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

Derek Lowe The 2002 Model

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

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

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March 25, 2015

Metformin for Aging in General?

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Posted by Derek

Here's an interesting report in the Wall Street Journal on plans to run a large clinical trial with metformin. That compound has a lot of effects, and many of them seem as if they could be beneficial in an aging population.

Dr. Barzilai expects to enroll more than 1,000 elderly participants in the randomized, controlled clinical trial to be conducted at multiple research centers and take five to seven years. The project is in the preliminary stages and permanent funding hasn’t yet been secured. Funding for the planning phase is coming from the American Federation for Aging Research, a nonprofit organization of which Dr. Barzilai is deputy scientific director.

The trial aims to test the drug metformin, a common medication often used to treat Type 2 diabetes, and see if it can delay or prevent other chronic diseases. (The project is being called Targeting/Taming Aging With Metformin, or TAME.) Metformin isn’t necessarily more promising than other drugs that have shown signs of extending life and reducing age-related chronic diseases. But metformin has been widely and safely used for more than 60 years, has very few side effects and is inexpensive.

I hope this gets off the ground, for just those reasons. The study itself will not be cheap, but (as the article notes) it could pioneer some ways of looking at aging in the clinic, and we need for people to be taking steps in that direction. The planet's population, on the average, is not getting any younger, as birth rates level off (or plunge outright), and healthy lifespan is a bigger and bigger issue.

andy Walsh, an FDA spokeswoman, said the agency’s perspective has long been that “aging” isn’t a disease. “We clearly have approved drugs that treat consequences of aging,” she said. Although the FDA currently is inclined to treat diseases prevalent in older people as separate medical conditions, “if someone in the drug-development industry found something that treated all of these, we might revisit our thinking.”

As well they might. This is worth keeping an eye on, for sure.

Comments (15) + TrackBacks (0) | Category: Aging and Lifespan | Clinical Trials

Transcelerate Status Report

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Posted by Derek

Here's a followup to something I wrote in 2012. That was when a joint venture called Trancelerate was announced to address precompetitive drug development issues, clinical trial design, and so on.

Someone asked me the other day what had come out of this, and I had to admit that I was stumped. So I'd like to throw the question open to the readership. Does anyone know of some things that can be pointed to that have emerged from Trancelerate? There was a progress report of sorts in Nature Reviews Drug Discovery, which mostly seems to have covered the venture's first year in operation. Otherwise, details have been scarce, from what I can see.

Comments (2) + TrackBacks (0) | Category: Clinical Trials | Drug Development

March 24, 2015

The Best Way to Halt a Clinical Trial

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Posted by Derek

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

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

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

March 20, 2015

Biogen's Alzheimer's Data

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Posted by Derek

If you're a rabid biotech investor, you already know all about Biogen's data this morning. If you're sane, or insane in some other, more interesting direction, then here's what's up: last December, the company released some Phase I data suggesting that their amyloid antibody, BIIB037 (aducanumab) was showing better-than-expected responses.

Some of you may be wondering about that. Clinical responses? In a Phase I study? Well, there's nothing stopping you from collecting the data, and in this case, since Biogen was dose-responsing the subjects, they looked both at the amounts of amyloid (using Lilly's imaging agent for this purpose) and they also gave the patients standard cognitive tests to see if something was happening. That's what has everyone so excited, because there does appear to have been a dose-response, by both measurements. I'm glad to hear it - there is a huge need for an Alzheimer's therapy, of course, and the failure rate has been so brutal in the clinic (arguably 100% - there are approved drugs, but they don't do much).

Here's more on this from Matthew Herper at Forbes. The thing is, although this is good news, many investors are taking it as incredible, world-changing news. Biogen stock has been gaining over the last few months on expectations, and today's data will probably keep the party going. That's an awful lot to pin on a bunch of Phase Ib data, I'd say. Especially since this is Alzheimer's. The only phase that matters in Alzheimer's is Phase III.

Biogen knows this - they're skipping right ahead to it, and good for them for taking the risk. But a risk it is. Every other Alzheimer's antibody trial has failed, even though some have tried to pretend otherwise. The data are not in yet on the more preventative trials, where you hit the earliest possible patient population, true. But the results have not been encouraging. Either Biogen is really on to something here (which is what the investors are betting on) or they're in for a crashing disappointment in a few years. Yep, a few years - that's how long it's likely to take to run a large, well-controlled Phase III in this area.

There are other things to think about. One big issue is that the sample sizes are very, very small. Adam Feuerstein (on Twitter) noticed that the cognitive decline in Biogen's placebo group was larger than one might have expected. And there does seem to be some brain swelling in patients who are APOE4 carriers. All of these things are going to have to be worked out, slowly and expensively, so if you see headlines that Biogen has cured Alzheimer's, don't believe them - yet. I hope they have, but no one knows that, or can know that, for some time to come.

As a side issue, the excitement in the company's stock is part of the general biotech stock run of the last two or three years. It has been a tremendous market, that's for sure - buying the biotech index in 2010 would have been pretty slick move, although you'd have also lost some hair by now wondering how long the party would continue. My guess is that the people who did buy it back then have already sold and regretted it, and maybe more than once. As someone who works in the industry, I've certainly benefited from the runup, so by warning about investor euphoria I'm actually working against my own short-term interests!

Comments (50) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

March 12, 2015

Drug Industry Trials vs. NIH-Funded Ones: Who Reports on Time?

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Posted by Derek

This article at NEJM is looking at how well clinical trial results are made public, which has been a big topic over the last few years. Let me say up front that the results are quite interesting, and that some news outlets appear to be misreporting them.

Since 2007, it's been required by law that anyone sponsoring a clinical trial in the US register it at, and report at least a summary of the results within one year after finishing data collection for the trial's primary endpoint (or within a year of stopping it for any other reasons). These authors (all from Duke) found that the data can be messy to work with. It's not clear which trials in the registry are subject to the above legal requirements, so they first used someone else's algorithm to identify over 32,000 "highly likely clinical trials". Then they picked out the ones that were listed as "completed" or "terminated" before August 31, 2012 (to give everyone time to report), and that took the number down to 13,327 trials, all of which ended between January 1, 2008 and that 2012 cutoff. Any trial reporting results (or filing a request for an extension) by September 27, 2013 was considered to be legally acceptable.

How did everyone do? Only 13% of all the trials reported data within one year of completion, but the authors say that they still can't be sure how many of the trials being analyzed were required to report during that time (there are exceptions related to whether an intervention has been approved for marketing or not). Here's where they tried to correct for this:

We manually reviewed a sample of 205 HLACTs to determine requirements for reporting (Tables S15A and S15B in the Supplementary Appendix). By reviewing approval dates and labeling information, we determined that 44 to 45% of industry-funded HLACTs in this sample were not required to report results, as compared with 6% of NIH-funded studies and 9% of those funded by other government or academic institutions. On the basis of this review, we estimated that during the 5-year period, approximately 79 to 80% of industry-funded trials reported summary results or had a legally acceptable reason for delay. In contrast, only 49 to 50% of NIH-funded trials and 42 to 45% of those funded by other government or academic institutions reported results or had legally acceptable reasons for delay.

That's the real take-home of this article. The authors themselves say that:

Before the passage of the FDAAA, industry sponsors received particular scrutiny for selective reporting. Since the enactment of the law, many companies have developed disclosure policies and have actively pursued expanded public disclosure of data. Curiously, reporting continues to lag for trials funded by the NIH and by other government or academic institutions. Pfizer has reported that the preparation of results summaries requires 4 to 60 hours, and it is possible that the NIH and other funders have been unable or unwilling to allocate adequate resources to ensure timely reporting.

That much seems clear: the drug industry has been doing a significantly better job of complying with the law than publicly funded trials have. Some of the reports about this paper have picked up on this, but others have landed on that 13% overall figure and gotten stuck, even though (as the paper itself shows) many of the trials in that set were not even legally required to report data. The most detailed report in the press is probably this one from NPR. They get the results of the paper right, which is more than I can say for some others. I particularly noted, and not happily, that Ben Goldacre tweeted that figure along with a link to his book, "Bad Pharma", which juxtaposition implies that this number is both germane and the fault of the drug industry. I expected better.

Comments (15) + TrackBacks (0) | Category: Academia (vs. Industry) | Clinical Trials

March 2, 2015

Of Proteasome Inhibitors and PAINs

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Posted by Derek

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

Kyprolis comes out looking pretty good:

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

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

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

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

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

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

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

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

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

February 19, 2015

Experience Phase III Failure, Twice

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Posted by Derek

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

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

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

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

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

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

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

February 5, 2015

"From All This You'd Imagine, That There Must Be Something Learned. . ."

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Posted by Derek

Eli Lilly's phase III clinical trial of semagacestat, a gamma-secretase inhibitor, was a notable disaster. The drug did absolutely nothing at all for Alzheimer's patients - in fact, if anything, it made them slightly worse. The amyloid hypothesis was not illuminated in any useful way by this work - in fact, if anything, the situation was more confused afterwards than it had been before, and that's saying something. For its part, Lilly spent a great deal of time and money that (in retrospect) could have been more usefully employed doing almost anything else.

Here's a paper that combs through the wreckage looking for what we can learn from all this. It's not an easy task:

Semagacestat was one out of the many candidate drugs that advanced as a γ-secretase inhibitor blocking Aβ generation in cell cultures, animals, and finally human. Only relatively late in the studies did it become clear that the potential side effects caused by blocking Notch-signaling were severely limiting the clinical use of semagacestat. In fact, from a scientific point of view, it remains puzzling why the company decided to move forward toward phase III tests with a dose (maximal 140 mg/day) that in none of the phase II tests had shown any significant impact on Aβ levels in the cerebrospinal fluid (CSF) of humans. Looking back, it seems clear that such a phase III trial was unlikely to test the amyloid hypothesis, as elaborated below.

The author, Bart de Strooper of Leuven and University College (London) argues that the bad effects of the drug can likely be assigned to its effects on Notch signaling, and that the eventual once-a-day dosing schedule may well have exacerbated the problem. Even the peripheral side effects (skin trouble, nausea) could have been enough to decrease the cognitive test scores of an Alzheimer's population. As for the drug's effects in the brain, it had a short enough half-life that combining this with q.d. dosing meant that there were periods where no drug at all would be expected to remain in the CSF. This may have actually stimulated beta-amyloid production during those periods - in fact, de Strooper argues that Lilly may have chosen one of the worst possible dosing protocols for the drug.

