparently doing no good at all, at least in the take-it-for-a-year-and-stop mode. Clinical trial design: a real high-wire act.

Comments (9) + TrackBacks (0) | Category: Cancer | Clinical Trials

June 1, 2009

Akt and Mek, But Not PDQ

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Posted by Derek

Well, the ASCO meeting has been roaring along, with dozens of press releases coming out. (Go to Google News and type that acronym in if you want to get the full experience). They range from the pretty-interesting to the despair-inducing, but one bit of news struck me as particularly worth noting. That's the early-stage deal between Merck and AstraZeneca to combine two of their development candidates in a Phase I trial.

That's Merck's AKT inhibitor MK-2206 and AZ's Mek inhibitor AZD6244, and there's room to think that combining those two mechanisms could be beneficial. But as that In Vivo Blog link details, this deal wasn't initiated through any official contact between the two companies. Rather, someone from Merck and someone from AZ got to talking while they were going through airport security in Dublin, and recognized each other's names. A mere year and a half later, the deal was born.

There's a lot to learn from that story. For one, big drug companies are not, for the most part, looking to do early-stage deals with other big drug companies. Perhaps we'll see more of these in the future, but in general, it's about the least likely form of partnership. Another thing to note is how long it took for this idea to bear fruit. Eighteen months is about right for companies of this size to make up their minds about something like this - and you can decide that (since the oncology field is so complicated) that this is a reasonable period of evaluation, or you can decide, equally objectively, that delays of that magnitude remind you of a sauropod turning around in puzzlement three hours after something bit its tail.

I'm impressed that the deal was made at all. The usual path for new ideas of this sort is to the graveyard, especially in very large organizations, so I have to assume that some people within each company must have really pushed things along to make it happen. It's part of the general bias toward inaction: it's harder to get beaten up for decisions that you didn't make, compared to decisions that you did. Missed opportunities are often invisible.

So, no matter how long it took, or even whether it works out, I still have to congratulate the people involved on getting this agreement to happen. It's worthwhile, I think, just because it's the sort of thing that doesn't happen very often. And I have the feeling that (in the coming years) we're going to have to explore a lot of things in this industry that haven't happened very often. We'll need the practice!

Comments (4) + TrackBacks (0) | Category: Business and Markets | Cancer | Clinical Trials | Drug Development | Drug Industry History

May 20, 2009

But You Can't Make Them Take It?

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Posted by Derek

Well, we can all study biochemical mechanisms in tumor cells every day of the week. And we can crank out tens of thousands of potential clinical candidates to hit them, run the assays, and then turn around and do it again. We can send things through all sorts of tox testing, take them to the clinic, try them against all sorts of terrible cancers, and amass enough data to make it through the FDA. Then we can let the oncologists continue to try variations, combinations, and regimens in the continuing search for something that works.

And every so often, we actually succeed. Childhood Hodgkin's lymphoma has one of the highest cure rates of all cancers. We can actually do something about that one (as opposed to, say, pancreatic cancer, which we can't do much about at all). Children who would otherwise die - and die slowly - now get a chance to live, to grow up.

But we can't, apparently, convince everyone of this. Many readers will have heard over the last few days of the case of Daniel Hauser of Minnesota, a 13-year-old diagnosed with Hodgkin's a few months ago. Instead of going in for rounds of chemotherapy, the boy (who has said that he doesn't believe that he's sick) and his family have opted for "Native American alternative therapy", and have fled from a court order. The boy's mother, who apparently does believe that he's sick, has said that she's treating him with "herbal supplements, vitamins, and ionized water".

These will, almost certainly, allow the lymphoma to kill him. Chemotherapy and radiation, on the other hand, will very likely allow him to live. If someone is bleeding to death from an arterial wound, anyone trying to heal them by invoking spiritual powers or alternative therapies would (and should) be shoved aside by any onlooker with a tourniquet. Daniel Hauser is bleeding to death as well: just more slowly, and in front of many more onlookers.

Comments (31) + TrackBacks (0) | Category: Cancer | Current Events | Snake Oil

May 7, 2009

Angiogenesis Inhibitors: Helping or Hurting?

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Posted by Derek

Now, here’s something to think about: can angiogenesis inhibitors, the famous class of tumor-starving cancer drugs, actually make some kinds of cancer worse?

This unnerving thought comes courtesy of two recent studies on VEGF pathway inhibitors which present what calls "intriguing, almost perplexing evidence" of just that. One team studied the effects of an anti-VEGF-receptor antibody or the VEGF kinase inhibitor Sutent (sunitinib) in mouse models of pancreatic cancer or glioblastoma multiformis. These are two very nasty tumors, and they’re just the sort of thing that people would like to be able to treat when a new drug comes along. But treatment with either the antibody or the small molecule significantly increased the number of metastatic cancers in the animal models, and I mean significantly: like 6% highly invasive tumors in the controls versus over 50% in the treated group. Admittedly, those numbers were in immune-compromised animals, but in mice with normal immune function, the numbers of metastatic tumors still rose by two- to four-fold.

The other study looked at injections of either metastatic breast cancer cell lines or melanoma lines in mouse models. The authors reproduced the effects of Sutent on the former – it inhibits growth of locally placed tumors, as it should (on past evidence). But if you inject cells into the bloodstream, the story is different. Pre- or post-injection treatment of the mice with Sutent led to an increase in metastatic tumors and a decrease in survival relative to untreated mice. Similar results were obtained with Nexavar (sorafenib), which also hits the VEGF kinase, among others.

That “among others” might be significant. The antibody study does make you think that this is a VEGF-driven effect, but it’s important to remember that both Sutent and Nexavar hit a famously wide variety of kinases. And as a Nature item on these results points out:

It is important to emphasize that both studies clearly recapitulate the clinical data that anti-angiogenic therapies can have significant, albeit transitory, effects on localized tumour growth. However, they raise interesting questions about the timing of anti-angiogenic therapy and whether combining these agents with chemotherapy or other targeted agents can counteract the observed unfavourable effects.

Oh, yes. Among these questions are whether the other VEGF-targeting drugs (like Genentech's Avastin) have this effect. You'd have to presume that they would. And what about other therapies directed at other anti-angiogenic targets?. They might, if the effect is brought on simply by low oxygen levels in tumor cells, or it might be something specific to VEGF. We also don't know, in general, which sorts of tumors respond in this way and which don't. But these findings should have effects on clinical practice, and soon. They didn't quite come out of the blue - it's been known since the anti-angiogenic drugs were developed that they didn't actually seem to cure cancers so much as knock them down for varying lengths of time. And in many cases, patients only survive a few months longer after treatment.

Every time I write something like that, though, I'm tempted to quote Peter Altenberg and say "What's so only"? But there still seems to be so much more potential in the idea - the same potential that led to a lot of hype and craziness a few years ago - and perhaps we're beginning to see where things went wrong. Can they be put right, or not?

And you know, perhaps it's for the best that Judah Folkman himself isn't still around to see these latest results. I don't think he would have despaired, but it wouldn't have been easy news for him to hear. . .

Comments (21) + TrackBacks (0) | Category: Cancer

May 6, 2009

Into the Clinic. And Right Back Out.

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Posted by Derek

Here's a good example of why all of us in the industry tiptoe into Phase I trials, the first-in-man studies. A company called SGX, recently acquired by Eli Lilly, has been developing a kinase inhibitor (SGX523) targeting the enzyme cMET. That's a well-known anticancer drug target, with a lot of activity going on in the space.

SGX's specialty is fragment-based design, and they've spoken several times at meetings about the SGX523 story. The starting point for the drug seems to have come out of X-ray crystallographic screening (the company has significant amounts of X-ray synchrotron beamline time, which you're going to need if you choose this approach). They refined the lead, in what (if you believe their presentations) was a pretty short amount of time, to the clinical candidate. It seems to have had reasonable potency and pharmacokinetics, very good oral bioavailability, no obvious liabilities with metabolizing enzymes or the dreaded hERG channel. And it was active in the animal models, however much you can trust that in oncology.

So off to the clinic they went. Phase I trials started enrolling patients in January of last year - but by March, the company had to announce that all dosing had been halted. That was fast, but there was a mighty good reason. The higher doses were associated with acute renal failure, something that most certainly hadn't been noticed in the mouse models, or the rats, or the dogs. It turns out that the compound (or possibly a metabolite, it's not clear to me) was crystallizing out in the kidneys. Good-looking crystals, too, I have to say. I can't usually grow anything like that in the lab; maybe I should try crystallizing things out from urine.

Needless to say, obstructive nephropathy is not what you look for in a clinical candidate. There's no market for instant kidney stones, especially when they appear all over the place at the same time. The patients in the Phase I trial did recover; kidney function was restored after dosing was stopped and the compound had a chance to wash out. But SGX523, which was (other than its unlovely structure) a perfectly reasonable-looking drug candidate, is dead. It didn't take long.

Comments (38) + TrackBacks (0) | Category: Cancer | Clinical Trials | Toxicology

April 30, 2009

Dendreon's Stock: What the Hey?

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Posted by Derek

We now have more data on Dendreon’s results for their prostate cancer therapy Provenge, and the numbers do, in fact, look good. This isn't a cure for refractory prostate cancer, but there seems to be a real statistical improvement in survival, with side effects no worse than the placebo group, and that should be enough for the FDA. In oncology you have to take what you can get.

What’s bizarre is the trading that went on in the company’s stock just before they started presenting on Tuesday. For reasons that are still unclear, a horrendous wave of selling hit within the space of a few minutes, and the stock went down as if hit with a club. Having risen to nearly $25 by about 1 PM, trading was halted in the stock at 1:27, with it now going for $11.81. As the company’s shareholders raved and cursed in utter consternation, the company was detailing exactly the results they’d been hoping to hear.

Wednesday, the stock shot straight back up to its former levels, but that doesn’t help the many people who (prudently, they thought) had put stop-loss orders in and had thus already been sold out. This Bloomberg story has a fellow who was cashed out at $9.31, which must make him wonder (1) just what the hell was going on, anyway, and (2) just what it means to halt trading in a stock, if you’re going to find yourself traded out of it at an even lower price.

I can’t help out with question (1) – I have to say, I’d like to know the answer to that one myself. But as for (2), that’s the problem with stop-loss orders, particularly in a stock that doesn’t have much of a float. Movements, especially downward ones, come suddenly and discontinuously, and the stock doesn't hit all the grace notes on the way down (as Fred Schwed
used to say).

So good luck to Dendreon, and to the patients who will use Provenge. Dendreon's investors, on the other hand, have probably been through the power-wash and spin cycle so many times that they hardly know what's hit them.

Comments (6) + TrackBacks (0) | Category: Business and Markets | Cancer

April 14, 2009

Dendreon's Revenge?

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Posted by Derek

Post updated below - DBL Dendreon is a company that's really been through it, as have their investors. Many will remember the upheaval back in 2007, when the company showed what they felt were impressive results for their autologous prostate cancer immunotherapy Provenge, got a favorable reception from the FDA's advisory panel, but were then hit with an "approvable" letter asking for more data. (Here are three posts on that: before, during, and after).

