About this Author
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: derekb.lowe@gmail.com
Twitter: Dereklowe
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Category Archives
February 6, 2012
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
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 (17)
+ TrackBacks (0) | Category: Cancer | Regulatory Affairs
January 20, 2012
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
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
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
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
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
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
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
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
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
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.' "
"Malignant?"
"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 (28)
+ TrackBacks (0) | Category: Biological News | Book Recommendations | Cancer | The Central Nervous System
November 15, 2011
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
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!
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+ TrackBacks (0) | Category: Business and Markets | Cancer
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!
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+ TrackBacks (0) | Category: Cancer | Clinical Trials
November 1, 2011
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.
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October 14, 2011
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.
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October 11, 2011
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?
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+ TrackBacks (0) | Category: Cancer | Clinical Trials | Drug Development | Drug Industry History
September 27, 2011
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 TheStreet.com (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.
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+ TrackBacks (0) | Category: Business and Markets | Cancer | The Dark Side
September 15, 2011
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.
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+ TrackBacks (0) | Category: Cancer | Chemical News
August 12, 2011
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.
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August 8, 2011
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. . .
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+ TrackBacks (0) | Category: Cancer | Drug Prices
August 4, 2011
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?
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July 8, 2011
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!
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+ TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs | The Dark Side
July 1, 2011
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?
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June 29, 2011
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.
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June 27, 2011
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. . .
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June 14, 2011
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. . .
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May 27, 2011
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.
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+ TrackBacks (0) | Category: Cancer | Clinical Trials | Why Everyone Loves Us
April 27, 2011
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.
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+ TrackBacks (0) | Category: Cancer | Drug Development
April 7, 2011
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.
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+ TrackBacks (0) | Category: Cancer
April 5, 2011
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.
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February 22, 2011
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?
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+ TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs
February 14, 2011
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.
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+ TrackBacks (0) | Category: Academia (vs. Industry) | Cancer | Drug Development | The Central Nervous System
January 31, 2011
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. . .
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+ TrackBacks (0) | Category: Cancer | Clinical Trials
January 24, 2011
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.
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+ TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs
January 4, 2011
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.
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+ TrackBacks (0) | Category: Analytical Chemistry | Cancer | Clinical Trials
December 17, 2010
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.
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+ TrackBacks (0) | Category: Cancer | Regulatory Affairs
December 1, 2010
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?
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+ TrackBacks (0) | Category: Aging and Lifespan | Cancer | Clinical Trials
November 18, 2010
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?
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+ TrackBacks (0) | Category: Cancer | Chemical News | Drug Industry History
October 20, 2010
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.
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+ TrackBacks (0) | Category: Cancer | General Scientific News
October 11, 2010
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?
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+ TrackBacks (0) | Category: Cancer | Chemical News | Drug Industry History
September 9, 2010
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.
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+ TrackBacks (0) | Category: Cancer
September 3, 2010
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?
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+ TrackBacks (0) | Category: Cancer
August 30, 2010
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.
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+ TrackBacks (0) | Category: Cancer | Drug Prices | Regulatory Affairs
August 17, 2010
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.
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+ TrackBacks (0) | Category: Cancer | Clinical Trials
August 16, 2010
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
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+ TrackBacks (0) | Category: Animal Testing | Cancer | Clinical Trials | Drug Development
June 23, 2010
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.
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+ TrackBacks (0) | Category: Cancer | Drug Development
June 22, 2010
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 (!)
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+ TrackBacks (0) | Category: Cancer | Regulatory Affairs
June 14, 2010
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. . .
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+ TrackBacks (0) | Category: Cancer | Cardiovascular Disease
June 8, 2010
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.
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+ TrackBacks (0) | Category: Cancer | Drug Prices
June 7, 2010
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.
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+ TrackBacks (0) | Category: Cancer | Drug Prices
June 3, 2010
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.
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June 2, 2010
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.
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+ TrackBacks (0) | Category: Cancer | Snake Oil
May 14, 2010
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.
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+ TrackBacks (0) | Category: Cancer | Clinical Trials
May 10, 2010
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.
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+ TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History | Press Coverage
May 7, 2010
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). 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.
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May 6, 2010
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.
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+ TrackBacks (0) | Category: Business and Markets | Cancer | Clinical Trials | Drug Development
May 3, 2010
Posted by Derek
A comment to this post on the Sirtris compound saga just had me checking Clinicaltrials.gov. 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.