And he goes on to point out just how little we know about gamma-secretase, both in the disease state and under normal conditions. He characterizes the entire Lilly trial as "premature", given the state of the field, and believes that it has in fact set back research in this area, industrial and academic. The article is a brief for the defense, from someone who clearly believes that gamma-secretase as a target has been ill served. It's hard to argue with him on that point, but at the same time, one reason it's been so poorly characterized is that coming up with good therapeutic approaches has been very difficult. Finding a gamma-secretase inhibitor with good properties has really been a long haul. In the end, the main lesson from the trial seems to be that we can't draw many lessons from the trial, which reminds me of what Hegel had to say about learning from history.

I'd be willing to bet that some of the people who are upset about semagacestat's failure and what it's done to the field were actually glad to see it go into the clinic at the time. Finally, we'd get some sort of data on this mechanism, even if this wasn't the best way to look at it. Had to be better than nothing, right? Well, this experience was more proof that there are worse things than nothing. The gamma-secretase field would have been better off if had continued to travel hopefully, rather than arriving at the end of that trial.

Comments (21) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Drug Development

January 30, 2015

Underpowered And Overinterpreted

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Posted by Derek

Time for another "watch those statistics" post. I did one about this time last year, and I could do one every couple of months, to be honest. Here's a good open-access paper from the Royal Society on the problem of p-values, and why there are so many lousy studies out there in the literature. The point is summed up here:

If you use p=0.05 to suggest that you have made a discovery, you will be wrong at least 30% of the time. If, as is often the case, experiments are underpowered, you will be wrong most of the time.

True, true, and true. If you want to keep the false discovery rate down to below 5%, the paper says, you should be going for p<0.001. And just how many studies, of all kinds, across all fields, hit that standard? Not too damn many, which means that the level of false discovery out there is way north of 5%.

(This paper) deals only with the very simplest ideal case. We ask how to interpret a single p-value, the outcome of a test of significance. All of the assumptions of the test are true. The distributions of errors are precisely Gaussian and randomization of treatment allocations was done perfectly. The experiment has a single pre-defined outcome. The fact that, even in this ideal case, the false discovery rate can be alarmingly high means that there is a real problem for experimenters. Any real experiment can only be less perfect than the simulations discussed here, and the possibility of making a fool of yourself by claiming falsely to have made a discovery can only be even greater than we find in this paper.

The author of this piece is David Coqulhoun, a fact that some people will have guessed already, because he's been beating on this topic for many years now. (I've linked to some of his prickly opinion pieces before). He's not saying something that a lot of people want to hear, but I think it's something that more people should realize. A 95% chance of being right, across the board, would be a high standard to aim for, possibly too high for research to continue at a useful pace. But current standards are almost certainly too low, and we especially need to look out for this problem in studies of large medical significance.

Update: what this post needed was this graphic from XKCD!

Comments (50) + TrackBacks (0) | Category: Clinical Trials | Drug Assays | General Scientific News | The Scientific Literature

January 14, 2015

The Duke/Potti Scandal, From the Inside

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Posted by Derek

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

January 12, 2015

Unstoppable Nivolumab

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Posted by Derek

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

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

January 7, 2015

Zafgen Wins Another Round

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Posted by Derek

Since I've been following the progress of Zafgen and their unusual drug candidate on the blog, I wanted to note that it just resoundingly passed another Phase II trial. This one was in patients who've gained weight to due hypothalamic injury. The Phase III is in the works.

Zafgen's compound is one that most of us would have put a red X through as soon as we saw its structure. Since I was writing earlier today about odd structures and the problems they can represent, it's important to keep the other side of the argument in mind: if you have solid data, no structure is too weird.

Comments (2) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity

December 19, 2014

Another Alzheimer's Antibody Goes Down

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Posted by Derek

The clinical failure rate for disease-modifying Alzheimer's therapies remains perfect, unfortunately: a flat 100%. The latest news is from Roche. Their in-licensed amyloid-targeting antibody (gantenerumab, from MorphoSys) came up empty on an interim trial analysis. Other trials are apparently continuing, but with what hopes?

Roche's rationale seems to be that these other trials are targeting milder and/or earlier forms of Alzheimer's. And it's true that if an antibody approach is going to show something, those are probably the patients where it will. (There are a number of such trials going on now). But the odds are very long. And the situation is complicated by companies wanting to get something, anything, out of these extremely expensive drug development efforts - and by many scientists who have committed their research careers to the amyloid hypothesis. Add in the terribly slow clinical readouts in any Alzheimer's trial and the large and desperate market for anything that works, and you have a tough landscape indeed.

Comments (26) + TrackBacks (0) | Category: Alzheimer's Disease | Alzheimer's Disease | Clinical Trials

November 20, 2014

Bind's Attempts To Remake Chemotherapy

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Posted by Derek

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

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

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

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

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

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

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

November 19, 2014

Wait, We Didn't Tell You About That Endpoint?

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Posted by Derek

Hmm. Via Twitter, we find this interesting example of moving the goalposts. NeoStem, a small stem-cell company, announced results the other day for a trial of their cardiac stem cell therapy. One bearish trader who'd been following them was surprised that the stock didn't drop more on the results, given that the trial didn't seem to have reached its primary endpoints at all.

But that's when he discovered that the primary endpoints had been changed. Here's the record at, and you can see that a lot has been taken out, and a lot added. Measurements of mycocardial perfusion have been de-emphasized, and if you guessed that the company saw no differences there in the trial data, your psychic powers are functional today. Measurements of major adverse cardiac events, though, have been added, and if you guessed that the company did see encouraging numbers there, you're two for two. And if by "encouraging", you meant "but still not statistically significant", then you should head for the race track this afternoon, because you're on fire.

So how much of this sort of thing is allowable? From what I know, this is over some sort of line, but I don't know the ins and outs of, never having seen a case quite like this before. Any thoughts? As for NeoStem themselves, their press release was all about "positive data", but the stock, which had moved up on Friday and Monday in anticipation, did end up with a substantial loss. Would it have been even more substantial if more people had read more closely?

Comments (28) + TrackBacks (0) | Category: Clinical Trials

November 17, 2014

Vytorin Actually Works

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Posted by Derek

The data from the IMPROVE-IT trial on cardiovascular outcomes for Vytorin have been released. And the combination met the primary endpoint: fewer heart attacks and strokes compared to those already on statin therapy alone.

Matthew Herper has an excellent roundup of the results and their context. The effect is real, but it's not gigantic, either, so the cost/benefit argument will go on (or at least it will for another couple of years, when the drug goes generic). It is a boost, though, for the use of LDL as a biomarker for cardiovascular risk: a different mechanism to lower LDL (cholesterol absorption inhibition), when added to a statin, decreased the risk. Some are wondering about other effects of ezetimibe (the cholesterol absorption inhibitor itself) influencing the result, but I'm not so sure about that. From what I know about the compound, it's hardly absorbed at all, and most of its effects are indeed in the gut wall. Update: nope, I'm hallucinating again.

Now it's time to speculate how things might have been if the earlier ENHANCE trial hadn't been handled so clumsily by Merck and Schering-Plough. The suspicion that brought on the drug hurt its sales, and according to today's results, hurt patients as well who didn't get treated with it. If you think being up front about bad results will hurt you, take a look at the costs of looking deceitful.

Comments (10) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials

November 13, 2014

Remember Vytorin? The Data Are Finally Coming.

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Posted by Derek

If you follow cardiovascular therapies, you'll no doubt have seen that a bit of information has come out on Merck's long, long, long-running IMPROVE-IT trial. That is the massive outcomes study for Vytorin, the combination of ezetimibe (the Schering-Plough cholesterol absorption inhibitor) and simvastatin (Merck's early statin drug). This combo ran into serious controversy back in 2008, when some clinical studies suggested that it had far less benefit than it should in some patients. The way that clinical data got released was not very glorious, either, and brought suspicions that the companies had tried to bury it. The only way to be sure was to run a big long-term study on cardiovascular outcomes. Such a trial was already underway even back in 2008, and here we are in 2014 without the numbers.

Over the years there have been various doubts and fears about what was going on. Early last year, there were reports that Merck was having to work over the data again, and that doesn't inspire confidence. But the Wall Street Journal noticed the other day that a Merck SEC filing mentioned that it had determined that the trial's results would not result in any accounting changes to the value the company had assigned to Vytorin.

Ed Silverman wonders at Pharmalot if it really matters at this point. The results could be very scientifically interesting, because there's a lot that we're not grasping about lipoproteins and their relation to disease. But both the ezetimibe combo (Vytorin) and ezetimibe itself (Zetia) are facing generic competition in perhaps 18 months (if the generic companies stay interested) - this is all coming too late in the life cycle to affect anything for Merck. It looks like we'll see the actual number later this month.

Update: Matthew Herper says that this could have a big effect on the use of surrogate markers in clinical trials. But that will happen only if, as he says, the most likely outcome doesn't happen. That outcome? "We Get Mud" - messy, hard-to-interpret data, with no strong signals to act on.

Second update: the data are out. The combination appears to be effective.

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

The Drug Worked, Unfortunately

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Posted by Derek

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

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

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

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

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

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

November 12, 2014

Near-Animal, Near-Human: The Future of Drug Testing?

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Posted by Derek

Here's a good article on animal models in drug discovery, and their many limitations.

We have moved away from studying human disease in humans,” (Elias) Zerhouni lamented to the NIH’s Scientific Review Management Board meeting. “We all drank the Kool-Aid on that one, me included.”

“The problem is that it hasn’t worked, and it’s time we stopped dancing around the problem,” he continued, suggesting researchers have become too reliant on questionable animal data. “We need to refocus and adapt new methodologies for use in humans to understand disease biology in humans.”

The article notes the controversy over mouse inflammation models, among others. I'd add pain as an area where something is clearly off kilter with the traditional animal models, and no one has ever been happy with xenograft models in cancer. (An entire post on "worst animal models" is here).

Well, just use human cell cultures you say, or at least you say if you've never tried it. The problem, of course, is that primary human cell cultures are often hard to keep going, and the things you have to do to keep them going often skew them away from being the sorts of cells you were hoping to study. There's nothing like a real in vivo system, unfortunately. Stem cells hold out a lot of promise for generating human cells of many types, but (as this article explains), the problem is that those cells are fresh, newly minted ones. And those don't always recapitulate the sorts of changes that you see in (for example) aging neurons.

It looks like we're moving towards re-creating real human organ-like tissue in vitro, as much as we can. That's not the least bit easy - there are so many factors that influence cellular physiology, from the obvious ones (constantly changing signals from blood chemistry) to the nonobvious (mechanical forces from nearby muscle contractions). The other way to do it (not discussed in the linked article) is to humanize the animal models as much as possible. One could imagine a rather unnerving "mouse" consisting of mostly (or completely) human tissues out in the periphery, for example.

I've defended animal models many times on this site, but my strongest arguments for them are (and remain) that there have to be some intermediate steps on the way to human trials, and that we don't have anything better that mice et al.. If something better comes along - and we do need something better - then out they go. The lack of really predictive models before human trials is the reason that 90% of all trials fail, and having 90% of all our trials fail is gradually squeezing drug research into a very tight corner indeed. Breaking out of it would be a real accomplishment.