Well, the company is back with more data, in 512 patients. And initial reports are that the numbers look good. They're doing a conference call as I write, so we'll know more shortly, and I'll update this post as things become more clear.

Update: Hmmm. On the conference call, the company has declined to present any numbers, saying that it's bound by a blackout requirement for its presentation at the American Urological Association on April 28th. Their main statement seems to have been that the drug met its primary endpoint, reducing the risk of death compared to a placebo. There are a lot of other questions about Provenge - whether it slows the progression of prostate cancer or not, for example - but survival is presumably the bottom line. That was the main focus of the whole trial (as opposed to the cancer-progression endpoint of their smaller, earlier one).

So we'll see at the end of the month how impressive the statistics look. The market's reacting well to the news, although you could argue that the stock has pulled back a bit. It closed yesterday at 7 and change, traded over 21 during the morning, and is around 17 now. (Of course, some of that pullback could be from people giddily selling their shares on the news, just as some of the spike could well have been some people rather less giddily covering their short positions).

Comments (17) + TrackBacks (0) | Category: Business and Markets | Cancer | Regulatory Affairs

March 26, 2009

The Motions of a Protein

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Posted by Derek

So, people like me spend their time trying to make small molecules that will bind to some target protein. So what happens, anyway, when a small molecule binds to a target protein? Right, right, it interacts with some site on the thing, hydrogen bonds, hydrophobic interactions, all that – but what really happens?

That’s surprisingly hard to work out. The tools we have to look at such things are powerful, but they have limitations. X-ray crystal structures are great, but can lead you astray if you’re not careful. The biggest problem with them, though (in my opinion) is that you see this beautiful frozen picture of your drug candidate in the protein, and you start to think of the binding as. . .well, as this beautiful frozen picture. Which is the last thing it really is.

Proteins are dynamic, to a degree that many medicinal chemists have trouble keeping in mind. Looking at binding events in solution is more realistic than looking at them in the crystal, but it’s harder to do. There are various NMR methods (here's a recent review), some of which require specially labeled protein to work well, but they have to be interpreted in the context of NMR’s time scale limitations. “Normal” NMR experiments give you time-averaged spectra – if you want to see things happening quickly, or if you want to catch snapshots of the intermediate states along the way, you have a lot more work to do.

Here’s a recent paper that’s done some of that work. They’re looking at a well-known enzyme, dihydrofolate reductase (DHFR). It’s the target of methotrexate, a classic chemotherapy drug, and of the antibiotic trimethoprim. (As a side note, that points out the connections that sometimes exist between oncology and anti-infectives. DHFR produces tetrahydrofolate, which is necessary for a host of key biosynthetic pathways. Inhibiting it is espccially hard on cells that are spending a lot of their metabolic energy on dividing – such as tumor cells and invasive bacteria).

What they found was that both inhibitors do something similar, and it affects the whole conformational ensemble of the protein:

". . .residues lining the drugs retain their μs-ms switching, whereas distal loops stop switching altogether. Thus, as a whole, the inhibited protein is dynamically dysfunctional. Drug-bound DHFR appears to be on the brink of a global transition, but its restricted loops prevent the transition from occurring, leaving a “half-switching” enzyme. Changes in pico- to nanosecond (ps-ns) backbone amide and side-chain methyl dynamics indicate drug binding is “felt” throughout the protein.

There are implications, though, for apparently similar compounds having rather different effects out in the other loops:

. . .motion across a wide range of timescales can be regulated by the specific nature of ligands bound. Occupation of the active site by small ligands of different shapes and physical characteristics places differential stresses on the enzyme, resulting in differential thermal fluctuations that propagate through the structure. In this view, enzymes, through evolution, develop sensitivities to ligand properties from which mechanisms for organizing and building such fluctuations into useful work can arise. . .Because the affected loop structures are primarily not in contact with drug, it is reasonable to envision inhibitory small-molecule drugs that act by allosterically modulating dynamic motions."

There are plenty of references in the paper to other investigations of this kind, so if this is your sort of thing, you'll find plenty of material there. One thing to take home, though, is to remember that not only are proteins mobile beasts (with and without ligand bound to them), but that this mobility is quite different in each state. And keep in mind that the ligand-bound state can be quite odd compared to anything else the protein experiences otherwise. . .

Comments (3) + TrackBacks (0) | Category: Biological News | Cancer | Chemical News | In Silico

February 11, 2009

Kinases: Hot or Not?

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Posted by Derek

For the last ten or fifteen years, untold amounts of time and money have been spent developing drugs to inhibit kinase enzymes. Just go take a look at KinasePro’s archives; that’ll give you the idea. Huge programs have been run at all the major drug companies, and any number of smaller ones have been founded just on the strength of one kinase inhibitor or another.

The enthusiasm isn’t hard to understand. For those of you outside the med-chem / biochem worlds, kinase enzymes are there to stick phosphate groups into other molecules, which is a very widely used signaling pathway. A phosphate completely changes the character of the part of a molecule where it’s attached, changing what other partners it will recognize and bind to. This takes place generally on to some sort of free OH group. That doesn’t narrow things down much, though, since there a lot of incredibly important small molecules with OH groups that get phosphorylated. Adding to the fun, several amino acids (serine, threonine, and tyrosine) have OH groups on them, and the means that nearly every decent-sized protein has plenty. The patterns of their phosphate groups turn their activities on and off, determine where they go and what they’ll recognize. It’s a major, major switching mechanism for protein activity – you can’t overstate its importance. Here's the classic family tree of the protein kinases, just to give you the idea. (And in case you’re wondering, there is indeed a whole different class of enzymes, the phosphatases, that take the things back off again - whole different bag of snakes, those guys).

There are hundreds and hundreds of kinase enzymes, and I think it’s safe to say that they’re involved in just about every important biochemical process you can think of. The downside of working on them is that, well, they’re involved in just about every important biochemical process you can think of. (Try this on for size, or this, to get the idea). How do you get them to do what you want?

Well, we’re still not sure about that. I go back far enough to remember when kinases were considered nearly impossible to work with as drug targets, because no one could figure out how you’d get selectivity. But once we figured out how to make molecules that recognized the “hinge” region common to most of these enzymes, the game was on. You can make blunderbuss molecules that inhibit dozens of enzymes at the same time, or (in some cases) you can narrow down on a mere handful, or on just one.

But how far do you want to go? That’s where we’re “over-asked”, as the German expression translates. The downstream effects of many of these enzymes are absolutely bewildering in normal cells, and the differences in disease states are even more of a tangle. It’s no surprise at all that most kinase inhibitors have shown up first in oncology, because that’s where you can get away with the most severe side effects. There are plenty of tempting opportunities in inflammation, diabetes, cardiovascular disease, and other areas, but those have been slower to come along.

The experience with the cancer-targeting drugs has been mixed. You have your Gleevec (imatinib) – pretty selective, works pretty well on a very limited group of patients. And you have your hand grenades, like Sutent (sunitinib) or Nexavar (sorafenib), which hit a lot of kinases and work (to some degree) on a lot of different things. But none of them are magic bullets, for sure. So do you want selectivity or not? The only answer we can offer is (still) “that depends”.

These days, there’s a distinct “kinase hangover” in the industry. It’s not as hot a field as it was. “Not again” is the usual feeling on seeing yet another patent or publication on yet another structure that inhibits XYZ kinase. It’s not as hot an area as it was a few years ago – the belief is that many of the best targets have either wiped out in the clinic, are being tried there now, or haven’t yielded reasonable chemical matter to even get there.

My guess is that we’re waiting, whether we know it or not, for our understanding of the biology to catch up. We have all these compounds, with all these different fingerprints, and we’ve generated this huge pile of mixed data that we can’t quite make sense of. That adds to the frustrated “been there” feeling. The cure for it is to have a better idea of what we’re doing and why, but that’s coming on much more slowly. And because that’s slow, the kinase field may never regain its hot status. But who knows, it may make it all the way to useful and valuable, bypassing “hot” completely.

Comments (19) + TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History

December 4, 2008

Curse Of the Lost Compounds

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Posted by Derek

There are some groups of compounds that seem to have a curse on them. They show up in drug screening, they have activity that’s often too good to ignore, but hardly anyone can manage to turn one of them into a drug.

Trifluoromethyl ketones are one example of this. They’re classic inhibitors of proteases, especially serine proteases, and of other enzymes that depend on a serine in their active site. That’s because that ketone really isn’t much of a ketone – the fluorines make the carbon rather unhappy when it’s in that state, electron-poor and ready to pick up a nucleophile and go tetrahedral again. Trifluoromethyl ketones are generally seen in their hydrated state, unless you take care to dry them out, and they’ll work an active-site serine OH into their scheme as well. So you end up with a covalent inhibitor, but a reversible one – the activity comes on slowly, and the compound comes off slowly, too. That trick can work with cysteine nucleophiles, and the hydrate form is also known to coordinate with active-site zinc atoms – so it’s no surprise that the enzyme inhibition literature on these things is mighty extensive: proteases, lipases, esterases, deacetylases, the list goes on for a while.

But although several of these have gone into the clinic over the years, I can’t think of one that’s make it all the way to the market (I’d be glad to hear of any that I’ve overlooked). The best guess is that this isn’t the fault of the functional group, but of the targets it’s been applied to. Some of these enzymes just haven’t panned out, so perhaps the trifluoromethyl ketone awaits its day in the sun.

Another group of this sort is the hydroxamic acid. Its strength is its coordination to zinc atoms, so you see it all over the place in the metallaloprotease literature, and in other zinc-y fields like histone deacetylases. And in vitro, it hardly has a peer. I’ve seen list after list in the literature comparing various zinc-binding head groups, and likely as not, the hydroxamic acid sets the standard every time.

But the reason you see those lists is that people are trying to find something that’ll work other than a hydroxamic acid. There are numerous complaints, ranging from “hydroxylamine is explosive on large scale, you know” and “they’re a pain to make reproducibly” through “they have ugly PK in the animal models” all the way up to “they’re toxic” and “how many of them have ever made it through the clinic?”. How much merit each of these have can be debated, but all together they make an unpleasant picture.

In this case, though, I do know of one that’s made it - SAHA (Zolinza, vorinostat). That one came out of a long-term academic project involving Paul Marks at Sloan-Kettering and Ron Breslow's lab at Columbia, and is one of the not-so-numerous examples of drugs that have made it from the university to the marketplace. Merck signed up to do the clinical and regulatory lifting on this one, and it's now marketed for cutaneous T-cell lymphoma.