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+ TrackBacks (0) | Category: Aging and Lifespan | Cancer | Clinical Trials
April 27, 2010
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.
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+ TrackBacks (0) | Category: Analytical Chemistry | Biological News | Cancer | Drug Assays
March 30, 2010
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. . .
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+ TrackBacks (0) | Category: Biological News | Cancer | Clinical Trials
March 29, 2010
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.
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+ TrackBacks (0) | Category: Cancer | Clinical Trials
March 26, 2010
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. . .
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+ TrackBacks (0) | Category: Cancer | Cardiovascular Disease | Clinical Trials | Drug Industry History
March 25, 2010
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. . .
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+ TrackBacks (0) | Category: Aging and Lifespan | Cancer | Snake Oil
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.
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+ TrackBacks (0) | Category: Biological News | Cancer | Clinical Trials | Pharmacokinetics
March 12, 2010
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.
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+ TrackBacks (0) | Category: Biological News | Cancer
February 26, 2010
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.
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+ TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs
February 22, 2010
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.
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+ TrackBacks (0) | Category: Cancer | Clinical Trials
January 11, 2010
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).
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+ TrackBacks (0) | Category: Biological News | Cancer | Diabetes and Obesity
January 7, 2010
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.
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+ TrackBacks (0) | Category: Biological News | Cancer | Infectious Diseases
October 5, 2009
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!
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+ TrackBacks (0) | Category: Aging and Lifespan | Biological News | Cancer | Current Events
September 11, 2009
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?
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+ TrackBacks (0) | Category: Biological News | Cancer
August 26, 2009
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. . .
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+ TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History | Patents and IP
August 4, 2009
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 clinicaltrials.gov, 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.
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+ TrackBacks (0) | Category: Academia (vs. Industry) | Cancer | Clinical Trials
June 9, 2009
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.
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+ TrackBacks (0) | Category: Cancer | Clinical Trials
June 1, 2009
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!
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+ TrackBacks (0) | Category: Business and Markets | Cancer | Clinical Trials | Drug Development | Drug Industry History
May 20, 2009
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.
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+ TrackBacks (0) | Category: Cancer | Current Events | Snake Oil
May 7, 2009
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. . .
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+ TrackBacks (0) | Category: Cancer
May 6, 2009
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.
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+ TrackBacks (0) | Category: Cancer | Clinical Trials | Toxicology
April 30, 2009
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.
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+ TrackBacks (0) | Category: Business and Markets | Cancer
April 14, 2009
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).
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March 26, 2009
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. . .
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February 11, 2009
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.
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December 4, 2008
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.
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September 19, 2008
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. . .
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September 12, 2008
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?
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September 8, 2008
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”
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August 1, 2008
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.
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July 22, 2008
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.
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June 23, 2008
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.
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+ TrackBacks (0) | Category: Cancer
April 9, 2008
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.
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+ TrackBacks (0) | Category: Cancer | Clinical Trials | Diabetes and Obesity | Toxicology
April 3, 2008
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”.
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+ TrackBacks (0) | Category: Animal Testing | Cancer | Cardiovascular Disease | Diabetes and Obesity | Drug Assays | Drug Development | Infectious Diseases | The Central Nervous System
January 16, 2008
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.
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+ TrackBacks (0) | Category: Cancer | Current Events | Drug Industry History
January 4, 2008
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.
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+ TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History
October 29, 2007
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. . .
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+ TrackBacks (0) | Category: Cancer | Drug Development | Infectious Diseases
September 17, 2007
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.
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+ TrackBacks (0) | Category: Cancer | Drug Development | Odd Elements in Drugs | Patents and IP | Why Everyone Loves Us
August 20, 2007
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. . .
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+ TrackBacks (0) | Category: Cancer | Drug Assays
June 4, 2007
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. . .
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+ TrackBacks (0) | Category: Cancer | Clinical Trials
April 19, 2007
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. . ..
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+ TrackBacks (0) | Category: Cancer
April 11, 2007
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
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.
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+ TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History
April 3, 2007
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.
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+ TrackBacks (0) | Category: Business and Markets | Cancer
April 2, 2007
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
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. . .
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+ TrackBacks (0) | Category: Business and Markets | Cancer | Clinical Trials
February 12, 2007
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
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
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
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
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
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 uncrowded one.
But really, good luck, guys. I hope the compound makes it through the mice, and the rats, and the dogs, and histopathology and formulation and GMP scale-up and all the rest of the whirlpools. Just try not to press-release the world every step of the way, OK?