Comments (23) + TrackBacks (0) | Category: Animal Testing | Biological News | Clinical Trials

November 5, 2014

Clinical Trials in Ebola

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Posted by Derek

So with various Ebola vaccines and therapies in development, how exactly are the necessary clinical trials going to be run? That's always a tricky business with an infectious disease that comes and goes - the current Ebola outbreak is by far the largest yet seen, but there are years when no cases are reported at all. You're not going to be able to round up a traditional clinical trial cohort very easily, and the difficulties are even greater considering the areas where the patients are most likely to be found.

Steve Usdin at BioCentury and Steve Kanters at The Lancet come to the same conclusion: adaptive clinical trial designs. Not everyone is on board with the idea of randomized clinical trials at all, though:

FDA, NIH, academic investigators and biopharmaceutical companies are collaborating on the design of an adaptive, randomized controlled trial of Ebola therapies that could be conducted in the U.S. and Liberia, Luciana Borio, FDA assistant commissioner for counterterrorism policy, told BioCentury last week.

The protocol will be a sharp departure from trials planned by Médecins Sans Frontières (MSF), the Wellcome Trust and other non-governmental organizations, which have argued randomized controlled studies are unethical as well as impractical. For Ebola, the control would consist of best supportive care, as no treatments have been approved.

FDA's Borio, however, contends that randomized, controlled trials are ethical, practical and necessary. The agency and NIH have forged a collaboration with investigators at the University of Nebraska Medical Center and Emory University to develop a protocol that will not only determine whether treatments are effective and safe, but also speed any compounds that pass the test to patients as part of a rapidly evolving standard of care.

I agree that running a traditional randomized trial in this situation would be a bad idea, but as much as I respect the work done by MSF, I disagree that we have to ditch the whole idea. With the standard of supportive care improving in West Africa, it could be very difficult to figure out if anything was helping at all. The adaptive/Bayesian designs make a lot of sense here. From the Lancet piece:

The first, and simpler, suggested adaptive trial design would combine response-adaptive randomisation and adaptive stopping rules. In combination, these optimise trial timing by stopping the trial as quickly as possible following the ascertainment of treatment benefit or harm. Clearly, a trial design that is more timely and whose end is based on either efficacy, inefficacy, or pre-determined sample size is more ethical than traditional designs, which primarily end based on predetermined sample sizes or time-periods. Furthermore, adaptive randomisation is a randomisation schedule that allows more patients to be given the treatment that appears to be more effective as the trial is conducted.

Data collection and standardization will still be a major challenge, but one that I think is worth meeting. Otherwise, I fear a bunch of "Well, that sort of helped, we kind of think" data, and that will do no one any good at all. There are many arguing that a randomized trial of the Ebola therapies would be unethical, but I don't see how anything else can be. The key is to make the trials as fast and effective as they can be.

Comments (9) + TrackBacks (0) | Category: Clinical Trials | Infectious Diseases

November 4, 2014

Novo Nordisk Braves the Obesity Market

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Posted by Derek

Everyone thinks of Novo Nordisk as a diabetes company (and that they are), but they're willing to use their expertise in related areas. And if you know a lot about insulin and blood sugar regulation, you may also end up knowing a fair amount about appetite and satiety signaling in the gut. The company has been developing a new dosage form of their Victoza (liraglutide) peptide drug for just that purpose, and it seems to be working in the clinic.

Liraglutide is a long-acting GLP-1 analog, and decreased appetite is already noted with compounds of this type. Novo is out with more Phase III data, and they look pretty strong. An FDA advisory panel meeting last month went very well, and they seem to be on target to head into the obesity market.

And it'll be interesting to watch what happens then. As an injectable, liraglutide isn't going to be something that people just take casually, but who knows, that might prompt better patient compliance and a bit more dedication to the other diet and exercise factors in weight loss, since you're already going to that much trouble. Obesity therapies have had a rough time in the market over the last few years, with Vivus, Orixigen, and Arena all struggling with their individual drugs. (All three of those stocks have fanatic followings, I might add, and I feel sure to hear from some of those folks just for having mentioned the companies). Will Novo's drug (renamed Saxenda for this market) have a better fate? (Some of that will depend, in the long run, on whether there are any problems with higher liraglutide doses, but so far, things look OK). And if it does, will it knock out one or more of the smaller players?

Comments (12) + TrackBacks (0) | Category: Business and Markets | Clinical Trials | Diabetes and Obesity

October 30, 2014

Nivolumab Racks Up Another Success

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Posted by Derek

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

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

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

October 29, 2014

Aileron Heads Toward the Clinic

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Posted by Derek

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

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

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

October 28, 2014

An Open-Source Cancer Pitch, Deconstructed

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Posted by Derek

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

October 27, 2014

Sarepta's Duchenne Therapy Is A Lot Further Away

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Posted by Derek

I wrote here about Sarepta, a small company having plenty of difficulty getting a therapy for Duchenne muscular dystrophy through the FDA. At that point, the problem was the accelerated-approval pathway, but things have now gotten a good deal worse.

Following a meeting with regulators in September, the biotech spelled out a new set of data that the FDA is looking for in the application, and the biotech says it will have to delay filing--another dramatic turning point for the company this year, which saw its shares plunge 30% on the news this morning.

Sarepta shares have been on a roller coaster ride over the past two years as the company was forced repeatedly to move the goal lines on a prospective approval for the drug, which so far has registered promising data from a tiny study involving only a dozen boys. The biotech today spelled out regulators' demands for imaging and longterm results as well as more safety data, all of which will stall the company until at least mid-2015--or longer.

To make matters worse, the CEO has been telling investors that the agency was much more favorable, and in fact was strongly considering an early approval for the drug even before any Phase III results came in. Those investors are deeply unhappy now, and the parents of the potential patients even more so. This whole situation is a terrible mess, and honestly, it looks as if it could have been avoided. From outside, Sarepta seems to have been trying to make far too much of a single small study (12 boys, and the data only looked good when you excluded two of them). You have to provide convincing data in this business, and that takes time and costs money. Trying to take shortcuts is a low-percentage move.

Comments (3) + TrackBacks (0) | Category: Business and Markets | Clinical Trials

October 6, 2014

Sunesis Fails with Vosaroxin

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Posted by Derek

When last heard from, Sunesis was trying to get some last compounds through clinical trials, having cut everything else possible along the way (and having sold more shares to raise cash).

Their lead molecule has been vosaroxin (also known as voreloxin and SNS-595), a quinolone which has been in trials for leukemia. Unfortunately, the company said today that the Phase III trial failed to meet its primary endpoint (and the stock's behavior reflects that, thoroughly). The company's trying to make what it can out of secondary endpoints and possible effects in older patients, but the market doesn't seem to be buying it.

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

September 29, 2014

The Case of Northwest Biotherapeutics

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Posted by Derek

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

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

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

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

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

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

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

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

September 17, 2014

Messed-Up Clinical Studies: A First-Hand Report

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Posted by Derek

This makes for a very disturbing read. The author details his participation in a clinical trial for an asthma therapy being developed by Amgen at a clinic in Newport Beach (CA). He doesn't say what the drug was, but my guess is that it's brodalumab, an anti-IL17 antibody which has been in trials for asthma and psoriasis.

What he recounts is very disturbing. Here's a sample:

Moment of Truth #2 came during one of the many whispering sessions they gave me. The lead technician had a disturbing habit of frequently pulling me into a corner or another room and whispering things like “We’re just going to say that you take this medication.” I had to fill out numerous questionnaires, and she would often stand over me and whisper which answer I should mark. At last, one day after a battery of breathing tests, questionnaires, and vital-sign checks, it was required that the doctor (listed as the principal investigator on this study) verify all this, personally examine me, and sign off on it. Amgen was very clear on that point. “But he’s not here today,” she whispered, “so we’re just going to mark this off and send it through. We’ve already done everything he was going to do anyway.” By now I knew this contractor was willfully and knowingly giving Amgen invalid data, and I resolved to stick with it only long enough to see what more I could learn. I’d already decided I would not complete the trial and contribute bad data to a medical clinical trial.

It gets worse from there. The comments to Brian Dunning's post are already starting to fill up with the expected "Yeah, that's what Big Pharma does" stuff. So I'd like to help provide an antidote to that: Hey Amgen! Hey FDA! Check out this Newport Beach trial center! Dig into these allegations, and do something about them. And tell everyone what you've found!

Update: some readers are asking how anyone can be sure that this description is real. We can't, although it's certainly a detailed description, and attached to the name of someone with a good bit of internet traffic and associated notoriety. Mind you, some of that associated notoriety is a conviction for wire fraud. But in a "cui bono" sense, I don't see any reason for someone to make up the details in this account.

And how accurate it is should be an immediate concern for Amgen. In this business, we not only have to be death on clinical trial fraud, but we also have to be seen to be death on clinical trial fraud, so that (1) other people won't get the impression that it's a good idea, and (2) the general public won't get the impression that we're a bunch of crooks. So one way or another, these allegations have to be looked at, pronto.

Second update: see the comments section. Adam Feuerstein reports that Amgen has told him that they're already investigating this, which is just what the company should be doing. Glad to see them moving this quickly!

Comments (23) + TrackBacks (0) | Category: Clinical Trials | The Dark Side

September 16, 2014

Update on Alnylam (And the Direction of Things to Come)

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Posted by Derek

Here's a look from Technology Review at the resurgent fortunes of Alnylam and RNA interference (which I blogged about here).

But now Alnylam is testing a drug to treat (familial amyloid polyneuropathy) in advanced human trials. It’s the last hurdle before the company will seek regulatory approval to put the drug on the market. Although it’s too early to tell how well the drug will alleviate symptoms, it’s doing what the researchers hoped it would: it can decrease the production of the protein that causes FAP by more than 80 percent.

This could be just the beginning for RNAi. Alnylam has more than 11 drugs, including ones for hemophilia, hepatitis B, and even high cholesterol, in its development pipeline, and has three in human trials —progress that led the pharmaceutical company Sanofi to make a $700 million investment in the company last winter. Last month, the pharmaceutical giant Roche, an early Alnylam supporter that had given up on RNAi, reversed its opinion of the technology as well, announcing a $450 million deal to acquire the RNAi startup Santaris. All told, there are about 15 RNAi-based drugs in clinical trials from several research groups and companies.

“The world went from believing RNAi would change everything to thinking it wouldn’t work, to now thinking it will,” says Robert Langer, a professor at MIT, and one of Alnylam’s advisors.