So it is possible to get a hydroxamic acid through. "Well, yeah," say the voices, "for cancer, sure. Home of the world's only boronic acid-containing drug. Home, if you really want to get down to it, of nitrogen mustards and God knows what else. Cancer." And it's true that the standards are a bit more relaxed there. I wouldn't necessarily want to give someone a hydoxamic acid every day for the rest of their life, true - the things coordinate iron, for one thing, which isn't always good. But there are other fields where short-term therapy makes sense, and we probably haven't seen the last of this functional group, either.

Comments (30) + TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History

September 19, 2008

Sunesis: No Substitutions Allowed?

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Posted by Derek

A colleague mentioned to me the other day that Sunesis Pharmaceuticals had let many of its remaining research staff go back during the summer – they’re battening down to try to get their main clinical candidate through for leukemia and ovarian cancer. That’s a common phase of life for a small company trying to go it alone. Clinical trials are expensive, and so are scientists, and sometimes a company finds that it can’t afford both at the same time. Amylin, to pick one example, went through so many cycles of that (starting in the mid-1990s) that I completely lost count.

The Sunesis news struck me, though, because if you go back a few years in the literature, they’re all over the place. The company was aggressively investigating (and promoting) a technique called “tethering” as a platform for drug discovery. Back around 2003, they were all over the journals with it.

Tethering was one of those neat ideas which seems to have been a lot of work to reduce to practice. It’s a variation, in its way, of another one of those techniques called Dynamic Combinatorial Chemistry. In DCC, you take a good-sized collection of compounds which can form reversible bonds with each other. Thiols (R-SH) have been used a lot, since they can form disulfides (R-SS-R), which can easily come apart and re-form with other thiols. In the presence of some target or template, such as the binding site of a protein, the idea is that any disulfide combination that manages to bind well will get enhanced in the final mixture, since it spends more time out of the swim of potential reactants. Comparing the product distribution with and without the target protein can point you to a potential lead structure to optimize. (You can also turn it around and make synthetic receptors (PDF) for molecules that you're interested in).

The idea behind tethering was, at least in one of its main variations, to introduce an extra thiol group into a target protein somewhere close to its active site. Then this mutant protein would be screening against a library of small molecules with thiol groups of their own, with the idea that if there was a binding site near that thiol that it would be found by preferential disulfide formation between it and some member of the screening library. Then came the second step. Normal, unmutated protein would be exposed to a mix of that preferred thiol and a library of other potential thiol coupling partners, in an attempt to find another preferred extension into the binding cavity. So this was basically a way to do DCC, but giving it a leg up by trying to make sure that there was a good amount of at least one thing that could bind to some relevant part of the target.

That tells you that standard from-the-ground-up DCC must have some difficulties, since if it worked as well as its concept you wouldn’t need to put your thumb on the scales like that. But I was never sure how well tethering worked, either. The company published numerous examples of it, but I don’t know if any of these compounds ever got anywhere (and indeed, I’m not at all sure that their current clinical candidate was discovered by this technique).

There are several places where things could break down. Making a mutant protein introduces some uncertainty, for starters. That SH group might not change things, or it might change them just enough so that the binding site you find doesn’t quite exist when you switch to the wild type. And any binding site you find in the first round isn’t necessarily a productive one – the original protein SH group was targeted to try to dangle out over the right part of the protein, but there are no guarantees about that. Past that, even if you get through the second round and find some new disulfide hits (no sure thing), they are, well. . .they’re disulfides. And those are poor bets for drugs.

That’s where the real weak point of DCC is in general, to my mind. Using reversible reactions gives you compounds with too much potential to fall apart, so the first thing you have to do is replace those bonds with something sturdier – and that’s not always easy, or even possible. There are very, very few clean substitutions available in the chemical world. Nothing’s quite like a nitrile except a nitrile, and there’s only one thing shaped exactly like a t-butyl group: another t-butyl. Likewise, the only thing that’s guaranteed to look and act like a disulfide is a disulfide. A two or three carbon chain replacement is the logical place to start, but that might be synthetically tricky, or (even more often) might turn out to be a completely different sort of compound once you’ve made it.

In the end, I think tethering turned out to be an excellent means to get some very interesting papers published in some good journals. (The publications have continued to this day). But beyond that, I’m not so sure. I’d be glad to hear from any ex-Sunesis people with other views. . .

Comments (23) + TrackBacks (0) | Category: Cancer | Drug Industry History

September 12, 2008

BMS vs. Imclone: Godzilla Exchanges Legal Language With Mothra

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Posted by Derek

I haven’t mentioned the attempt by Bristol-Meyers Squibb to buy out Imclone until now, but there’s a nice . The reasons for the move are unsurprising – BMS would like all the revenue from Erbitux, instead of just a share of it, and sees some value coming up in Imclone’s pipeline (such as their development drug candidate IMC-11F8, vide infra). They’ve waiting quite a while, and apparently feel that the time is right – the only question is how much money such a move will cost them.

And that’s the question, all right, since Carl Icahn started talking this week about a mysterious preliminary offer from some unnamed other company for significantly more money ($70/share) than BMS is putting up. A lot of investors seem to have expected a sigh, a roll of the eyes, and a reach back into the pocket for more money - IMCL has been trading above the original $60/share offer. But that’s not what they’re getting, at least so far.

In a letter, Bristol-Meyers Squibb’s CEO is now reminding Icahn of a few things that you’d think would be obvious. One of them is that their offer is well-supported and requires no due diligence, as opposed to nebulous preliminary figures from companies that no one will name. The next paragraph is even more to the point:

As you know, Bristol-Myers holds the exclusive, long-term marketing rights in the United States to ERBITUX® and related compounds, including IMC-11F8. Bristol-Myers has no intention of agreeing to any modifications to these rights. ImClone also should understand that our offer is for the entire company, and any potential restructuring of the company could severely jeopardize ImClone’s value and deprive ImClone’s stockholders of the benefits of our offer.

That’s about the size of it, and I think that this message is being delivered in the way that Icahn understands best – right across the top of the head, with some good wrist action. There’s no reason for BMS to give up on their rights to Imclone’s products, except on terms that would make other potential buyers lose interest. Why would they? There is, I should add, quite a dispute between the two companies about who has the rights to that development antibody, IMC-11F8. Imclone has recently been acting as if BMS has no rights to it at all, but as that WSJ link makes clear, two years ago they clearly stated to Merck KGaA that the antibody falls within the scope of the BMS agreement. It's hard for me to see how they'll get out of that, and even if they do, it'll take a lot of expensive wrangling.

So, if there really is a company willing to go to $70 a share for Imclone, with revenue still flowing to BMS and plenty of legal uncertainty on top of that, well, this is the time for them to speak up. I’m not sure that there is one, despite what Icahn says, but perhaps he’s hoping for one to materialize. He’s always reckoned Imclone to be worth vast amounts more than people who know anything about oncology think it is, so maybe he sees no problem with those figures. Anyone else live in the same world?

Update: Icahn has already replied, in a fashion that makes this affair look to go on a while. He says that he "doesn't understand the point" of the BMS letter, and goes on to say:

. . .With respect to a potential restructuring of ImClone, rest assured that we will act in what we consider the best interests of all our shareholders and not just Bristol.

Obviously, should you wish to make another offer which you believe we would not find inadequate, you are free to do so. Upon receipt of that offer, we will respond appropriately.

Well! My guess is at this point that BMS will sit tight and wait to see if anyone really wants to get in on all this action - betting, reasonably I think, that no one will. I would enjoy it if they raised their bid to, say, $60.25, just to steam up Icahn's windows, but I assume that they're above that. As time goes on, with no competing bids in sight, I would think that Icahn and his board-of-buddies would have to submit the BMS bid to the shareholders - wouldn't they?

Comments (3) + TrackBacks (0) | Category: Business and Markets | Cancer

September 8, 2008

The Complicated Causes of Cancer

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Posted by Derek

Since I was just banging on the table (or the lab bench) the other day about how many diseases aren’t single-factor, and about how many diseases (like cancer) aren’t even single diseases, I thought this would be a good time to haul out some evidence for that. The data are here thanks to some recent papers by groups who are sequencing various tumor lines, looking for common mutations as new drug targets. (The Cancer Genome Atlas, an NIH project, is behind a lot of work in this area).

But what’s become clear, if it wasn’t already, is that various cancer lines have a startlingly wide array of mutations. Recent work from Bert Vogelstein’s group at Johns Hopkins (with a host of collaborators) and from the CGA itself now show that there are an average of 63 mutations in pancreatic cancer cells, and 47 in glioblastomas, two of the nastiest tumors around. The first impulse might be to think “Great! Plenty of drug targets to go around!”

But hold on. For one thing, even though these mutations are surely not all equal, the fact that there are so many makes you wonder about whether attacking any one of them alone can make much of a difference. And different patients can have varying suites of those mutations, so it’s difficult to imagine that going after just one or two of those targets will be enough to treat a majority of cases. This work follows up on earlier studies in other tumor lines, all of which seem to point in the same direction: patients who are currently classed as having the same type of cancer really don’t.

This won’t come as a surprise to most oncologists, who have seen for themselves the widely varying responses to current therapies. The challenge is to figure out what these various changes mean, and how to classify patients to give them the best therapy. It’s not going to be easy. Just doing the math on the possible interactions of several dozen mutations with a list of possible treatment regimes is enough to make you pause. The hope is that most patients will fall into broad categories, which will line up, more or less, with broad categories of treatment. But it’s not going to be a good fit, most likely, and even getting those approximations to work is taking a lot of time and effort. (Just think back about how long you’ve been hearing about the wonderful new age of personalized medicine. . .)

We're not going to be able to do this, either, without a second (and much harder) stage of research: figuring out why these various mutations are important. Some of them seem to make reasonable sense, but it's not at all clear what a lot of them are doing, especially in concert with each other. There's an awful lot of ditch-digging work out there waiting to be done. For now, the quotes from Vogelstein in a Nature News summary can’t be improved on, though. This is the current state of the art, and it’s up to us to improve on it:

"It is apparent from studies like ours that it is going to be even more difficult than expected to derive real cures. . . It is extremely unlikely that drugs that target a single gene, such as Gleevec, will be active against a major fraction of solid tumours”

Comments (22) + TrackBacks (0) | Category: Cancer | Drug Development

August 1, 2008

GSK Layoffs: Yes, Again

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Posted by Derek

The ax is falling again at GlaxoSmithKline. This time it’s the oncology group.

Last month the cardiovascular people got this same treatment, you’ll recall, and there was some disagreement about how many jobs were being affected. But it looks like the company is moving one by one through its Centers of Excellence in Drug Discovery (CEDDs) and running a most excellent scythe through them. By the time they’re through, the total number of layoffs looks like it will be substantial indeed.

That’s because inside each area so far the cutbacks are pretty sweeping. Total oncology head count is apparently being reduced by about 40%. Discovery chemistry seems, unfortunately, to be getting it a bit worse, since some of the sub-areas aren't losing head count at all. The estimates I have are that of the c. 120 chemists in the area, about 60 are losing their jobs. That includes the entire oncology med-chem group at the Research Triangle Park location, and from what I'm told, none of them are being relocated to the Philadelphia-area sites. So much for discovering Tykerb, et al.