Comments (8)
+ TrackBacks (0) | Category: Business and Markets | Cancer
October 9, 2006
Posted by Derek
A few miscellaneous notes this morning: I had an e-mail from a reader who asks "Why is Imclone stock worth anything at all?" He was referring to the competition they're now facing from Amgen, and the managerial turmoil that's been going on for months now. For my part, I think that IMCL is worth something, but I sure don't think it's worth $29.44/share, which is where I went short on Friday. (In the future, if I write about them, I'll make note of that fact each time in the interest of disclosure). I realize that this puts me on the other side of the fence from Carl Icahn, a person whose stock-picking judgment I might normally defer to. But in this case, I think I may know more about cancer therapies than Icahn does. We'll find out.
On an unrelated topic, I have a request. Does anyone know of a commercial source for a library of diverse phenyl carbamates? I realize that that's not the usual sort of diversity library - if I were after secondary amines, the offers just wouldn't stop. I can find scattered examples from various suppliers, but if someone had a bunch already collected, it would be a great time-saver. Any ideas?
But finally, though, physics is more on my mind than chemistry this morning. I'm digesting the unpleasant implications of this map, courtesy of the US Geological Survey. . .
Comments (2)
+ TrackBacks (0) | Category: Cancer | Current Events
September 20, 2006
Posted by Derek
So, it turns out that Imclone doesn't actually own a key patent covering uses of its only money-maker, Erbitux. This case has been dragging on for years in one form or another, a bizarre story well chronicled here at Fortune. This is another case of prior art invalidating a patent:
The trial is the culmination of a strange 20-year saga. It pits three distinguished scientists from Israel's Weizmann Institute against ex-colleague Joseph Schlessinger. . .The scientists accuse Schlessinger of absconding with their idea of combining a monoclonal antibody with chemotherapy, taking it to a corporate predecessor of Sanofi-Aventis, and secretly applying for a patent on it. While the application was pending, Aventis licensed the rights exclusively to ImClone. (Schlessinger denied impropriety and claimed credit for the antibody and the combination.)
ImClone had reason to question who the inventor was as early as 1994, when the U.S. Patent Office rejected its application on the grounds that the Weizmann scientists had published an article describing the combination idea before Aventis filed for the patent. ImClone told the patent office it would provide support for its claim, then dropped the application. The company later refiled, and the patent office relented.
Imclone was never able to back up that claim in the end, so out goes their patent. (The Israeli scientists, as Yeda Research and Development, still have a valid patent of their own which they just licensed to Amgen). This is the sort of thing that I don't think should be patented to start with - I have a big problem with broad method-of-treatment claims - but the prior publication makes that a moot point in this case as far as Imclone's concerned. Analysts are estimating that this loss could cut Imclone's earnings by 10 to 20 per cent, which they certainly don't need.
Carl Icahn, the company's largest individual shareholder (behind Bristol-Meyers Squibb), has seen enough. He was elected to the board of directors today, and lost no time sending an open letter calling for the CEO's head. Icahn's no fool as an investor, but I have to question his judgment in hanging on to his Imclone position with such tenacity. Not that Big Carl cares, but I've been telling people to sell the stuff for a long time now, because I don't like their prospects.
I didn't count on this patent loss, though - I just had them downrated in general. And it seems this opinion is shared by others in the industry. Back earlier this year Imclone announced with great blasts of trumpets that it would entertain offers to be bought. Reaction to this opportunity didn't meet their expectations, though, because in August they took themselves off the block, saying that the offers they'd received had been inadequate. It's especially notable that Bristol-Meyers Squibb didn't see fit to buy them out, especially considering that many of Imclone's stockholding fanatics have always seen that as a safety net.
So if BMS, who know Imclone inside out, doesn't want them, why does Carl Icahn? The stock did make it back to $40 per share after I last stuck my tongue out at it around $34. But now it's at $29. . .
Update: as per the comments, here's an excellent and detailed summary of this litigation from PatentBaristas. There are a lot of odd features to the case - check out the part where the Imclone scientist had a suspiciously good memory of a key conversation from twenty years ago. . .
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+ TrackBacks (0) | Category: Business and Markets | Cancer
September 6, 2006
Posted by Derek
When I tell people that I work for a drug company, they often want to know what disease I'm working on. I've been able to give all kinds of answers over the years, and most of them go over well. Everyone's glad to hear that you're doing research on diabetes, cancer, Alzheimer's or other widespread high-profile problems. Of the areas I've spent time in, cancer probably has the most cachet on this scale, since almost everyone knows of someone who's had serious trouble with one form or another.