Those Phase III results will be great to see - that's the real test of a technology like this one. A lot of less daring ideas have fallen over when exposed to that much of a reality check. If RNAi really has turned the corner, though, I think it could well be just the beginning of a change coming over the pharmaceutical industry. Biology might be riding over the hill, after an extended period of hearing hoofbeats and seeing distant clouds of dust.

There was a boom in this sort of thinking during the 1980s, in the early days of Genentech and Biogen (and others long gone, like Cetus). Proteins were going to conquer the world, with interferon often mentioned as the first example of what was sure to be a horde of new drugs. Then in the early 1990s there was a craze for antisense, which was going to remake the whole industry. Antibodies, though, were surely a big part of the advance scouting party - many people are still surprised when they see how many of the highest-grossing drugs are antibodies, even though they're often for smaller indications.

And the hype around RNA therapies did reach a pretty high level a few years ago, but this (as Langer's quote above says) was followed by a nasty pullback. If it really is heading for the big time, then we should all be ready for some other techniques to follow. Just as RNAi built on the knowledge gained during the struggle to realize antisense, you'd have to think that Moderna's mRNA therapy ideas have learned from the RNAi people, and that the attempts to do CRISPR-style gene editing in humans have the whole biologic therapy field to help them out. Science does indeed march on, and we might possibly be getting the hang of some of these things.

And as I warned in that last link, that means we're in for some good old creative destruction in this industry if that happens. Some small-molecule ideas are going to go right out the window, and following them (through a much larger window) could be the whole rare-disease business model that so many companies are following these days. Many of those rare diseases are just the sorts of things that could be attacked more usefully at their root cause via genomic-based therapies, so if those actually start to work, well. . .

This shouldn't be news to anyone who's following the field closely, but these things move slowly enough that they have a way of creeping up on you unawares. Come back in 25 years, and the therapeutic landscape might be a rather different-looking place.

Comments (18) + TrackBacks (0) | Category: Biological News | Business and Markets | Clinical Trials | Drug Development

September 10, 2014

Clinical Trial Fraud

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Posted by Derek

Bizarre news from Evotec - see what you make of this press release:

Evotec AG was informed that US company Hyperion Therapeutics, Inc. ("Hyperion") is terminating the development of DiaPep277(R) for newly diagnosed Type 1 diabetes.

In a press release published by Hyperion on 08 September 2014 at market opening in the US, the company states that it has uncovered evidence that certain employees of Andromeda Biotech, Ltd. ("Andromeda"), which Hyperion acquired in June 2014, engaged in serious misconduct, involved with the trial data of DiaPep277. Hyperion announced that it will complete the DIA-AID 2 Phase 3 trial, but will terminate further development in DiaPep277.

Here's the Hyperion press release, and it details a terrible mess:

The company has uncovered evidence that certain employees of Andromeda Biotech, Ltd., which Hyperion acquired in June 2014, engaged in serious misconduct, including collusion with a third-party biostatistics firm in Israel to improperly receive un-blinded DIA-AID 1 trial data and to use such data in order to manipulate the analyses to obtain a favorable result. Additional evidence indicates that the biostatistics firm and certain Andromeda employees continued the improper practice of sharing and examining un-blinded data from the ongoing DIA-AID 2 trial. All of these acts were concealed from Hyperion and others.

The Company has suspended the Andromeda employees known to be involved, is notifying relevant regulatory authorities, and continues to investigate in order to explore its legal options. Hyperion employees were not involved in any of the improper conduct.

What a nightmare. All biomedical data are vulnerable to outright fraud, and it gives a person the shivers just thinking about it. I can only imagine the reactions of Hyperion's management when they heard about this, and Evotec's when Hyperion told them about it. What, exactly, the Andromeda people (and the third-party biostatistics people) thought they were getting out of this is an interesting question, too - did they hope to profit if the company announced positive results? That's my best guess, but I'm not sleazy enough (I hope) to think these things through properly.

Comments (17) + TrackBacks (0) | Category: Business and Markets | Clinical Trials | The Dark Side

September 2, 2014

Novartis Impresses Where Others Have Failed

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Posted by Derek

There is some good news from the clinic today. Novartis reported data on LCZ696, a combination therapy for congestive heart failure, and the results have really grabbed a lot of attention. (The trial had been stopped early back in March, so the news was expected to be good). This is a combo of the angiotensin II antagonist valsartan and a neprilysin (neutral endopeptidase) inhibitor, AHU-377.

Compared to enalapril, the standard ACE inhibitor therapy for CHF, the Novartis combo lowered the risk of cardiovascular death by 20% and the risk of hospitalization by 21%, while having at least as good a safety profile as the generic ACE drug. Those are powerful arguments for the company to make, both to physicians and to insurance payers, so the future of the therapy, barring any sudden misfortunes, looks assured. There's not a lot that you can do for people with congestive heart failure as it is, and this looks like a real advance.

As Matthew Herper mentions, though, this isn't the first time that a similar combination has been tried in CHF. A few years ago, Bristol-Myers Squibb had a major failure with a single drug that inhibited both the ACE and neprilysin enzyme pathways, Vanlev (omapatrilat). That compound had a persistent problem with angioedema, as detailed here, and that led to its eventual rejection by the FDA on risk/benefit grounds, after a great deal of expensive Phase III work. Back in 2002, in the early days of this blog, I predicted that no ACE/endopeptidase combination would ever see the light of day again, which shows you how much I know about it. But I wasn't alone, that's for sure. It's very interesting and surprising that LCZ696 has worked out as well as it has, and it's a very worthwhile question to wonder what the difference could have been. Balance between the two pathways? Having an receptor antagonist on the ACE end rather than an enzyme inhibitor? Whatever it was, it seems to have done the trick.

The only question I have about the new combo is how it would compare to an ACE/diuretic combination, which (from what I know) is also a standard course of therapy for CHF patients. On the other hand, you'd expect that a diuretic might also be added to LCZ696 treatment - it was shown that it could be combined with omapatrilat, since they're all different mechanisms.

And one other point - I always make this one in these kind of situations. I'm willing to bet that critics of the drug industry, who like to go on about "me-too" drugs and lazy industrial research efforts, would have had LCZ696 on the list of eye-rolling follow-up drugs (that is, if they'd been paying attention at all). I mean, the angiotensin pathway is thoroughly covered by existing drugs, and neprilysin/NEP has been targeted before, too (both by omapatrilat and by Pfizer's so-called "female Viagra", UK-414,495). But there's an awful lot we don't know about human medicine, folks.

Update: here's a deep look at the IP and patent situation around the combo.

Update 2: and here's a detailed exchange about the way the trial was conducted and the drug's possible impact.

Comments (7) + TrackBacks (0) | Category: "Me Too" Drugs | Cardiovascular Disease | Clinical Trials

Exelixis Against the Wall

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Posted by Derek

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

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

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

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

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

August 28, 2014

Drug Repurposing

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Posted by Derek

A reader has sent along the question: "Have any repurposed drugs actually been approved for their new indication?" And initially, I thought, confidently but rather blankly, "Well, certainly, there's. . . and. . .hmm", but then the biggest example hit me: thalidomide. It was, infamously, a sedative and remedy for morning sickness in its original tragic incarnation, but came back into use first for leprosy and then for multiple myeloma. The discovery of its efficacy in leprosy, specifically erythema nodosum laprosum, was a complete and total accident, it should be noted - the story is told in the book Dark Remedy. A physician gave a suffering leprosy patient the only sedative in the hospital's pharmacy that hadn't been tried, and it had a dramatic and unexpected effect on their condition.

That's an example of a total repurposing - a drug that had actually been approved and abandoned (and how) coming back to treat something else. At the other end of the spectrum, you have the normal sort of market expansion that many drugs undergo: kinase inhibitor Insolunib is approved for Cancer X, then later on for Cancer Y, then for Cancer Z. (As a side note, I would almost feel like working for free for a company that would actually propose "insolunib" as a generic name. My mortgage banker might not see things the same way, though). At any rate, that sort of thing doesn't really count as repurposing, in my book - you're using the same effect that the compound was developed for and finding closely related uses for it. When most people think of repurposing, they're thinking about cases where the drug's mechanism is the same, but turns out to be useful for something that no one realized, or those times where the drug has another mechanism that no one appreciated during its first approval.

Eflornithine, an ornithine decarboxylase inhibitor, is a good example - it was originally developed as a possible anticancer agent, but never came close to being submitted for approval. It turned out to be very effective for trypanosomiasis (sleeping sickness). Later, it was approved for slowing the growth of unwanted facial hair. This led, by the way, to an unfortunate and embarrassing period where the compound was available as a cream to improve appearance in several first-world countries, but not as a tablet to save lives in Africa. Aventis, as they were at the time, partnered with the WHO to produce the compound again and donated it to the agency and to Doctors Without Borders. (I should note that with a molecular weight of 182, that eflornithine just barely missed my no-larger-than-aspirin cutoff for the smallest drugs on the market).

Drugs that affect the immune system (cyclosporine, the interferons, anti-TNF antibodies etc.) are in their own category for repurposing, I'd say, They've had particularly broad therapeutic profiles, since that's such a nexus for infectious disease, cancer, inflammation and wound healing, and (naturally) autoimmune diseases of all sorts. Orencia (abatacept) is an example of this. It's approved for rheumatoid arthritis, but has been studied in several other conditions, and there's a report that it's extremely effective against a common kidney condition, focal segmental glomerulosclerosis. Drugs that affect the central or peripheral nervous system also have Swiss-army-knife aspects, since that's another powerful fuse box in a living system. The number of indications that a beta-blocker like propanolol has seen is enough evidence on its own!

C&E News did a drug repurposing story a couple of years ago, and included a table of examples. Some others can be found in this Nature Reviews Drug Discovery paper from 2004. I'm not aware of any new repurposing/repositioning approvals since then, but there's an awful lot of preclinical and clinical activity going on.

Comments (35) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Drug Industry History | Regulatory Affairs

August 20, 2014

Amicus Fights Its Way Through in Fabry's

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Posted by Derek

Perseverance is a critical variable in drug discovery. Too little of it, and you are absolutely guaranteed to fail - no drug has ever made it to market without trying the patience of everyone involved. Too much of it, and you are very nearly guaranteed to waste all your money: most drug development projects don't work, and eventually reach a point where no amount of time or money could make them work, either. Many are the efforts where leaders have gritted their teeth, redoubled their efforts, and led everyone further into the abyss.

But sometimes these things come through, and that's what seems to have happened with Amicus and their drug migalastat for Fabry's. It's a protein chaperone, one the the emerging class of drugs that work by stabilizing particular protein conformations to help regain function. At the end of 2012, Amicus and their partner GSK announced clinical trial results that didn't meet significance, which prompted GlaxoSmithKline to return rights to the drug to Amicus.