Are all of the CEDDs going to get this same treatment, or to the same degree? GSK isn’t saying, but I’d certainly bet on this sort of thing happening again as the year goes on. What the company’s research arm will look like when it’s all over is anybody’s guess, too, but there’s one thing for sure: it’ll be a heck of a lot smaller.

And whether this new trimmed-down inlicensed/outsourced GSK will be any more productive is anybody’s guess either. But we won’t know that for a long time. It’ll take quite a while just for all of these changes to stop reverberating through the company, for one thing, and then it’ll be several years after that before it’ll be possible to look at the pipeline and have a majority of it be a product of the new organization. As I’ve said before, this is one the biggest challenges in trying to engineer a large-scale change in a drug discovery shop – the lag time before you see the effects.

I’m already seeing resumes, but I’d like to invite any readers who know of openings for experienced drug discovery positions to either mention them in the comments or email me about them for a future post. (I did a lot of that during my own experience with a site closure, but of course, this time I don’t know most of the people involved personally). At the rate things are going, I’m going to have to start running classified ads down the right side of the page.

Comments (53) + TrackBacks (0) | Category: Business and Markets | Cancer

July 22, 2008

Vytorin: Another Round of Nasty Results

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Posted by Derek

Merck took the unusual step of delaying its earnings release yesterday until after the close of the market. A report on another clinical study of Vytorin (ezetimibe), their drug with Schering-Plough, was coming out, so they put the numbers on hold until after the press release yesterday afternoon. Naturally, this led to a lot of speculation about what was going on. A conspiracy-minded website vastly unfriendly to Schering-Plough suspected some sort of elaborate ruse to drum up publicity.

But that sort of thinking doesn't take you very far, unless you count the distance you rack up going around in circles. As it turned out, the SEAS trial (Simvastatin and Ezetimibe in Aortic Stenosis) was, in fact, very bad publicity indeed for the drug and for both companies. In fact, a real conspiracy would have made sure that these numbers never saw the light of day, or were at least released at 6 PM on a Friday. But no, the spotlight was on them good and proper.

This trial studied patients with chronic aortic stenosis, which is a different condition than classic atherosclerosis. The two have enough similarities, though, that there has been much interest in whether statin treatment could be effective. The primary endpoint, a composite of aortic valve and general cardiovascular events, was missed. Vytorin was no better than placebo. It reached significance against one secondary endpoint, reducing the risk of various ischemic events, but not in any dramatic fashion.

That's not necessarily a surprise, since there's not a well-established therapy for aortic stenosis (thus the trial design versus placebo). As several commenters to the conference call after the press conference pointed out, this shouldn't change clinical practice much at all. But it's not what Merck and Schering-Plough needed to hear, that's for sure, because the sound bite will be "Vytorin Fails Again".

Actually, the sound bite will be even worse than that. There are a lot of headlines this morning about another observation from the SEAS trial: that significantly more patients in the treatment arm of the study were diagnosed with cancer. That's a red warning light, for sure, but in this case we have at least some data to decide how much of one.

For one thing, as far as I know there have been no reports of increased cancer among the patients taking Vytorin out in the marketplace - of course, one could argue that this might have been missed, but if the effect were as large as seen in the SEAS study, I don't think it would have been. Analyses of the earlier Vytorin trials and the ongoing IMPROVE-IT trial versus Zocor have also shown no cancer risk, and the latter trial is continuing. So for now, it would appear that either this was a nasty result by chance, or (a longer shot) that there's something different about the aortic stenosis patients that leads to major trouble with Vytorin.

None of these scientific and statistical arguments, and I mean none of them, will avail Schering-Plough and Merck. Among people who've heard of Vytorin at all, the first thing that will come to mind is "doesn't work", and after today's headlines, the second thing that will come to mind is "cancer". Just what you want, to put out press releases that your compound, even though it failed to work again, isn't actually a cancer risk. You really couldn't do worse; a gang of saboteurs couldn't have done worse. Of course, there's no such gang: the companies themselves authorized these trials, thinking that there were home runs to be hit. But all these sidelines - familial hypercholesteremia, aortic stenosis - have only sown fear, confusion, and doubt. The only thing that I can see rescuing Vytorin as a useful drug is for the IMPROVE-IT results to show really robust efficacy in its real-world patients. And I wonder if even that could be enough.

Comments (19) + TrackBacks (0) | Category: Business and Markets | Cancer | Cardiovascular Disease | Clinical Trials | Toxicology

June 23, 2008

Auroral Activity

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Posted by Derek

If you go to the med-chem or pharmacology literature databases and type "Aurora kinase", you'd better stand back. A geyser of publications will come spraying out, most of them having to do with Aurora A and/or Aurora B as possible targets for cancer therapy. These enzymes are involved in different phases of cell division, among other things, and a lot of evidence points to them as key players in several cancer lines. There are a number of inhibitors compounds known for them as well, in various stages of development, some of which are selective and some of which hit both to different degrees. Attempts to unravel all the functions of the kinases through these compounds, and through various loss/gain of function mutations in cells, have been. . .well, "complex" is a judicious term to use. The functions of the two enzymes may well be tied to each other, so getting a clear look has been hard.

There's a new paper that illustrates just why it hasn't been easy. This one looks at an AstraZeneca compound, ZM447439, which inhibits both Aurora A and Aurora B in enzyme assays, but in cells seems to be the closest match to a clear knockout of B. The authors started with a well-known cancer cell line (HCT-116), and picked out mutants that had acquired resistance to the drug. They turned out, indeed, to have mutated forms of Aurora B in them, and when they introduced those mutant forms into other cells, they also became able to grow in the presence of ZM447439. That's about as good a test of mechanism as you're going to get in the oncology field, and as the commentary on the paper says, "Even had the authors stopped at this point, it would have been an important contribution."

But they kept on digging, and good for them - perhaps they were (rightly) suspicious that everything was working out a bit too neatly. They then chose two other Aurora inhibitors, VX-680 (which hits both forms) and MLN8054, which is known to be selective for Aurora A. When the cells with mutant forms of Aurora B were exposed to the VX compound, they grew anyway - which makes sense from the Aurora B side of things, since they could well have mutated the efficacy away from this compound, in the same way they got away from the AstraZeneca one. But VX-680 definitely seems to hit Aurora A, too - so is that pathway not doing anything at all for efficacy?

Well, when they treated the Aurora B mutant lines with the Aurora-A-selective MLNM compound, they died off, implying that Aurora A inhibition can do the job all by itself, so there's a pretty blatant contradiction here. The authors advance the two hypotheses that have to be looked at: either Aurora A is a good target and the VX compound isn't doing as much against it as everyone thought, or Aurora A inhibition is largely useless (at least in HCT-116 cells!), and the MLNM compound has another target that no one's realized yet. (It's important to realize that this situation could vary from tumor to tumor - here's a suggestion that Aurora A might be the way to go for pancreatic cancer, for example).

And there's another, rather troubling take-home lesson, having to do with the alacrity with which these cells mutated away from sensitivity to the Aurora inhibitors. As the authors put it:

"The rather surprising picture emerging from our studies and from previous studies on Abl and other tyrosine kinases is that the kinase scaffold is very tolerant of mutations in the hinge loop that lines the ATP-binding site. A discouraging consequence of this fact is that these mutations are likely to affect a wide range of ATP-competitive inhibitors—even ones from distinct chemical classes—as most ATP competitors are sensitive to the active site's architecture, to which the mutated residues contribute considerably."

Put simply, the kinases we're targeting have more room to maneuver than we do as medicinal chemists. They can mutate quite a bit and still function, shedding the key binding motifs that our drugs are targeting along the way. We're going to have to work a lot harder to come up with effective combinations.

Comments (12) + TrackBacks (0) | Category: Cancer

April 9, 2008

And You Thought Exubera Was A Disaster Before

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Posted by Derek

I don't usually do more than one post a day, but this really caught my eye. In an ongoing review of Pfizer's (now discontinued) inhaled insulin (Exubera), an increased chance of lung cancer has turned up among participants in the clinical trials. Six of the over four thousand patients in the trials on Exubera have since developed the disease, versus one of the similarly-sized control group. Six isn't many, but with that large a sample size, it's something that statistically can't be ignored, either.

The concerns would have to be, naturally, that this number could increase, since damage to lung tissue might take a while to show up. This, needless to say, completely ends Nektar's attempts to find another partner for Exubera. Their stock is getting severely treated today (down 25% as I write), but things are even worse for another small company, Mannkind, that's been working on their own inhaled insulin for years now (down 58% at the moment).

There's no guarantee that another inhaled form would cause the same problems, but there's certainly no guarantee that it wouldn't, either. Whether this is an Exubera-specific problem, an insulin-specific one, or something that all attempts at inhaled proteins will have to look out for is just unknown. And unknown, in this case, is bad. It's going to be hard to make the case to find out, if this is the sort of potential problem waiting for your new product. Inhaled therapeutics of all sorts have taken a huge setback today.

Comments (20) + TrackBacks (0) | Category: Cancer | Clinical Trials | Diabetes and Obesity | Toxicology

April 3, 2008

Whose Guess Is Better?

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Posted by Derek

I was having a discussion the other day about which therapeutic areas have the best predictive assays. That is, what diseases can you be reasonably sure of treating before your drug candidate gets into (costly) human trials? As we went on, things settled out roughly like this:

Cardiovascular (circulatory): not so bad. We’ve got a reasonably good handle on the mechanisms of high blood pressure, and the assays for it are pretty predictive, compared to a lot of other fields. (Of course, that’s also now one of the most well-served therapeutic areas in all of medicine). There are some harder problems, like primary pulmonary hypertension, but you could still go into humans with a bit more confidence than usual if you had something that looked good in animals.

Cardiovascular (lipids): deceptive. There aren’t any animals that handle lipids quite the way that humans do, but we’ve learned a lot about how to interpolate animal results. That plus the various transgenic models gives you a reasonable read. The problem is, we don’t really understand human lipidology and its relation to disease as well as we should (or as well as a lot of people think we do), so there are larger long-term problems hanging over everything. But yeah, you can get a new drug with a new mechanism to market. Like Vytorin.

CNS: appalling. That goes for the whole lot – anxiety, depression, Alzheimer’s, schizophrenia, you name it. The animal models are largely voodoo, and the mechanisms for the underlying diseases are usually opaque. The peripheral nervous system isn’t much better, as anyone who’s worked in pain medication will tell you ruefully. And all this is particularly disturbing, because the clinical trials here are so awful that you’d really appreciate some good preclinical pharmacology: patient variability is extreme, the placebo effect can eat you alive, and both the diseases and their treatments tend to progress very, very slowly. Oh, it’s just a nonstop festival of fun over in this slot. Correspondingly, the opportunities are huge.