The antithesis of cancer's situation is probably obesity. No matter how many headlines come out on its epidemic nature, huge public health consequences, and so on, it still doesn't get you the respect that other indications do. There are several reasons for this, the first of which is the seriousness of the disease, as defined by life expectancy. For better or worse, obesity patients are going to survive for much longer periods than cancer patients.
Scientifically, this actually makes the field more difficult to work in. Frankly, with most of the current cancer therapies, all we can offer is a few more months or (in some cases) years of life for most patients, so until recently long-term side effect issues haven't been a big concern. (Note, though, that this is changing). But obesity therapies are going to be used for longer periods of time. Obesity is associated with a shorter lifespan, true, but the level of obesity that some people are wanting to treat doesn't have that great an effect on mortality, and the survival rate with even morbid obesity is one heck of a lot better than with most kinds of cancer.
Getting back to the seriousness problem, another issue is that for many people, it's hard to shake the image of obesity as something that could be better treated by just eating less food and getting off the couch. I realize that that's not always a fair judgement, and my heart does indeed go out to people who put on weight more easily than the average person. But that said, there can be little doubt that eating fewer calories and doing a bit more exercise would take off untold numbers of pounds nationwide. The question is, as physicians will tell you, is whether anyone is going to do those things. If they can be more motivated by taking an obesity drug along with changing their diet and doing some exercise, then perhaps the drugs will have partially proved their worth. Of course, you could argue that similar effects at that level might be obtained by pills filled with, say, oat bran, billed as wonderful new obesity therapies: Placebatrim, anyone?
No, we're not going to be able to get away with that one. That's a market for the "nutritional supplement" people. An obesity drug from a real pharmaceutical company is going to have to really do something to get past the FDA, and it's going to have to be extremely safe in order to stay on the market. (Thus the current state of the obesity drug market). Anything that meets these criteria will make a huge amount of money. But respect? Fair or not, that might be asking too much. . .
Comments (22)
+ TrackBacks (0) | Category: Cancer | Diabetes and Obesity
June 4, 2006
Posted by Derek
Over the last few years, there's been more attention paid to a problem in cancer therapy that is going to keep us all very busy: drug resistance. Everyone's heard about this topic in reference to antibiotics, and with good reason. But the same thing happens in oncology, which makes sense. Despite a lot of major differences, in both cases we're trying to kill off robust, fast-dividing cells that have a lot of genetic variation in them. Anything that doesn't respond to the drug is going to have an open field in front of it.
The situation in cancer might actually turn out to be worse than in antibiotics, disturbing though that sounds. For one thing, cancer cell lines are often rather genetically unstable, which may well be how they ended up becoming cancer cell lines in the first place. So mutants are pretty easy to come by. Counterbalancing that, they don't have a quick way of transferring genetic material to each other like bacteria do, which means that we don't have to restrict the use of the therapies like we have to with antibiotics. Each patient is an island, fortunately.
The real difficulty is that antibiotics are typically taken for a set course of treatment - you knock the infection down enough to where the patient's immune system can clean up the rest, and everything's done. But cancer therapies, the kind that we're turning out now, are likely going to be more like insulin is for diabetics - you're going to be taking them for a long time, quite possibly for the rest of your life, which gives plenty of time for something bad to happen. It's impossible to know whether all the cancer cells disappear, or whether they're just lying low. So no one's sure yet what will happen ifyou go off of the drugs, and as you can imagine, that's data which is going to be hard to obtain.
Gleevec (imatinib) is a good example. There are all too many patients who have taken the drug for longer periods and have seen it lose its effectiveness, which must be really a wrenching experience. The kinase that the drug targets (Bcr-Abl) turns out to have a number of mutant forms that are unaffected by Gleevec, so any cells that have (or develop) these variants are free to cut loose. Interestingly, it may be the case that Bcr-Abl itself sets up conditions inside the cell that favor development of mutations, which for cancer cells could be something of a survival tool.
The only way around such problems is to make new drugs, just like in the antibiotic field. Two of the most advanced ones are AMN107 (nilotinib) and BMS354825 (dasatinib). Dasatinib had a good ASCO meeting, with an FDA committee recommending its approval, and with new data being presented comparing it head to head with Gleevec. So far, it looks like it's superior to higher doses of Gleevec in CML patients who've started to show resistance, but this is all with blood markers (as opposed to real survival data, which naturally takes longer to come in). But so far, so good.