Who kept on with it. And who announced today that the second Phase III study had come back positive, enough so that they plan to file for regulatory approval. (The belief is that the first Phase III enrolled an inappropriate mix of patients). Congratulations to the company, who may well have given many Fabry's patients their first opportunity for an oral therapy for their disease.

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

August 15, 2014

Incomprehensible Drug Prices? Think Again.

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Posted by Derek

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Comments (42) + TrackBacks (0) | Category: Cancer | Clinical Trials | Drug Prices | Regulatory Affairs | Why Everyone Loves Us

August 11, 2014

Is The Current Patent System Distorting Cancer Research?

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Posted by Derek

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

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

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

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

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

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

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

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

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

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

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

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

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

July 28, 2014

Targacept Comes Up Empty, Yet Again

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Posted by Derek

Targacept's attempt to salvage something by testing TC-5214 for overactive bladder has failed. John Carroll at FierceBiotech counts eight straight failed clinical trials from this company: a record? I don't see anyone beating that very easily, that's for sure. Nicotinic receptors have proven to be a very, very difficult field to work in, and I'm not sure that Targacept has anything left in their tank.

Comments (26) + TrackBacks (0) | Category: Business and Markets | Clinical Trials

July 23, 2014

Neratinib Comes Through For Puma

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Posted by Derek

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

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

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

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

July 14, 2014

Targacept Fumbles the Bad News on Alzheimer's

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Posted by Derek

Targacept has been working on some very hard therapeutic areas over the years, and coming up dry - dramatically so. They may have just done it again.

They've been testing TC-1734 in Alzheimer's over the last year or so, a partial agonist at nicotinergic receptors. That was a long-shot mechanism to start with, although to be sure, every Alzheimer's drug is a long-shot mechanism. This would be a stopgap compound even if it worked, like the existing acetylcholinesterase compound Donepezil.

And the company has apparently released the results of the clinical trial on its web site, inadvertently, you'd have to assume. The news first came out from BioRunUp on Twitter, and the text of the announcement was the the compound had failed to show superiority to Donepezil. The company has made no official announcement (as I write, anyway), and the press release itself appears to have been taken down a little while ago. But here's a screen shot, if you're interested. The stock (TRGT) has already reacted to the news, as you'd imagine it would, suddenly dropping like a brick starting at just before 2:30 PM EST. Not a good way to get the news out, that's for sure. . .

Comments (10) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

July 10, 2014

A Drug Candidate from NCATS

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Posted by Derek

I've written several times about the NIH's NCATS program, their foray into "translational medicine". Now comes this press release that the first compound from this effort has been picked up for development by a biopharma company.

The company is AesRx (recently acquired by Baxter), and the compound is AES-103. This came from the rare-disease part of the initiative, and the compound is targeting sickle cell anemia - from what I've seen, it appears to have come out of a phenotypic screening effort to identify anti-sickling agents. It appears to work by stabilizing the mutant hemoglobin into a form where it can't polymerize, which is the molecular-level problem underlying the sickle-cell phenotype. For those who don't know the history behind it, Linus Pauling and co-workers were among the first to establish that a mutation in the hemoglobin protein was the key factor. Pauling coined the term "molecular disease" to describe it, and should be considered one of the founding fathers of molecular biology for that accomplishment, among others.

So what's AES-103? Well, you'll probably be surprised: it's hydroxymethyl furfural, which I would not have put high on my list of things to screen. That page says that the NIH screened "over 700 compounds" for this effort, which I hope is a typo, because that's an insanely small number. I would have thought that detecting the inhibition of sickling would be something that could be automated. If you were only screening 700 compounds, would this be one of them?

For those outside the business, I base that opinion on several things. Furans in general do not have a happy history in drug development. They're too electron-rich to play well in vivo, for the most part. This one does have an electron-withdrawing aldehyde on it, but aldehydes have their own problems. They're fairly reactive, and they tend to have poor pharmacokinetics. Aldehydes are, for example, well-known as protease inhibitors in vitro, but most attempts to develop them as drugs have ended in failure. And the only thing that's left on the molecule, that hydroxymethyl, is problematic, too. Having a group like that next to an aromatic ring has also traditionally been an invitation to trouble - they tend to get oxidized pretty quickly. So overall, no, I wouldn't have bet on this compound. There must be a story about why it was tested, and I'd certainly like to know what it is.

But for all I know, those very properties are what are making it work. It may well be reacting with some residue on hemoglobin and stabilizing its structure in that way. The compound went into Phase I in 2011, and into Phase II last year, so it does have real clinical data backing it up at this point, and real clinical data can shut me right up. The main worry I'd have at this point is idiosyncratic tox in Phase III, which is always a worry, and more so, I'd think, with a compound that looks like this. We'll see how it goes.

Comments (19) + TrackBacks (0) | Category: Clinical Trials | Drug Development

July 9, 2014

Studies Show? Not So Fast.

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Posted by Derek

Yesterday's post on yet another possible Alzheimer's blood test illustrates, yet again, that understanding statistics is not a strength of most headline writers (or most headline readers). I'm no statistician myself, but I have a healthy mistrust of numbers, since I deal with the little rotters all day long in one form or another. Working in science will do that to you: every result, ideally, is greeted with the hearty welcoming phrase of "Hmm. I wonder if that's real?"

A constant source for the medical headline folks is the constant flow of observational studies. Eating broccoli is associated with this. Chocolate is associated with that. Standing on your head is associated with something else. When you see these sorts of stories in the news, you can bet, quite safely, that you're not looking at the result of a controlled trial - one cohort eating broccoli while hanging upside down from their ankles, another group eating it while being whipped around on a carousel, while the control group gets broccoli-shaped rice puffs or eats the real stuff while being duct-taped to the wall. No, it's hard to get funding for that sort of thing, and it's not so easy to round up subjects who will stay the course, either. Those news stories are generated from people who've combed through large piles of data, from other studies, looking for correlations.

And those correlations are, as far as anyone can tell, usually spurious. Have a look at the 2011 paper by Young and Karr to that effect (here's a PDF). If you go back and look at the instances where observational effects in nutritional studies have been tested by randomized, controlled trials, the track record is not good. In fact, it's so horrendous that the authors state baldly that "There is now enough evidence to say what many have long thought: that any claim coming from an observational study is most likely to be wrong."

They draw the analogy between scientific publications and manufacturing lines, in terms of quality control. If you just inspect the final product rolling off the line for defects, you're doing it the expensive way. You're far better off breaking the whole flow into processes and considering each of those in turn, isolating problems early and fixing them, so you don't make so many defective products in the first place. In the same way, Young and Karr have this to say about the observational study papers:

Consider the production of an observational study: Workers – that is, researchers – do data collection, data cleaning, statistical analysis, interpretation, writing a report/paper. It is a craft with essentially no managerial control at each step of the process. In contrast, management dictates control at multiple steps in the manufacture of computer chips, to name only one process control example. But journal editors and referees inspect only the final product of the observational study production process and they release a lot of bad product. The consumer is left to sort it all out. No amount of educating the consumer will fix the process. No amount of teaching – or of blaming – the worker will materially change the group behaviour.

They propose a process control for any proposed observational study that looks like this:

Step 0: Data are made publicly available. Anyone can go in and check it if they like.

Step 1: The people doing the data collection should be totally separate from the ones doing the analysis.

Step 2: All the data should be split, right at the start, into a modeling group and a group used for testing the hypothesis that the modeling suggests.

Step 3: A plan is drawn up for the statistical treatment of the data, but using only the modeling data set, and without the response that's being predicted.

Step 4: This plan is written down, agreed on, and not modified as the data start to come in. That way lies madness.

Step 5: The analysis is done according to the protocol, and a paper is written up if there's one to be written. Note that we still haven't seen the other data set.

Step 6: The journal reviews the paper as is, based on the modeling data set, and they agree to do this without knowing what will happen when the second data set get looked at.

Step 7: The second data set gets analyzed according to the same protocol, and the results of this are attached to the paper in its published form.

Now that's a hard-core way of doing it, to be sure, but wouldn't we all be better off if something like this were the norm? How many people would have the nerve, do you think, to put their hypothesis up on the chopping block in public like this? But shouldn't we all?

Comments (20) + TrackBacks (0) | Category: Clinical Trials | Press Coverage

June 26, 2014

Alzheimer's Bonds

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Posted by Derek

I wrote a couple of years ago about Andrew Lo of MIT, and his idea for securitization of drug discovery. For those of you who aren't financial engineers, that means raising funds by issuing securities (bonds and the like), and that's something that (as far as I know) has never been used to fund any specific drug development project.

Now Pharmalot has an update in an interview with Lo (who's recently published a paper on the idea in Science Translational Medicine). In particular, he's talking about issuing "Alzheimer's bonds", to pick a disease with no real therapies, a huge need for something, and gigantic cost barriers to finding something. Lo's concerned that the risks are too high for any one company to take on (and Eli Lilly might agree with him eventually), and wants to have some sort of public/private partnership floating the bonds.

We would create a fund that issues bonds. But if the private sector isn’t incentivized on its own, maybe the public sector can be incentivized to participate along with some members of the private sector. I will explain. But let’s look at the costs for a moment. The direct cost of treating the disease – never mind home care and lost wages – to Medicare and Medicaid for 2014 is estimated at $150 billion. We did a calculation and asked ourselves what kind of rate of return can we expect? We came up with $38.4 billion over 13 years. . .

. . .Originally, I thought it could come from the private sector. We’d create a fund – a mega fund of private investors, such as hedge funds, pension, various institutional investors. The question we asked ourselves is will they get a decent rate of return over a 13-year period? The answer, which is based on a best guess, given the risks of development and 64 projects, and we believed the answer was ‘no.’ It wouldn’t be like cancer or orphan diseases. It’s just not going to work. I come from that world. I talked to funds, philanthropists, medical experts. We did a reality check to see if we were off base. And it sounded like it would be difficult to create a fund to develop real drugs and still give investors a reasonable rate of return – 15% to 20%.

He's now going around to organizations like the Alzheimer's Association to see if there's some interest in giving this a try. I think that it's going to be a hard sell, but I'd actually like to see it happen. The difficulty is that there's no way to do this just a little bit to see if it works: you have to do it on a large scale to have any hope of success at all, and it's a big leap. In fact, the situation reminds one of. . .the situation with any given Alzheimer's drug idea. The clinical course of the disease, as we understand it now, does not give you any options other than a big, long, expensive path through the clinic (which is why it's the perfect example of an area where all the risk is concentrated on the expensive late stages). Lo is in the position of trying to address the go-big-or-go-home problem of Alzheimer's research with a remedy that requires investors to go big or go home.