Anti-infectives: good, by comparison. It’s not like you can’t have clinical failures in this area, but for the most part, if you can stop viruses or kill bugs in a dish, you can do it in an animal, or in a person. The questions are always whether you can do it to the right extent, and just how long it’ll be before you start seeing resistance. With antibacterials that can be, say, "before the end of your clinical trials". There aren’t as many targets here as everyone would like, and none of them is going to be a gigantic blockbuster, but if you find one you can attack it with more confidence than usual.

Diabetes: pretty good, up to a point. There are a number of well-studied animal models here, and if your drug’s mechanism fits their quirks and limitations, then you should be in fairly good shape. Not by coincidence, this is also a pretty well-served area, by current standards. If you’re trying something off the beaten path, though, a route that STZ or db/db rats won’t pick up well, then things get harder. Look out, though, because this disease area starts to intersect with lipids, which (it bears saying again) We Don't Understand Too Well.

Obesity: deceptive in the extreme. There are an endless number of ways to get rats to lose weight. Hardly any of them, though, turn out to be relevant to humans or relevant to something humans would consider paying for. (Relentless vertigo would work to throw the animals off their feed, for example, but would probably be a loser in the marketplace. Although come to think of it, there is Alli, so you never know). And the problem here is always that there are so many overlapping backup redundant pathways for feeding behavior, so the chances for any one compound doing something dramatic are, well, slim. The expectations that a lot of people have for a weight-loss therapy are so high (thanks partly to years of heavily advertised herbal scams and bizarre devices), but the reality is so constrained.

Oncology: horrible, just horrible. No one trusts the main animal models in this area (rat xenografts of tumor lines) as anything more than rough, crude filters on the way to clinical trials. And no one should. Always remember: Iressa, the erstwhile AstraZeneca wonder drug from a few years back, continues to kick over all kinds of xenograft models. It looks great! It doesn’t work in humans! And it's not alone, either. So people take all kinds of stuff into the clinic against cancer, because what else can you do? That leads to a terrifying overall failure rate, and has also led to, if you can believe it, a real shortage of cancer patients for trials in many indications.

OK, those are some that I know about from personal experience. I’d be glad to hear from folks in other areas, like allergy/inflammation, about how their stuff rates. And there are a lot of smaller indications I haven’t mentioned, many of them under the broad heading of immunology (lupus, MS, etc.) whose disease models range from “difficult to run and/or interpret” on the high side all the way down to “furry little random number generators”.

Comments (9) + TrackBacks (0) | Category: Animal Testing | Cancer | Cardiovascular Disease | Diabetes and Obesity | Drug Assays | Drug Development | Infectious Diseases | The Central Nervous System

January 16, 2008

Judah Folkman

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Posted by Derek

So Judah Folkman is no longer with us. He's considered to be the father of the idea that many tumors help to make their own blood supply, through angiogenesis, and that this could be a way to impede their growth. Since his first papers on the topic were published back in 1971, I think he does indeed get the credit. And he should not only get the credit for having the idea, but for publishing it and sticking with it. (Here's an interview with Folkman where he talks about this and much more).

Interestingly, it had been noted as long ago as 1941 that transplanted tumors in animals managed to link in to the existing blood supply through the formation of new vessels, but no one knew what to do with this result. (Here's a history of the field from a few years ago). It's not surprising that it took so long for the idea to catch on, though. It was by no means clear back in 1971, much less 1941, how blood vessels could be raised up by signaling from their target tissue. It wasn't until much later that the signaling pathways for blood vessel growth were discovered. Vascular endothelial growth factor, for example, was only found in 1983, and its functions didn't become clear until 1989 (timeline).

Folkman's death (which took place in the Denver airport, of all places) has brought back memories of the (in)famous Gina Kolata article on Folkman's work in the New York Times from 1998, a front-pager which featured James Watson's notorious quote about how Folkman was going to cure cancer in two years. I wrote about that one in the early days of my blog, and again here when Entremed finally gave up on the compounds that Kolata and the Times had hyped to the skies. The year 2000 came and went without a cancer cure, and many more years are going to go by as well. That's because, as I and many others never tire of pointing out, cancer isn't a single disease, and will never have a single cure. It's like looking for a cure for bad writing - it comes in so many different varieties, for so many different reasons, and therefore needs many different fixes.

Comments (6) + TrackBacks (0) | Category: Cancer | Current Events | Drug Industry History

January 4, 2008

Plants For Cancer?

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Posted by Derek

A reader sends along this article from the New York Times about Chris Kilham, an ethnobiotanist from U. Mass - Amherst looking for medicinally active plants in Peru. The article has lots of local Peruvian color, but it doesn’t neglect the money involved:

” Products that once seemed exotic, like ginseng, ginkgo biloba or aloe vera, now roll off the tongues of Westerners. All told, natural plant substances generate more than $75 billion in sales each year for the pharmaceutical industry, $20 billion in herbal supplement sales, and around $3 billion in cosmetics sales, according to a study by the European Commission.”

It’s worth noting, though, that none of those three once-exotic plants (exotic when – twenty-five years ago?) are the source of any major revenue for the pharmaceutical industry, unless you count aloe-vera sunscreen line extensions and the like. Kilham himself has some definite opinions on the value of plant-derived drugs:

Mr. Kilham believes multinational drug companies underutilize the medicinal properties in plants. They pack pills with artificial compounds and sell them at huge markups, he says. He wants Westerners to use the pure plant medicines that indigenous peoples have used for thousands of years.

“People in the U.S. are more cranked up on pharmaceutical drugs than any other culture in the world today,” Mr. Kilham said. “I want people using safer medicine. And that means plant medicine.”

Unpacking those statements is a chore, though. Just to pick a big one, “pure plant medicine” is a tricky concept, as any natural products chemist will tell you. Are we talking ground whole plants here (and if so, which parts, grown where?) Extracts (and if so, which fractions?) Purified single compounds?

Moving to the next difficulties, would these plant medicines somehow not be sold at such huge markups? Take a look at the herbal supplement industry for a reality check on that one. And if we in the drug industry could get such drugs with less trouble and effort than our “artificial” ones, why wouldn’t we do so – especially if they have fewer side effects? (Side effects cost us money, too, you know). Finally, are those natural compounds really safer than the nasty artificial ones? Not as far as I’ve ever seen – they come out the same in genotoxicity studies, for one thing. The whole “artificial” versus “natural” division is generally a sign of lazy thinking, in my experience. There’s no wholesome Gaia-derived goodness to be found in a plant-derived natural products, and they weren’t somehow made for us to use as medicines. Some are harmless, some are toxic – same as everything else.

Then there’s this interesting part:

“So-called bioprospectors can make their fortunes by bringing those advantages to the attention of companies who identify the plant’s active compound and use it as a base ingredient for new products that they patent.

Some 62 percent of all cancer drugs approved by the Food and Drug Administration come from such discoveries, according to a study by the United Nations University, a scholarly institution affiliated with the United Nations.”

Hmm. Examples? The only “bioprospector” that I can recall making a fortune in this way was Russell Marker, the founder of Syntex, who realized that Mexican yams contained an excellent starting material for steroid synthesis. Mind you, that was in 1944. If anyone has a more recent example of an Indiana Jones figure stumbling out of the jungle clutching a profitable wonder root, please do let me know. Whole companies have been founded on the idea of cashing in on active natural products and indigenous medicines. None of them, as far as I can tell, have made any fortunes yet, and some of them have done the reverse. Shaman Pharmaceuticals is the obvious example. I know someone who was right in the middle of their drug discovery effort. It wasn’t pretty, and it sure wasn’t profitable.

Besides, the Times reporter should have asked Kilham himself about cancer therapies. Here's a 2005 interview with him:

"I don't see the cancer herb category becoming a major category any time soon. I believe that the majority of people who get cancer are still going to turn to a conventional medical doctor. I think the greatest majority will. . ."

And that study by the UN doesn’t appear to have dug all that deeply. (It should be noted up front that oncology and anti-infectives are the two areas where natural product-derived compounds are by far the most well-represented). That 62 per cent figure for cancer drugs would seem to come directly from this 2003 paper in the Journal of Natural Products, from a group at the Natural Products branch of the National Cancer Institute. A closer look at the figures show that they list 140 drugs available over the years 1981-2003 (note that many of these are no longer first-line therapies). The 62% figure comes from excluding all the antibodies, proteins, and vaccines (10% of the total) and counting straight natural products (14%), semisynthetic compounds derived from them (26%) and synthetic compounds whose active pharmacophore came from a natural product lead (14%).

You can draw the line wherever you like, but by rigorously crunchy standards only that first 14% qualifies. If we’re going to draw some line between “natural” and “artificial”, everything else is on the other side of it. There’s no denying that natural products are and have been a great source of active compounds and structural leads, of course. But the vast majority of drugs come from us chemists, cranking out the man-made (and man-improved) structures.

The other problem with that number is that, if anything, it may represent a peak. The kinase inhibitors that have been approved in recent years are all completely synthetic compounds, and the antibody and vaccine ranks are swelling, too. Ranked by sales, there are 19 oncology drugs in the most recent top 200 list I can find, and only one of them is a straight natural product (taxol, at #169). Taxotere, at #37, is a semisynthetic derivative of taxol, and irinotecan at 122 is a semisynthetic as well. But to my eyes, that’s about it. Getting data by usage is harder (without paying for it!), but the older natural products would come out looking better ranked by total prescriptions filled. In most cases, though, they’re no longer first-line therapies.

So natural products aren’t dead, by any means. But they aren’t an untouched gold mine, either. Someone tell the Times.

Comments (38) + TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History

October 29, 2007

Bacterial Infection: Better Or Worse Than Cancer?

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Posted by Derek

There’s been a steady stream of reports in the news about methacillin-resistant Staph. aureus. It’s not a new problem, but (like other nasty infections) it does get a lot of press when the media start paying attention. Works in reverse, too – on the viral front, have you noticed the much reduced number of bird-flu-will-kill-us-all stories this year as we head toward winter? This despite the likelihood of bird flu killing us all being as high (or low) as ever, as far as I can tell.

But the resistant bacteria problem is certainly no joke, and there doesn’t seem to be any reason why it won’t gradually get worse over time. It struck me the other day that antiinfectives, as a drug research field, might be moving toward a similar spot to oncology. In both cases, you have a problem with rapidly multiplying cells, giving you a serious medical outcome - often in cancer, and increasingly with infections. The average tumor is a lot more worrisome than the average infection, of course, but that’s something we can only say with confidence in the industrialized world, and we've only been able to say it for the last sixty or seventy years. As cancer gradually becomes more manageable and infections gradually become less so, the two might eventually meet – or even switch places, which would be bad news indeed. (In some genetically bottlenecked species, in fact, the two problems can overlap, which is fortunately extremely unlikely in humans).