These might remain useful for longer, since their binding modes are somewhat different than Gleevec, and whole classes of mutant Bcr-Abl forms are still susceptible. But resistance will surely keep cropping up. We're going to be a this for a long time.
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June 1, 2006
Posted by Derek
Well, the American Society for Clinical Oncology (ASCO) meeting is almost upon us, and it's time for the annual blizzard of misinformation. I'm not talking about the presentations at the meeting, which are no better or worse than the usual scientific meeting. No, I mean the press releases and subsequent press reports, of which the Reuters item I'm going to highlight today is a depressingly good example.
The headline reads "Big Pharma Expected to Dominate Key Cancer Meeting", which isn't such a good start. Any time you see the industry being divided up into "Big Pharma" and "Biotech", as this piece does, an alarm bell should go off in your head. We need to get clear on what "biotech" means, or dump the term altogether. I'm in favor of the second choice, although that's not going to happen, because all the categories are mixed up, anyway. The tiny-DNA-and-protein versus big-chemical-drug storyline doesn't work so well these days. If Genentech and Amgen aren't Big Something, I'd like to know who is. And on the other end of the scale, was Sugen a "biotech" because they were small (even though they make small organic molecules instead of protein-based drugs?) How about Vertex, or OSI?
My favorite part of the article is this one:
Big pharma's interest in cancer comes about five years after Novartis' launch of the targeted leukemia drug Gleevec.
Gleevec was initially expected to be a niche product, but its effectiveness and benign side-effect profile led to sales last year of $2.2 billion.
Let's take those in order. "Big Pharma's interest in cancer" has, in fact, been pretty constant. It's our success that comes in fits and starts. The article would makes it seem as if we can turn on the clinical research tap at will - when we finally get around to it, anyway. But there are no sudden waves of interest that show up in clinical research meetings - you're seeing the end result of decisions taken eight or ten years ago. When do you think we started the projects that are now being presented at ASCO, anyway?
And as for Gleevec, which is a fine drug that does well by its small intended patient population, let me say (again) that I think that a good amount of it is being wasted. There are, to the best of my knowledge, not enough people with GIST or CML (the two cancers that it's been approved to treat) to account for its sales, not even nearly enough. Gleevec was indeed expected to be a niche product. In terms of the people it can effectively treat, it still is.
It's not for lack of trying. Here are a few attempts from just the last few months: endocrine tumors, renal cell carcinoma, metastatic melanoma, germ cell tumors, refractory myeloma, and advanced hepatocellular carcinoma. In some types of tumor, Gleevec may actually make things worse.
Again, I'm not going off on Gleevec because it's a bad drug,. It isn't. It's pretty typical of what we have to offer these days in cancer: very good effects in a small number of people, some help for a slightly larger number, and nothing much for most. Talk of a "benign side effect profile" is ridiculous for many of the newer agents, because they can only be considered benign with compared to the old ones, which were toxicologically the scourge of the earth. Compared to cisplatin, sure we look good. Who doesn't?
There were surely be more of this kind of thing over the next few days. My advice is to ignore the cancer news until things calm down a bit and we can get a better read on what's really happening. There's going to be too much dust in the air for that this weekend.
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April 26, 2006
Posted by Derek
There are all sorts of excellent reasons not to cut down the rainforests of Borneo. Biological diversity, erosion, local climate, sheer aesthetics. . .no one should have to scratch their head for very long. But this isn't one of them, at least not the way it's being sold:
"Plants thought to help treat or cure cancer, AIDS and malaria have been found in the rainforests of Borneo, a report from the Swiss-based global conservation group WWF said on Thursday. . . A promising anti-cancer substance has been found in a Borneo shrub by researchers for an Australian pharmaceutical firm, while a chemical found in latex produced by a tree appears to be effective against the replication of HIV, the report said.
In the bark of another species of tree, the researchers discovered a previously unknown substance which in laboratory tests appeared to kill the human malaria parasite, it added."
Going to the source of the story, one finds more details:
"According to the report, Cerylid Biosciences – an Australian pharmaceutical company – has identified a promising anti-cancer substance in a shrub found in Sarawak. A compound present in the plant Aglaia leptantha has been found to effectively kill 20 kinds of human cancer cells in laboratory tests, including those that cause brain and breast cancer, and melanoma.
“The fact that the compound is very effective against a number of tumour cells, presents a very good
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