The hope is that you could learn enough along the way to change the risk equation in media res. There's an old science fiction story by A. E. van Vogt, "Far Centaurus", which featured (among other things - van Vogt stories generally had several kitchen sinks included) a multidecade suspended-animation expedition to Alpha Centauri. The crew arrive there to find the planets already covered with human-populated cities, settled by the faster-than-light spaceships that were invented in the interim. We don't need FTL to fix Alzheimer's (fortunately), but there could be advances that would speed up the later parts of Lo's fund. But will this particular expedition ever launch?

Comments (24) + TrackBacks (0) | Category: Alzheimer's Disease | Business and Markets | Clinical Trials | Drug Development

June 24, 2014

Taking Risks - You Have To, So Do It Right

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Posted by Derek

In case you hadn't seen it, I wanted to highlight this post by Michael Gilman over at LifeSciVC. He's talking about risk in biotech, and tying it to the processes of generating, refining, and testing hypotheses. "The hypothesis", he says, "is one of the greatest intellectual creations of our species", and he's giving it its due.

I agree with him that time spent rethinking your hypothesis is often time well spent, whether for a single bench experiment or (most especially for) a big clinical trial. You need to be sure that you're asking the right question, that you're setting it up to be answered (one way or another), and that you're going to be able to get the maximum amount of useful information when that answer comes in, be it a Yes or a No. Sometimes this setup is obvious, but by the time you get to clinical trial design, it can be very tricky indeed.

For drug discovery, Gilman say, there are generally three kinds of hypothesis:

Biological hypothesis. What buttons do we believe this molecule pushes in target cells and what happens when these buttons are pushed? What biological pathways respond?

Clinical hypothesis. When these pathways are impacted, why do we believe it will move the needle on parameters that matter to patients and physicians? How will this intervention normalize physiology or reverse pathology?

Commercial hypothesis. If the first two hypotheses are correct, why do we believe anyone will care? Why will patients, physicians, and payers want this drug? How do we expect it to stand out from the crowd?

Many are the programs that have come to grief because of some sort of mismatch between these three. Clinical trials have been run uselessly because the original drug candidate was poorly characterized. Ostensibly successful trials have come to nothing because they were set up to answer the wrong questions. And ostensibly successful drug candidates have died in the marketplace because nobody wanted them. These are very expensive mistakes, and some extra time spent staring out the window while thinking about how to avoid them could have come in handy.

Gilman goes on to make a number of other good points about managing risk - for example, any experiment that shoulders a 100% share of the risk needs to be done as cheaply as possible. I would add, as a corollary, ". . .and not one bit cheaper", because that's another way that you can mess things up. At all times, you have to have a realistic idea of where you are in the process and what you're taking on. If you can find a way to do the crucial experiment without risking too much time or money, that's excellent news. On the other end of the scale, if there's no other way to do it than to put a big part of the company down on the table, then you'd better be sure that getting the answer is going to be worth that much effort. If it is, then be sure to spend the money to do it right - you're not going to get a second shot that easily.

The article also shows how you want to manage such risks across a broader portfolio. You'd like, if possible, to have plenty of programs that are front-loaded with their major risks, the sorts of things that you're not necessarily going to have to hopping around the room with crossed fingers while you're waiting for the Phase III data. It's impossible to take all the risk out of a Phase III, true - but if you can get some of the big questions out of the way earlier, without having to go that far, so much the better. A portfolio made up of several gigantic multiyear money furnaces - say, Alzheimer's or rheumatoid arthritis - will be something else entirely.

Comments (10) + TrackBacks (0) | Category: Clinical Trials | Drug Development


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Posted by Derek

No time for a morning blog post - I'm too busy exhaling sighs of relief around here. I'll see everyone later on in the day (on some other topic entirely). What a business this is!

Comments (29) + TrackBacks (0) | Category: Clinical Trials

June 23, 2014

The Virtual Clinical Trial: Not Quite Around the Corner

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Posted by Derek

Here's one of those "Drug Discovery of. . .the. . .Future-ure-ure-ure" articles in the popular press. (I need a reverb chamber to make that work property). At The Atlantic, they're talking with "medical futurists" and coming up with this:

The idea is to combine big data and computer simulations—the kind an engineer might use to make a virtual prototype of a new kind of airplane—to figure out not just what's wrong with you but to predict which course of treatment is best for you. That's the focus of Dassault Systèmes, a French software company that's using broad datasets to create cell-level simulations for all different kinds of patients. In other words, by modeling what has happened to patients like you in previous cases, doctors can better understand what might happen if they try certain treatments for you—taking into consideration your age, your weight, your gender, your blood type, your race, your symptom, any number of other biomarkers. And we're talking about a level of precision that goes way beyond text books and case studies.

I'm very much of two minds about this sort of thing. On the one hand, the people at Dassault are not fools. They see an opportunity here, and they think that they might have a realistic chance at selling something useful. And it's absolutely true that this is, broadly, the direction in which medicine is heading. As we learn more about biomarkers and individual biochemistry, we will indeed be trying to zero in on single-patient variations.

But on that ever-present other hand, I don't think that you want to make anyone think that this is just around the corner, because it's not. It's wildly difficult to do this sort of thing, as many have discovered at great expense, and our level of ignorance about human biochemistry is a constant problem. And while tailoring individual patient's therapies with known drugs is hard enough, it gets really tricky when you talk about evaluating new drugs in the first place:

Charlès and his colleagues believe that a shift to virtual clinical trials—that is, testing new medicines and devices using computer models before or instead of trials in human patients—could make new treatments available more quickly and cheaply. "A new drug, a succesful drug, takes 10 to 12 years to develop and over $1 billion in expenses," said Max Carnecchia, president of the software company Accelrys, which Dassault Systèmes recently acquired. "But when it is approved by FDA or other government bodies, typically less than 50 percent of patients respond to that therapy or drug." No treatment is one-size-fits-all, so why spend all that money on a single approach?

Carnecchia calls the shift toward algorithmic clinical trials a "revolution in drug discovery" that will allow for many quick and low-cost simulations based on an endless number of individual cellular models. "Those models start to inform and direct and focus the kinds of clinical trials that have historically been the basis for drug discovery," Carnecchia told me. "There's the benefit to drug companies from reduction of cost, but more importantly being able to get these therapies out into the market—whether that's saving lives or just improving human health—in such a way where you start to know ahead of time whether that patient will actually respond to that therapy."

Speed the day. The cost of clinical trials, coupled with their low success rate, is eating us alive in this business (and it's getting worse every year). This is just the sort of thing that could rescue us from the walls that are closing in more tightly all the time. But this talk of shifts and revolutions makes it sound as if this sort of thing is happening right now, which it isn't. No such simulated clinical trial, one that could serve as the basis for a drug approval, is anywhere near even being proposed. How long before one is, then? If things go really swimmingly, I'd say 20 to 25 years from now, personally, but I'd be glad to hear other estimates.

To be fiar, the article does go on to mentions something like this, but it just says that "it may be a while" before said revolution happens. And you get the impression that what's most needed is some sort of "cultural shift in medicine toward openness and resource sharing". I don't know. . .I find that when people call for big cultural shifts, they're sometimes diverting attention (even their own attention) from the harder parts of the problem under discussion. Gosh, we'd have this going in no time if people would just open up and change their old-fashioned ways! But in this case, I still don't see that as the rate-limiting step at all. Pouring on the openness and sharing probably wouldn't hurt a bit in the quest for understanding human drug responses and individual toxicology, but it's not going to suddenly open up any blocked-up floodgates, either. We don't know enough. Pooling our current ignorance can only take us so far.

Remember there are hundreds of billions of dollars waiting to be picked up off the ground by anyone who can do these things. It's not like there are no incentives to find ways to make clinical trials faster and cheaper. Anything that gives the impression that there's this one factor (lack of cooperation, too much regulation, Evil Pharma Executives, what have you) holding us back from the new era, well. . .that just might be an oversimplified view of the situation.

Comments (15) + TrackBacks (0) | Category: Clinical Trials | In Silico | Regulatory Affairs | Toxicology

June 20, 2014

Stem Cells: The Center of "Right to Try"

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Posted by Derek

I wanted to point out an excellent editorial on the whole "Right to Try" issue at Nature. The authors note correctly that stem cells are the therapeutic area where these battles are being fought most often, since their regulatory status (particularly with any sort of autologous cell treatment) is sometimes unclear, the number of possible treatments (well-intentioned and otherwise) is huge, and the medical need is even bigger.

Many countries have made such experimental stem cell treatments more widely available without proof of efficacy. We're not just talking about the usual "medical tourism" list, although those countries are certainly on this one, but places like Japan and Australia. That cuts both ways. Proponents of the idea say that these countries are making more progress than the US for this reason, but a look at what's happened since these regulations were loosened isn't always encouraging. It's very, very, hard to open up such trials without opening them up to the sort of people who will gladly exploit patients for as long as possible without caring if any efficacy is ever proven or not.

Even the idea of putting products up for sale and into consumers' bodies on the basis of phase I data is disturbing. Early-stage clinical trials reveal only whether a product is safe enough for continued testing, not for widespread use. Some 80% of products that make it through phase I clinical trials fail in later studies — about half of those proving to be insufficiently effective and one-fifth insufficiently safe.

When test subjects are paying for the product under investigation, establishing efficacy is hard: controls, randomization, masking and other hallmarks of clinical research break down. Many stem-cell clinics offer their procedures for disparate conditions, further complicating post-market studies.

Under the guise of 'patient-funded clinical trials', clinics in the United States and Mexico persuade people who are seriously ill to pay tens of thousands of dollars for procedures. Because such patients have been told that a product is experimental, they have little recourse when hoped-for cures fail to materialize. Companies can thus profit from selling hope. With their products already on the market, they have little reason to conduct rigorous, conclusive research.

Stem cells, as has been said many times on this side, are surely one of the most overhyped areas in all of medical research. This has been true for at least ten years now, and the hype does not die down. Some may remember that this was an issue during the 2004 presidential election. I'll bet if you took a poll back then and asked where the field would be by 2014, that the general public would have bet on it being much more advanced than it is now. The usual reason applies: it's because this area of research is extremely, inhumanly complicated and difficult, but people get tired of hearing that and think that it's an excuse for some other factor.

There are libertarian and free-market groups behind several of the legal initiatives in the US, who honestly believe that the current FDA structure is an impediment to medical progress, and that this sort of deregulation will end up helping more people more quickly. I believe that their motives are sincere - not everyone pushing these ideas is looking for a quick buck. But the people who aren't need to look around and realize how many quick-buck artists are surrounding them. Every libertarian reform needs to have someone thinking "OK, less regulation and more freedom of choice, check. But what are the ways that this could be abused by unscrupulous SOBs? Can those abuses mount up to where they cancel out the good that's done on the other end?"

In this case, I think that danger is very real, and very likely. As opposed to the caricatures that you hear from people on the left end of the political spectrum, many free-market types, in my experience, have good hearts. Perhaps too good, in some cases. It would never occur to them personally to immediately turn around and use this newly loosened regulatory environment to start looting desperately ill people of their money. But it sure would occur to some others. Homo homini lupus: man is a wolf to man.