There are, of course, a lot of differences between the two fields, not least of which is that you’re fighting human cells in one case and prokaryotes (or worse, viruses) in the other. But many of those differences actually come out making infectious diseases look worse. The transmissibility of bacteria and viruses make them serious contenders for causing havoc, as they have innumerable times in human history, and they can grow more quickly in vivo than any cancer. It’s only the fact that public health measures allow then to be contained, and the fact that we’ve had useful therapies for many of them, that makes people downrate the infectious agents. If either (or both) of those change, we’re going to be rethinking our priorities pretty quickly.

What this means for drug development is that some researchers will have to rethink their attitudes towards antiinfective drugs. For serious infections, we're going to have to think about these projects the way we've traditionally thought of oncology agents - last-ditch therapies for deadly conditions. Anticancer therapies have long had more latitude in their side effects, therapeutic ratios, and dosing regimes, and antibiotics for resistant infections are in the same position. For some years now, there's been a problem that new drugs in this field would perforce have small markets, since they'd be used only when existing agents fail. That market may not be as small as it used to be. . .

Comments (13) + TrackBacks (0) | Category: Cancer | Drug Development | Infectious Diseases

September 17, 2007

Arsenic, Patents, and the World

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Posted by Derek

As I was mentioning the other day, the latest issue of Nature Medicine has the details on a story that doesn’t, on the face of it, do the industry any credit. About twenty years ago, there were reports out of China that a solublized form of arsenic was very effective in treating acute promyelocytic leukemia, a rare (and fatal) form of the disease. Arsenic had been used as a folk remedy for such conditions, as it has been for many others (often with much less justification!), but its most common compounds (like arsenic trioxide) are tremendously insoluble. The Chinese authors had found a way to make that one go into solution where it could be dosed, but didn’t disclose it in their publication.

That left the door open to someone else, namely a small company called PolaRx. They found a way to do the same thing with the oxide (as far as anyone can tell), and got a patent on its use in oncology. Over years, mergers, and reshuffles, the patent finally ended up in the hands of Cephalon, who now market the soluble arsenic trioxide. However, a course of treatment costs about $50,000, which means that for many patients around the world, the drug is totally out of reach.

Even across the entire world, there aren’t that many patients for this therapy, so the price would tend to be high no matter what. It’s worth remembering that production costs are not a major factor in the pricing of most drugs. We’re not indifferent in this business to how much it costs us to make something, far from it, but we try to keep that a small part of the price. So what does set the price? What sets the price is what sets most prices in this world: what the market will bear. A drug that only treats a small number of patients every year is going to cost a lot of money, no matter what it’s made out of. A company will not market a compound unless they can use its profits to help defray the costs of all the things that don’t make it to market at all.

Cephalon is charging what their market will bear, which is their right, but their market is the health insurance organizations of the industrialized world. That’s another thing to remember – drug companies aren’t selling direct to patients most of the time. They’re selling to insurance companies, and first-world health insurance will put up with a lot of things that no one else can or will. There’s a lot of room to talk (and to complain) about this (I think it distorts pricing signals something fierce), but all the complaints have to start with the realization that this is how things are now set up. Cephalon, for its part, says that it’s open to compassionate use of its drug – that is, providing it to people in need who absolutely cannot afford it. With any luck articles like the Nature Medicine one will help to get the word out about that, and we’ll see how well they follow through.

It’s tempting to blame the patent system for this whole situation – after all, the only reason the company can charge these prices is that they’re the only ones who can sell it, right? But perversely, this might actually show the need for more use of patents rather than less. As another piece in Nature has helpfully reminded people, patents not only grant a period of exclusivity. In return for that, you have to tell people how to replicate your invention.

The alternative, in countries that don’t follow this system, is usually secrecy, and I can’t help but think that this is why the original Chinese work didn’t disclose all the details. A strong patent system eliminates a lot of trade-secret grey areas: someone owns a discovery (for a predetermined period of time), no one owns it, or everyone owns it. There’s none of this “someone owns it until someone else finds out about it” stuff.

But my guess is that the Chinese lab, being used to a trade-secret (or government-secret) culture, reflexively held back their important details. If they wanted to make sure that no one could patent anything, they would have (or at least should have) put all the information out into the public domain, where it would have been prior art against anyone attempting to file on it. (But see below - would that have helped get it through clinical trials, or not?) It’s worth noting that if a patent had been filed back in the early 1990s, the drug would not only have come to the world’s markets faster, the patent would also be much closer to expiration by now, opening up its production. The US researcher who formed PolaRx and filed the patent, Raymond Warrell (now chairman of Genta), stands up for it in the Nature Medicine article, and like it or not, he has a point, too, saying that the patent stimulated interest in the compound: "Without the patent, it would have remained a curious Chinese drug, not available to anyone else." I should note that there may well be room to argue about the validity of the patent, from prior-art concerns, but no one (as far as I know) has seen fit to challenge it.

But I can say for sure that without intellectual property protection in the US and Europe, no drug company would have touched the compound. Without industrial input, the drug would have either never reached the market at all (arsenic trials were a hard sell at the FDA), or would have likely come on more slowly. (That ticking patent clock does keep an organization moving, I can tell you). And now its success in the market has other companies working on improved versions of the therapy. This is how our world works, and (for better or worse) there's no requirement that it be aesthetically appealing.

Comments (8) + TrackBacks (0) | Category: Cancer | Drug Development | Odd Elements in Drugs | Patents and IP | Why Everyone Loves Us

August 20, 2007

The Current Cancer Long-Jump Record

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Posted by Derek

As I've mentioned before, advances in molecular biology have continued to make all sorts of brute-force approachs possible - things that would have been laughed at (or, more likely, not even proposed at all) a few years ago.

Another recent example of this is a paper earlier this year in Nature from the group of Michael White at UT-Southwestern. The authors selected a lung cancer cell line that's know to be very sensitive to Taxol (paclitaxel), and looked for possible targets that might increase the drug's effectiveness. (It's a good compound to pick for a study like this, since it's simultaneously quite effective and quite toxic).

So, how do you go fishing for such combinations? These days, you set up 21,127 experimental wells, each one contained some cells and some silencing RNA molecules targeting, one at a time, 21,127 different human genes. And you look to see if knocking down expression of any of those genes increased the potency of a normally ineffective dose of the drug. (There were four different siRNAs per gene, actually, and each one was run in triplicate with and without Taxol, leading to a Whole Lotta 96-well plates. I'm glad I'm not paying for all the pipet tips, I can tell you that for sure.)

As you'd imagine, working up the data from this kind of thing takes as long, or longer, than setting one up. After comparing everything to the control wells and to each other several different ways, they ended up with 87 candidate genes whose knockdown seems to make the drug more effective. Gratifyingly, many of these make one kind of sense or another - there are several genes, for example, that are known to be involved in spindle formation, which is the target of paclitaxel itself.

Even more interestingly, not all the hits were obvioius. Another group of genes code for parts of the proteasome. That part of the cell is targeted by Millennium's Velcade (bortezomib), and it's recently been reported that the combination of Velcade and paclitaxel is more effective than expected. And there's another combination that seemingly hasn't been tried at all: the experiment suggests that inhibitors of vacuolar ATP-ase should synergize with Taxol, and (as it happens) a compound called salicylihalamide A has been looked at for just that target. They tried this experimental combination out on the cells, and it seems to work well - so, in humans?

As a commentary in the New England Journal of Medicine on this work dryly put it, "This hypothesis should be tested." And so it should. I've always had doubts about how far one can extrapolate cell data in cancer studies, but this kind of thing will tell us for sure. If something hits from this work, more such studies will come pouring out - they're getting easier to do all the time, you know. . .

Comments (8) + TrackBacks (0) | Category: Cancer | Drug Assays

June 4, 2007

Phase Zero?

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Posted by Derek

We have a new phrase to toss around in in the industry: "Phase Zero". That's what they're calling a recent trial of an anticancer drug from Abbott (ABT-888), which was tested in humans before any safety dosing (Phase I) had been done.

So, how exactly can you do that? By giving extremely small amounts of the drug, that's how, and looking to see if you can detect a change in some marker for eventual efficacy. In this case, the marker was inhibition of the activity of PARP, poly(ADP-ribose) polymerase, which is involved in the cellular response to DNA damage. Inhibiting it should make cells much more likely to die once such damage had been detected, which one of many such signals that cancer cells tend to ignore under normal conditions. Abbott's drug seemed to do the trick, so work on it will continue.

The good part of this is that the drug got into humans more quickly than usual, and that its mechanism of action has now been verified (to a first degree of approximation, anyway - it hits the target). This should make a company a bit more confident about moving on to larger trials, and could potentially weed out losers early in the game.

But there are bad parts, too. For one thing, the patients in a phase zero trial have no hope of benefit from the drug: the dose is just too small. The small doses could give results that (for better or worse) aren't relevant to the later real-world ones, too. Another problem is that reliable biomarkers are thin on the ground despite great sums of money being spent to find and validate them. If you're going to let the future of your drug ride on one of these trials, you'd better be confident that you know what it's telling you. (And if you're not going to let the future of the drug ride on a phase zero trial, why are you running one, eh?)

What would be worth knowing is how many drugs fail because of lack of effect on their intended target, as opposed to those which hit the target but still have no effect. You'd also want to know: of that first group, what portion are going to be amenable to robust biomarker studies. Those two fractions would tell you how much of an impact this whole idea will have. Right now, I think the error bars are way too large to make a prediction. . .

Comments (10) + TrackBacks (0) | Category: Cancer | Clinical Trials

April 19, 2007

Let A Thousand Flowers Bloom

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Posted by Derek

If you want to see a bunch of press releases from biotech companies that you've never, ever heard of in your life, just go over to Google News and type in "AACR", sorting by date. That meeting just wound up, and it was the usual fiesta of early- and late-stage oncology data.

But cancer is an odd field for drug development. There are (relatively speaking) many more targets, since the disease itself is a huge fragmented bunch of different indications. And we don't have nearly enough knowledge to have a good idea - any idea, most of the time - about which of these targets are more likely to work, and against which forms of cancer. The trials themselves tend to be smaller (thus cheaper), since the course of the disease is often so relentless, and if you get a drug to market, you don't have to take out ads on the Super Bowl to promote it to oncologists.

All that means that the entry barrier to the field is lower, and there are plenty of niches. And boy, are they filled by a lot of microscopic companies. I keep up with things fairly well, but there are outfits presenting at AACR that might as well be from the asteroid belt for all I know about 'em. . ..

Comments (5) + TrackBacks (0) | Category: Cancer

April 11, 2007

Amgen: The Pythian Oracle Laughs Again

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Posted by Derek

Amgen's not getting a lot of good press these days. They're famously the House that EPO built, but (in a familiar story) they may have pressed their lead franchise too far. An excellent backgrounder can be found here at Nature Biotechnology. In short, the company was coining money in the renal market, and looked for new areas where EPO could be of use (and of profit). Chemotherapy-induced anemia looked like a winner, and Amgen aggressively promoted EPO's use in oncology. (Correction - the real extension was into cancer-associated anemia, not just that induced by chemotherapy. See the comments for more - DBL). But (as the editorial details), this whole strategy is backfiring disastrously.