Comments (37) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs | Snake Oil

June 16, 2014

A "Right to Try" Debate

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Posted by Derek

For those interested in the "Right to Try" debate, BioCentury TV has a program that includes both the pro and the con sides of the debate. Worth a look to see how sharply opinions divide on this issue - and I don't see them converging any time soon.

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

June 10, 2014

Right To Try: Here We Go

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Posted by Derek

At what point should an experimental drug be made available for anyone to try it? The usual answer is "Unless you're enrolled in a clinical trial, then not until it's no longer an experimental drug". There's always compassionate use, but that's a hard topic to deal with, and one that has a different answer for every drug. Otherwise, the regulatory position is that volunteers take unproven drugs, and paying patients take the ones that have been through testing and review.

Colorado would like to try something different. They've passed a "Right To Try" law, which allow a therapy to be prescribed after it's passed Phase I and is under active investigation in Phase II. (Arizona, Louisiana, and Missouri are heading in the same direction). Insurance companies are not required to pay for these, it should be noted, nor are drug companies required to offer access. But if there are willing patients and a willing company, they can work together. The patient has to be suffering from a terminal illness, and has to have exhausted all approved therapies (if any).

As my fellow science-blogger David Kroll notes, though, this doesn't seem to add much past what was already allowed by the FDA:

I submit that this seemingly well-meaning but meaningless Colorado act does nothing but create a sense of false hope for similar families. The act does nothing more than assuage the concerns of lawmakers that they haven’t done enough to help their constituents. Instead, they’ve done a disservice.

At Science-Based Medicine there are similar thoughts from oncologist David Gorski. He goes into the details of the law that's under consideration in Arizona, and worries that it has such broad definitions that it opens the door to unscrupulous operators. I've worried about that as well. The Arizona law also allows the companies (at their discretion) to charge for providing the drugs (Colorado's allows for at-cost charging). The fear is that some unscrupulous operators could run the lightest, breeziest "Phase I" trial they possibly could, and then settle down into a long, lucrative spell of milking desperate patients while their "Phase II' trials creep along bit by bit. I realize that that's not a very nice thing to assume about people, but as a character in The War of the Worlds says about a similar predatory proposal, there are those who would do it cheerful. In fact, we already have evidence of people working in just this fashion.

These arguments have come up around here before, when Andy Grove (ex-Intel) proposed changing the structure of clinical trials (more here), and when Andy Eschenbach (ex-FDA) proposed something similar himself. Balancing these things is very hard indeed, and anyone who says it isn't either hasn't thought about the situation enough or is eager to sell you something. We've come to Chesterton's Gate again:

There exists in such a case a certain institution or law; let us say, for the sake of simplicity, a fence or gate erected across a road. The more modern type of reformer goes gaily up to it and says, “I don’t see the use of this; let us clear it away.” To which the more intelligent type of reformer will do well to answer: “If you don’t see the use of it, I certainly won’t let you clear it away. Go away and think. Then, when you can come back and tell me that you do see the use of it, I may allow you to destroy it.

Gorski (in that Science-Based Medicine link above) has many other good points, but there's one more that I'd like to emphasize. Some of these laws seem to be based on the idea that there are all sorts of wonderful cures out there that for some reason are tied up in sloth and red tape. It isn't so. Clearing out bureaucratic obstacles, while no picnic, is still a lot easier than discovering drugs. And allowing patients access after a Phase I does not offer very good odds, considering that almost all clinical failures take place later than that. Plenty of tox gets discovered later than that, too - only the fast and nasty stuff gets picked up in Phase I.

So overall, I think that these laws offer, for the most part, chances for people to feel good about themselves for voting for them, and chances for patients to get their hopes up, likely for no reason. Even with that, I don't see them doing much harm compared to the existing regulatory regime, except for the provisions that offer companies the chance to charge money. Those give the added bonus of opening the door to unscrupulous quacks, some of whom might have very creative ideas of what "at cost" might mean.

According to Biocentury, a Colorado company is already planning to offer access through this program:

Neuralstem Inc. (NYSE-M:CUR) plans to take advantage of Colorado's right-to-try law to offer patients access to an experimental, unapproved human neural stem cell (hNSC) therapy (NSI-566) to treat amyotrophic lateral sclerosis. President and CEO Richard Garr told BioCentury the company will not apply for an IND or other permission from FDA, noting that "the Colorado right-to-try law allows a company to prescribe for a fatal disease a therapy that has passed a Phase I safety trial and is being actively pursued in a Phase II trial." Garr said Neuralstem's hNSC ALS therapy meets these criteria, and the company plans to start a Phase III trial next year.
Neuralstem is in the process of training surgeons and identifying a hospital and neurologists in Colorado to administer the hNSC therapy. The therapy will be administered with the identical procedure, cells and training as a clinical trial, but without FDA oversight and without "the artificial limitations built around a trial," said Garr. "The whole point of right-to-try is it sits parallel to the clinical trial process, it is not instead of clinical trials." Neuralstem has not determined whether it will charge Colorado patients.

I know nothing about Neuralstem or their therapy, so I'll defer comment until I learn more. Looks like we're going to see how this works, whether we're ready for it or not.

Comments (25) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Regulatory Affairs

June 9, 2014

Good News! Our Alzheimer's Drug Didn't Work!

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Posted by Derek

Alzheimer's disease is one of the notorious rocks of drug development. Around it are piles of debris, shipwrecks of clinical research programs large and small. But late last week, as yet another company sailed in close, something new happened.

Unfortunately, that may not mean "new" an in "good". A small company called AFFiRiS (that's really how they spell it) was testing a vaccine against beta-amyloid (an idea that has been tried numerous times before, although with the immune system you never know what'll happen next). Here's what happened next:

On June 4, AFFiRiS AG offered a smattering of results from its Phase 2 clinical trial of AD02, an active vaccine for Alzheimer’s disease derived from the company’s proprietary method of making synthetic antigens based on the Aβ peptide. At a press conference in Vienna, company scientists reported that among older people with early Alzheimer’s, a placebo group fared better than any other. Patients in this group reportedly had less cognitive decline over the course of 18 months, correlating with less hippocampal shrinkage. This group had been injected not with any Aβ-based antigen, but only with what the company calls an immunomodulator that was part of the AD02 formulation. Company scientists then named this placebo formulation AD04, and said they planned to explore options for clinical development.

Now, not every story about this actually picks up on this switcheroo. Try this one: you'd think that the company marched into the clinic with several vaccine ideas and got one of them to work. But that's not what happened.

I'm having a lot of trouble with this idea. Serendipitous discoveries there are, and this may be one of them. But I very much doubt it. The company provided no real data in their announcement - no error bars, no actual numbers. The "immunomodulator" was present in the actual vaccine formulation, but those patients (apparently) showed no effect. That Alzforum story linked above also notes that the company took two clinical rating scales, usually used separately and combined them into their own composite score. It is generally a safe bet that no one does that unless that was the only way that their results look promising.

So no, I have to disagree with the company that these results represent some sort of breakthrough. Breakthroughs in the clinic have clearly stated sample sizes, and error bars, and don't require any mixing and stirring of the numbers. Odds are excellent that this is noise. AFFiRiS (can't say I enjoy typing that) can move ahead with its mysterious immunomodulator if they like, and for the sake of Alzheimer's patients everywhere we can hope that it does something. But when a small company tries to say "Oh look, turns out our control group is actually a new Alzheimer's therapy! Isn't that great!", well, I think some skepticism is appropriate.

Comments (25) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

May 28, 2014

Would You Have Advanced BBI608?

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Posted by Derek

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

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

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

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

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

May 19, 2014

AstraZeneca Looks At Its Own History, And Cringes

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Posted by Derek

While we're talking about AstraZeneca, here's a look at their recent drug development history from the inside. The company had undertaken a complete review of its portfolio and success rates (as well they might, given how things have been going overall).

In this article, we discuss the results of a comprehensive longitudinal review of AstraZeneca's small-molecule drug projects from 2005 to 2010. The analysis allowed us to establish a framework based on the five most important technical determinants of project success and pipeline quality, which we describe as the five 'R's: the right target, the right patient, the right tissue, the right safety and the right commercial potential. A sixth factor — the right culture — is also crucial in encouraging effective decision-making based on these technical determinants. AstraZeneca is currently applying this framework to guide its R&D teams, and although it is too early to demonstrate whether this has improved the company's R&D productivity, we present our data and analysis here in the hope that it may assist the industry overall in addressing this key challenge.

That already gets things off to a bad start, in my opinion, because I really hate those alliterative "Five Whatevers" and "Three Thingies" that companies like to proclaim. And that's not just because Chairman Mao liked that stuff, although that is reason enough to wonder a bit. I think that I suffer from Catchy Slogan Intolerance, a general disinclination to believe that reality can be usefully broken down into discrete actions and principles that just all happen to start with the same letter. I think these catchphrases quantify the unquantifiable and simplify what shouldn't be simplified. The shorter, snappier, and more poster-friendly the list of recommendations, the less chance I think they have of being any actual use. Other than setting people's teeth on edge, which probably isn't the goal.

That said, this article itself does a perfectly good job of laying out many of the things that have been going wrong in the big pharma organizations. See if any of this rings a bell for you:

. . .However, with the development of high-throughput and ultra-high-throughput screening and combinatorial chemistry approaches during the 1980s and 1990s, as well as the perception that a wealth of new targets would emerge from genomics, part of this productivity issue can also be attributed to a shift of R&D organizations towards the 'industrialization' of R&D. The aim was to drive efficiency while retaining quality, but in some organizations this led to the use of quantity-based metrics to drive productivity. The hypothesis was simple: if one drug was launched for every ten candidates entering clinical development, then doubling or tripling the number of candidates entering development should double or triple the number of drugs approved. However, this did not happen; consequently, R&D costs increased while output — as measured by launched drugs — remained static.

This volume-based approach damaged not only the quality and sustainability of R&D pipelines but, more importantly, also the health of the R&D organizations and their underlying scientific curiosity. This is because the focus of scientists and clinicians moved away from the more demanding goal of thoroughly understanding disease pathophysiology and the therapeutic opportunities, and instead moved towards meeting volume-based goals and identifying an unprecedented level of back-up and 'me too' drug candidates. In such an environment, 'truth-seeking' behaviours to understand disease biology may have been over-ridden by 'progression-driven' behaviours that rewarded scientists for meeting numerical volume-based goals.