First off, anemia doesn't appear to be a major cause of chemotherapy side effects. If that weren't bad enough, a series of clinical trials have shown that patients receiving standard therapy plus EPO do worse than usual. As of last month, all forms of EPO now have a new black-box label warning. Not ugly enough yet? OK, the company has admitted that it knew about some of this data but didn't talk about it for months. The SEC is investigating them for that decision, and Medicare is looking at whether the company has been overcharging. Their CFO just announced that he's "pursuing other interests".

A sample of the Nature B. editorial makes its point well:

"Amgen does not come out of this well. Although seeking new indications for existing medicines is clearly a valid strategy, the company appears to have miscalculated the balance between expansion and the risks to its existing business—and potentially opened itself to charges that it has recklessly endangered patients' lives. . .

Furthermore, Amgen has surely miscalculated strategically. Any benefits from the commercial push to extend Aranesp into new oncology markets are likely to bring relatively modest returns—Aranesp's 2006 sales in cancer-associated anemia, for example, were approx. $500 million. But the repercussions of failure will be felt not only in cancer but also potentially across all EPO markets. A proportion of the whole $7.1 billion Epogen and Aranesp franchise—nearly 50% of Amgen's total revenue in 2006—is thus under threat."

Amgen isn't the first drug company to have over-reached. Everyone's going to try to make the most of their existing drugs, especially when there aren't all that many things coming along to replace them. But readers with some classical background may well think of Croesus crossing the Halys every time they hear about this kind of thing. . .

Comments (11) + TrackBacks (0) | Category: Business and Markets | Cancer | Why Everyone Loves Us

April 5, 2007

Awful, No Doubt. But Not As Awful as Before?

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Posted by Derek

Cancer drugs have a terrible history in clinical trials. The most definitive figure, from development candidates of the 1980s and up to the mid-1990s or so, was a cold, hard, 95% failure rate. That beat even the central nervous system (CNS) drug category, which is a spacious haunted mansion all its own. One reason for this is that all kinds of things get thrown at oncology targets, because there's so much unmet need in the category. Whenever someone comes up with a new technology - monoclonal antibodies, antisense DNA (or RNA interference), disease-altering vaccines, etc. - you can bet that someone's going to try it out on a cancer target. Not all this stuff is going to work, needless to say.

But I wonder if that figure still holds. Starting later on in the 1990s, and gathering speed ever since, a lot of the small-molecule drug candidates in the cancer area have been kinase inhibitors. Now, back when I took my first pharma job, those compounds weren't in very good favor, partly because the key structural motifs that everyone uses today hadn't been worked out yet. If you mentioned kinase inhibitors in the labs, likely as not someone would spit in the sink and say something rude about staurosporine.

That was one of the early potent kinase inhibitors, a fairly nasty natural product. (Note: outdated web page in that link, which fits the subject). All sorts of people worked on staurosporine-like compounds during the 1980s and beyond, and most all those projects came to grief of one sort or another. It gave the whole field an unhealthy look.

There were also good reasons to think that no really selective kinase inhibitors could be discovered (since the enzymes have many structural similarities), and that the resulting broad-spectrum compounds would have just too many side effects to be useful. But molecular biology was uncovering a role for many kinase enzymes in cancer and other disease states, so people kept taking a crack at the area, and finally some far less ugly compound classes were discovered that broke the field open. Once decent compounds were in hand, it was found that they weren't as toxic as everyone had feared. Selectivity was still an issue, but you could sort of tune the structures to inhibit various groups of kinases over others.

I would not want to hazard a guess as to how many kinase inhibitors have gone into development over the past ten or twelve years. It's a pile, for sure - just look at KinasePro and Xcovery to get the idea. I will guess, though, that they haven't failed at quite that horrific 95% rate, and that a 1995-2010 survey of the field will show an improvement. Mind you, the record-holder in the earlier survey was, cardiovascular area, where only about 85% of the compounds collapsed, so don't think I'm talking about a huge increase. But when only one out of twenty of your drugs makes it, getting up to two in twenty means that you have twice as many drugs.

Comments (11) + TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History

April 3, 2007

Vaccines Everywhere

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Posted by Derek

You know, small-molecule folks like me are going to have to learn to deal with immunology. I don't mind saying that it's not my field - yet - but who knows, perhaps it will be. The recent successes of Dendreon and (today) Cell Genesys prompt these thoughts. Both companies have shown useful efficacy with immune-based prostate cancer therapies, good enough to make you wonder how effective these things will eventually be when we understand more about what's going on.

As things stand, there are a bewildering number of possibilities. Both of these vaccines depend on production of GM-CSF secreting cells (a powerful cytokine which stimulates white blood cell production and activity), but they're rather different otherwise. Dendreon's Provenge is autologous, that is, derived from each patient's own cells, for one thing, while the Cell Genesys GVAX vaccine isn't individualized at all (that is, allogeneic). That's just the first choice to make. There are all sorts of options about what kinds of cells to use, which antigens to decorate them with and what proteins to have them secrete, how to administer them to patients singly and in combination with other conventional chemotherapies, and so on. This work has been going on for years now, and I've no doubt that a lot of blind alleys have been followed. And a lot more will get followed, too, but the results so far are pretty impressive. They're beating the small-molecule conventional therapies in the difficult cases, that much is clear. It's important to remember that the patients are still dying of cancer, but they're taking noticeably longer to do it, which is success in our era.

We'll probably see a rush into the stocks of every company that has both "cancer" and "vaccine" in its 10-K filings, but I'd say be careful. For example, if you bought Cell Genesys last week, you're quite happy. But if you bought it this time last year, you're still in the red. Although I find these current results quite interesting, the field is still very young indeed. Companies are targeting prostate cancer because it's a non-essential organ (so it doesn't matter if the immune system trashes it), but they're also going to be going after tumors in rather more vital organs like the lung and pancreas. Development of immune therapies in those areas is going to be full of more excitement than some of the stockholders will be ready for.

Comments (4) + TrackBacks (0) | Category: Business and Markets | Cancer

April 2, 2007

Failure: Not Your Friend, But Definitely Your Companion

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Posted by Derek

Here's something that you don't see discussed very often, but it's worth some thought: what kind of personality do you need to have to do drug discovery research? Clearly, any conclusions are going to carry over well to other fields, but drug work has some peculiarities that can't be ignored.

The most obvious one is that the huge, horrible, overwhelming majority of projects never lead to a marketed drug. Many readers will have seen the sobering statistics of 85 to 95% failure rates in the clinic, but (bad as that is) it doesn't get across the number of times that projects get nowhere near the clinic at all. Take it from the top: the majority of targets that are screened for chemical matter don't turn up anything useful (it's not even close). The majority of the ones that do still die on their way to clinical trials. And then a solid 90% of those don't make it to market.

So, if you define yourself as a success by whether or not you've put something on a pharmacy shelf, you've set a very high bar, one that many people in basic research don't reach. It's different for people further down the line, where the field has already narrowed. But if you're working on early med-chem, for example, you're likely to go years between realistic shots at a drug you can claim part of the credit for.

That'll vary by your company's culture, too. Some companies bang out projects like a sawmill spitting out boards - or try to, anyway - while others carefully take their time for years and years. There's no certain advantage to either method, as far as I can see (else the companies doing the best one would have taken over by now and driven other modes out of existence). But you'll certainly have more shots on goal at the first type of company, which might keep your spirits up. Of course, the fact that you're largely going to be getting more chances to fail in the clinic might just depress them again, so you have to take that into account.

It'll also vary by therapeutic area. Central nervous system projects are going to run slower than oncology ones, by and large. In cancer, the clinical goals are comparatively clear, and where the disease is often (and most terribly) progressing at such a pace to give you solid numbers in a reasonably short period. Contrast that to Alzheimer's disease, for example, whose ruinous clinical trials could take years to tell you anything useful. Cancer will also give you more shots per compound, since a drug that does zilch for pancreatic cancer (and most do just that) might be useful in the lung or liver. While what we call cancer is several hundred diseases, what we call Alzheimer's might only be one. Depression and schizophrenia are clearly more complicated and split up, but (as opposed to cancer), there's no easy way to tell how many types there are or what particular one a patient might be presenting with, so the clinical work is correspondingly more difficult.

So, this is the pharmaceutical world you're going to have to live in. If you take each drug project personally, as an indicator of your own worth, you're probably not going to make it. You'll be beaten down by the numbers. As an antidote, a bit of realistic fatalism is helpful, although too much of it will shade into ah-that'll-never-work cynicism, which is the ditch on the other side of the road from prideful optimism. I'd recommend learning to enjoy the upside surprises, and to not be surprised by the failures (while still looking them over to see if there's something you can avoid next time around). You really have to draw a line between the things you can affect through your own talent and hard work, and the things you can't. Most of the crucial stuff is in the second category. A sense of humor about your own abilities and limitations will serve you well. But that goes for a lot of other jobs besides the drug business, doesn't it?

Comments (15) + TrackBacks (0) | Category: Alzheimer's Disease | Cancer | Drug Development | The Central Nervous System | Who Discovers and Why

March 26, 2007

Vectibix Lurches A Bit

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Posted by Derek

Amgen served up a nasty surprise on Friday with the results of a trial they're running on their Vectibix (panitumumab) cancer therapy. It's an EGFR inhibitor (same space as Imclone's Erbitux) and this trial was the first to test a "dual biologics" approach to colon cancer. One group got the standard of care (oxaliplatin and irinotecan chemotherapy, plus Genentech's Avastin VEGF inhibitor), and other other got that plus Vectibix.

Unfortunately, in one of those unexpected results that cancer trials are always delivering, the two-protein-therapeutics group actually showed slightly worse survival data than did the standard-of-care group, and that takes care of that. By itself, this result isn't enough to call Vectibix a failure by any means. But its expected rise to overshadow Erbitux has clearly been delayed.

Imclone's stock price reflects this. Does it ever - my modest short position in their stock is now underwater good and proper. Their stock's up 45% so far this year, with a lot of that in just the last two weeks. But these are early days (he said to himself abstractedly, looking out the window with his brokerage statement in his lap). Both drugs are in similar Phase III trials against colorectal cancer (as that first link, to Bioworld Today, details) and eventually we're going to have about as good a head-to-head comparison as you can expect in this area. Whether that'll be enough to decide anything, well. . .

Comments (7) + TrackBacks (0) | Category: Business and Markets | Cancer | Clinical Trials

February 12, 2007

A Good Day's Work

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Posted by Derek

So, you're asking yourself, "Why do people invest in biotech and small-pharma stocks?" You could especially ask yourself that after reading this New York Times article from Sunday, which describes how Xoma (yep, they're still around) has vaporized $700 million dollars, and counting, in its 25-year history.

Well, here's why: as I write this, Onyx Pharmaceuticals is up a solid 90% on the day. They're partners with Bayer on the kinase inhibitor Nexavar (sorafenib), and the companies today reported positive data in treating hepatic cancer. This wasn't long after the drug had pretty much whiffed on melanoma, so the news came as a bit of a surprise (thus that 90% updraft).

My guess is that it came as a surprise to the people doing the study as well. Liver cancer is a bigger market than anything that Nexavar is approved for, and you'd think that it would have been one of the first trials run if it were considered a high-percentage play. But cancer is tricky, and we don't understand it worth beans. You have to do the experiments, and you have to realize going in that you only have a vague idea of how they might go.

So that's one reason that biotech stocks continue to get buyers - for the same reason that lottery tickets do. It would be interesting to know which one has returned more money over the years, although I'm afraid I already know the answer. But long-term, biotech has the edge, because (slowly and with infinite pains) we're learning what we're doing. . .

Disclosure: I have a financial interest in Bayer stock - I have no exposure to Onyx (damn it all) or Xoma.

Comments (17) + TrackBacks (0) | Category: Business and Markets | Cancer

February 5, 2007

Good Mistakes?

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Posted by Derek

Here's an interesting press release on a potential new class of anticancer drugs. It has a nice hook ("Lab mistake leads to cancer finding!"), and the work itself isn't bad at all. It's an neat biochemical result, which might eventually lead to something. You have to know a bit about drug discovery and development to spot the problem, though - and not that many people do, which provides the ecological niche for this whole blog, frankly.

The discovery (from the University of Rochester) has to do with PPAR-gamma compounds, an area of research I've spent some time in. I didn't spend enough time there to understand it, mind you - no one has spent enough time to do that yet, no matter how long they've been at it. I wrote about some of the complexities here in 2004, and things have not become any more intelligible since then. The PPARs are nuclear receptors, affecting gene transcription when small molecules bind to them. There are, however, zillions of different binding modes in these things and they affect a list of genes that stretches right out the door. Some get upregulated, some down, and these vary according to patterns that we're only beginning to understand.

The Rochester group found that a particular class of compounds, the PPAR-gamma antagonists, had an unexpected toxic effect on some tumor cell lines. Their tubulin system was disrupted - that's a structural protein which is very important during cell division, and is the target for other known oncology drugs (like Taxol). The PPAR ligands seem to be messing with tubulin through a different route than anyone's seen before, though, and that definitely makes it worth following up on.

But the tone of the press release is too optimistic. (I should turn that line into some sort of macro, since I could use it twenty times a day). It mentions "high-dose" PPAR antagonist therapy as a possible cancer treatment, but take a look at the concentrations used: 10 to 100 micromolar. Even for cells in a dish, that's really hammering things down. And there's hardly any chance that you could attain these levels in a real-world situation, dosing a whole animal (or human). As blood levels go, those are huge.

But how about using more potent compounds? Of the three that are mentioned in the paper, BADGE is pretty dead, but the other two are actually quite potent. Tellingly, nothing happened at all with any of them up to 1 micromolar. These things will mess with other PPAR-gamma driven processes at much lower concentrations, so you have to wonder what's really going on here. And keep in mind that other PPAR compounds whose mode of action is roughly the opposite of these have been suggested as potential anticancer agents, too - this sort of thing happens all the time with nuclear receptors, and reflects their head-grabbing complexity.

This is still worth figuring out; don't get me wrong. There might be a new mechanism here that could lead to something, eventually, although it looks to be a tough problem. But that's the part of this work that's interesting - the level of activity seen here isn't. If I had a dollar for every compound that affects tumor cells at 50 micromolar, I wouldn't need to be sending my CV out these days.

Comments (5) + TrackBacks (0) | Category: Cancer | Drug Assays

January 11, 2007

An Innocent Question

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Posted by Derek

If you're on the editorial staff of J. Med. Chem., and you've got one of those "Perspective" review articles to go over, and it's on the very important (and very complex) topic of the binding of kinase inhibitors, something that's going to catch the eyes of lots of people all over the place. . .wouldn't you (and your referees) want to make sure that the paper has the correct structures in it? Even down to the level of obscure drugs like, say, Gleevec? Kinase Pro is just asking. . .

Comments (4) + TrackBacks (0) | Category: Cancer | The Scientific Literature

January 10, 2007

Reality, Here In This Little Dish

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Posted by Derek

I've noticed a few stories making the rounds recently about possible new cancer therapies. Johns Hopkins has press-released the work of a group there on, and several news outlets have picked up on a British study on the effect of vanilloid agonists (such as the hot-pepper compound capsaicin) on cancer cells.

And all this is fine, until the word "cure" starts being tossed around. It always is. The number of times you see it, though, is inversely proportional to how reliable your favorite news source is. I wish the Nottingham and JHU people all the best in their research, and I hope that their projects lead to something good. But they have a long way to go, which you might not realize from the "Johns Hopkins Patents Cancer Cure" and "Hot Peppers Can Cure Cancer" headlines.

You see, these studies are all on cell cultures. I've worked on several cancer research programs, and I'm sure that other readers who've done the same can back me up here: unless you've seen cancer drug discovery work at close range, you may have no idea of just how many compounds work against cancer cells in a dish. It isn't that hard. I have absolutely no idea of how many thousands of compounds I could dig up from our files that will just totally wipe out a lot of the common cancer cell lines - in culture, that is.

We don't even bother looking at a compound unless it goes through cultured cell lines like a flaming sword. Problem is, a good number of those compounds will go through normal cells in the same fashion, which isn't exactly what the oncology market is looking for. And of the ones that are left, the ones that aren't hideous toxins - well, a lot of those hit the skids when they go into a live mouse model. Drug candidates that rip through the cell assays but fizzle in the mouse are very easy to come by. Anyone who does oncology drug discovery can furnish you with piles of them, and you're welcome to the darn things.

Now comes the really ugly part. We've ditched the nonselective cell killers, and we've shaken out the compounds that can't cut it in a live animal. How many of these actually work in human beings? Nowhere near as many as we'd like, that's for sure. AstraZeneca's drug Iressa is always useful to keep in mind. That one was going to be a huge hit, back when it was in development. But in real patients, well. . .for the vast majority of them, it just doesn't do much at all. There are a few responders (some of whom we can screen for), but otherwise, you'd have to call the compound a massive failure in the real world. Oh, but you should see it kick through the cell assays, and watch what it'll do for the mice.

Our assays just aren't that predicitive. It's a big problem, and everyone in the field knows it, but so far (despite crazy expenditures of time, money, and brainpower), no one's been able to improve things much. Anyone who does cancer work knows not to celebrate until the human trials data come back, and you'd better be careful even then. So the next time you read about some amazing thing happening to cells in a dish, well - wish the researchers luck. And go back to what you were doing before. There's time.

Comments (11) + TrackBacks (0) | Category: Cancer | Drug Assays | Drug Development

November 20, 2006

Sell! (It's Not Just Me)

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Posted by Derek

Since I mentioned a little while ago that I'd gone short Imclone stock (at $29 and change), it was heartening to see Gretchen Morgensen make the exact same case against them in the New York Times on Sunday. (Subscriber link). The article makes much of the company's recent patent troubles, and the competition for their lone drug, Erbitux:

But neither the new competition from Amgen nor the legal ruling on the Yeda matter seems to worry the hopefuls who have bid up ImClone shares in recent weeks. These speculators also appear undaunted by results earlier this month from a drug trial in patients with midstage colorectal cancer. ImClone had hoped that the trial would show a survival benefit; it did not.

Two analysts, at Merrill Lynch and Citigroup, predicted that the trial results would mean stagnant market share for Erbitux and growth prospects for Vectibix. Both analysts rate ImClone a “sell.” Bristol-Myers Squibb, which owns 17 percent of ImClone, said in its most recent quarterly filing that Yeda might seek damages for infringement on past Erbitux sales and royalties on future sales of the drug. If Yeda licenses its patent to other companies, Bristol-Myers acknowledged that new competition for Erbitux would arise, but added that it was too early to tell what impact such a development would have on its business.

Investors are going to have to catch up with therapeutic reality here: Erbitux is a drug of limited utility. All cancer drugs are, unfortunately. "Cancer" is a catch-all term for hundreds of distinct disorders of cell division and growth, and no one drug is likely to be efficacious across much of that range. Even in its best applications, though, Imclone's drug is only fair-to-good. Meanwhile, progress in the field (though incremental) is very real, and every slightly better compound that comes along is going to capture a lot of market share.

So when I hear Carl Icahn going on about how he wants the company to step up its marketing efforts, I have to roll my eyes. The thing is, to some extent cancer drugs market themselves. They already sell much more than a purely rational calculation would predict. That's because many clinicians try them all, against all sorts of things, no matter what the label says. And it's not like no one's heard of Imclone or Erbitux, so there's only so much that a whiz-bang selling campaign can accomplish. Icahn is trying to apply the lessons he's learned from other industries to pharmaceuticals, a tempting idea that has sent more than one R&D-based organization rolling off the edge of the table.

I know that I've linked to this post of mine several times - it's the one where I talk about all the times I've told people to sell Imclone. But you know, it's been good advice. After all, I took it myself, and I didn't even own the stock. . .

Comments (6) + TrackBacks (0) | Category: Business and Markets | Cancer

October 30, 2006

Blow The Trumpets

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Posted by Derek

Here's my latest contender for an award in the highly competitive Desperate Press Releases category: Albany Molecular says that it has an anticancer compound. Well, it has one that's going to move into "advanced preclinical testing", and if everything goes perfectly, they'll try to submit an IND by the end of 2007. Which means that the first bit of Phase I testing, the toe-in-the-water look at blood levels, can be realistically expected no sooner than sometime in 2008.

The headline is "Albany Molecular to Test Cancer Compound", which the unwary might suppose means that they're going to test it against, well, human cancer. But who knows when that might happen, because I read the press release to mean that the compound hasn't even gone through real small-animal toxicity testing. Is that a long way from human cancer patients? Is Auckland a long way from Albany?

Now, I understand that AMRI hasn't been down this road too many times before. Looking at this chart, it appears that this project is the most advanced they have, and I don't recall them ever heading for the clinic before. That's because the company has been mainly an outsourcing venture, a place to get compounds and libraries made for you. With that business model under pressure, they've decided to give in to temptation and become a drug company.

It's not an easy living, and they're just getting started at it. The programs they have listed are all at the seedling stage, just barely edging into reality by the standards of people who've seen things crash in Phase III. There are probably plenty of people at AMRI who feel the same way, actually - I know that they have a number of scientists and managers who've worked at other drug companies over the years. They know the score, even if their PR department doesn't.

The compound being trumpeted today is said to be a tubulin inhibitor, which puts it in the same class as the taxanes. That's an interesting cancer target, and it's not always easy to get good chemical matter against it. Still, there have been a lot of compounds reported over the years, many of which have never been heard from again. Here's a recent review (PDF, which may be subscriber-only) on the compounds that are already in the clinic. It's a tough area, and not exactly an unc