Thought so. Pause to shiver a bit (that's what I did - it seemed to help). The AZ team looked at everything that had been active during the 2005-2010 period, from early preclinical up to the end of Phase II. What they found, compared to the best figures on industry averages, was that the company looked pretty normal in the preclinical area (as measured by number of projects and their rates of progression, anyway), and that they actually had a higher-than-usual pass rate through Phase I. Phase II, though, was nasty - they had a noticeably higher failure rate, suggesting that too many projects were being allowed to get that far. And although they weren't explicitly looking looking beyond Phase II, the authors do note that AZ's success rate at getting drugs all the way to market was significantly lower than rest of the industry's as well.

The biggest problem seemed to be safety and tox. This led to many outright failures, and to other cases where the human doses ended up limited to non-efficacious levels.

During preclinical testing, 75% of safety closures were compound-related (that is, they were due to 'off-target' or other properties of the compound other than its action at the primary pharmacological target) as opposed to being due to the primary pharmacology of the target. By contrast, the proportion of target-related safety closures rose substantially in the clinical phase and was responsible for almost half of the safety-related project closures. Such failures were often due to a collapse in the predicted margins between efficacious doses and safety outcomes, meaning it was not possible to achieve target engagement or patient benefit without incurring an unacceptable safety risk.

On top of this problem, an unacceptable number of compounds that made it through safety were failing in Phase II though lack of efficacy. There's a good analysis of how this seems to have happened, but a big underlying factor seems to have been the desire to keep progressing compounds to meet various targets. People kept pushing things ahead, because things had to be pushed ahead, and the projects kept being scooting along the ground until they rolled off into one ravine or another.

And I think that everyone with some experience in this business will know exactly what that feels like - this is not some mysterious ailment that infected AstraZeneca, although they seem to have had a more thorough case of it than usual. Taking the time to work out what a safety flag might be telling you, understand tricky details of target engagement, or figure out the right patient population or the right clinical endpoint - these things are not always popular. And to be fair, there are a near-infinite number of reasons to slow a project down (or stop it altogether), and you can't stop all of them. But AZ's experience shows, most painfully, that you can indeed stop too few of them. Here's a particularly alarming example of that:

In our analysis, another example of the impact of volume-based goals could be seen in the strategy used to select back-up drug candidates. Back-up molecules are often developed for important projects where biological confidence is high. They should be structurally diverse to mitigate the risk for the programme against compound-related issues in preclinical or early development, and/or they should confer some substantial advantage over the lead molecule. When used well, this strategy can save time and maintain the momentum of a project. However, with scientists being rewarded for the numbers of candidates coming out of the research organization, we observed multiple projects for which back-up molecules were not structurally diverse or a substantial improvement over the lead molecule. Although all back-up candidates met the chemical criteria for progression into clinical testing, and research teams were considered to have met their volume-based goals, these molecules did not contribute to the de-risking of a programme or increase project success rates. As a consequence, all back-up candidates from a 'compound family' could end up failing for the same reason as the lead compound and indeed had no higher probability of a successful outcome than the original lead molecule (Fig. 6). In one extreme case, we identified a project with seven back-up molecules in the family, all of which were regarded as a successful candidate delivery yet they all failed owing to the same preclinical toxicology finding. This overuse of back-up compounds resulted in a highly disproportionate number of back-up candidates in the portfolio. At the time of writing, approximately 50% of the AstraZeneca portfolio was composed of back-up molecules.

I'm glad this paper exists, since it can serve as a glowing, pulsing bad example to other organizations (which I'm sure was the intention of its author, actually). This is clearly not the way to do things, but it's also easy for a big R&D effort to slip into this sort of behavior, while all the time thinking that it's doing the right things for the right reasons. Stay alert! The lessons are the ones you'd expect:

An underlying theme that ran through the interviews with our project teams was how the need to maintain portfolio volume led to individual and team rewards being tied to project progression rather than 'truth-seeking' behaviour. The scientists and clinicians within the project teams need to believe that their personal success and careers are not intrinsically linked to project progression but to scientific quality, smart risk-taking and good decision-making.

But this is not the low energy state of a big organization. This sort of behavior has to be specifically encouraged and rewarded, or it will disappear, to be replaced by. . .well, you all know what it's replaced by. The sort of stuff detailed in the paper, and possibly even worse. What's frustrating is that none of these are new problems that AZ had to discover. I can bring up my own evidence from twelve years ago, and believe me, I was late to the party complaining about this sort of thing. Don't ever think that it can't happen some more.

Comments (46) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Drug Industry History

May 16, 2014

The Real Numbers on Tamiflu

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Posted by Derek

I've been meaning to cover this controversy about Tamiflu (oseltamivir). The Cochrane group has reviewed all the clinical data obtainable on the drug's efficacy, and has concluded that it doesn't have much. That's in contrast to an earlier review they'd conducted in 2008, which said that, overall, the evidence was slightly positive.

But as Ben Goldacre details in that Guardian piece, a comment left on the Cochrane paper pointed out that the positive conclusions were almost entirely due to one paper. That one summarized ten clinical studies, but only two of the ten had ever appeared in the literature. And this sent the Cochrane Collaboration on a hunt to find the rest of the data, which turned out to be no simple matter:

First, the Cochrane researchers wrote to the authors of the Kaiser paper. By reply, they were told that this team no longer had the files: they should contact Roche. Here the problems began. Roche said it would hand over some information, but the Cochrane reviewers would need to sign a confidentiality agreement. This was tricky: Cochrane reviews are built around showing their working, but Roche's proposed contract would require them to keep the information behind their reasoning secret from readers. More than this, the contract said they were not allowed to discuss the terms of their secrecy agreement, or publicly acknowledge that it even existed. . .Then, in October 2009, the company changed tack. It would like to hand over the data, it explained, but another academic review on Tamiflu was being conducted elsewhere. Roche had given this other group the study reports, so Cochrane couldn't have them.

And so on and very much so on. Roche's conduct here appears shameful, and just the sort of thing that has lowered the public opinion of the entire pharma industry. And not just the public opinion: it's lowered the industry in the eyes of legislators and regulators, who have even more direct power to change the way pharma does business. Over the years, we've been seeing a particularly nasty Tragedy of the Commons - each individual company, when they engage in tactics like this to product an individual drug, lowers the general standing of the industry a bit more, but no one company has the incentive to worry about that common problem. They have more immediate concerns.

So what about Tamiflu? After years of wrangling, the data finally emerged, and they're not all that impressive:

So does Tamiflu work? From the Cochrane analysis – fully public – Tamiflu does not reduce the number of hospitalisations. There wasn't enough data to see if it reduces the number of deaths. It does reduce the number of self-reported, unverified cases of pneumonia, but when you look at the five trials with a detailed diagnostic form for pneumonia, there is no significant benefit. It might help prevent flu symptoms, but not asymptomatic spread, and the evidence here is mixed. It will take a few hours off the duration of your flu symptoms.

I've never considered it much of a drug, personally, and that's without any access to all this hard-to-get data. One of the biggest raps on oseltamivir is that it has always appeared to be most effective if it could be taken after you've been infected, but before you know you're sick. That's not a very useful situation for the real world, since a person can come down with the flu any time at all during the winter. Goldacre again:

Roche has issued a press release saying it contests these conclusions, but giving no reasons: so now we can finally let science begin. It can shoot down the details of the Cochrane review – I hope it will – and we will edge towards the truth. This is what science looks like. Roche also denies being dragged to transparency, and says it simply didn't know how to respond to Cochrane. This, again, speaks to the pace of change. I have no idea why it was withholding information: but I rather suspect it was simply because that's what people have always done, and sharing it was a hassle, requiring new norms to be developed. That's reassuring and depressing at the same time.

That sounds quite likely. No one wants to be the person who sets a new precedent in dealing with clinical data, especially not at a company the size of Roche, so what we might have here is yet another tragedy of the commons: it would have been in the company's best interest to have not gone through this whole affair, but there may have been no one person there who felt as if they were in any position to do something about it. When in doubt, go with the status quo: that's the unwritten rule, and the larger the organization, the stronger it holds. After all, if it's a huge, profitable company, the status quo clearly has a lot going for it, right? It's worked so far - who are you, or that guy over there, to think about rearranging it?

Comments (12) + TrackBacks (0) | Category: Clinical Trials | Infectious Diseases | Why Everyone Loves Us

May 1, 2014

Merrimack Wins One

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Posted by Derek

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

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

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

April 29, 2014

Concert's First Drug: Not So Great

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Posted by Derek

Concert Pharmaceuticals, famous among medicinal chemists as the apparent leaders in the "deuterated drug" strategy, has reported clinical trial results for their lead compound, CTP-499. Unfortunately, it missed its primary endpoint of improving albumin/creatinine ratios in patients. There are some signs that it might be doing some good, and some room to argue that this endpoint is not as good a choice as it seemed to be at the time, but overall, these are not good numbers.

And as this article in Xconomy shows, the initial read on these numbers actually hit last summer, while Concert was readying an IPO. They pulled it, realizing the effect that the results would have on their fund-raising abilities, and took the compound into a second 24-week round of testing, the results of which we're seeing now. Fortunately for Concert, another compound (CTP-354) showed enough promise in the interim to be the peg for their public offering, which went off in February (pretty much just in time, given what's happened in the biotech market since then).

It's a bit alarming to realize how much of a small company's fortunes depend on, well, fortune. Maybe that should be a capital-F Fortune, the blindfolded goddess depicted in allegorical paintings holding a large wheel on which people's standing rose and fell. You'd like to be able to control things, and you try to as much as possible, but a lot is riding on things that are outside of anyone's control whatsoever: what the results are, and what the scientific and financial weather is when they appear.

Comments (15) + TrackBacks (0) | Category: Business and Markets | Clinical Trials

April 7, 2014

Cancer Immunotherapy's Growing Pains

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Posted by Derek

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

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

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

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

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

March 24, 2014

Google's Big Data Flu Flop

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Posted by Derek

Some of you may remember the "Google Flu" effort, where the company was going to try to track outbreaks of influenza in the US by mining Google queries. There was never much clarification about what terms, exactly, they were going to flag as being indicative of someone coming down with the flu, but the hype (or hope) at the time was pretty strong:

Because the relative frequency of certain queries is highly correlated with the percentage of physician visits in which a patient presents with influenza-like symptoms, we can accurately estimate the current level of weekly influenza activity in each region of the United States, with a reporting lag of about one day. . .

So how'd that work out? Not so well. Despite a 2011 paper that seemed to suggest things were going well, the 2013 epidemic wrong-footed the Google Flu Trends (GFT) algorithms pretty thoroughly.

This article in Science finds that the real-world predictive power has been pretty unimpressive. And the reasons behind this failure are not hard to understand, nor were they hard to predict. Anyone who's ever worked with clinical trial data will see this one coming:

The initial version of GFT was a particularly problematic marriage of big and small data. Essentially, the methodology was to find the best matches among 50 million search terms to fit 1152 data points. The odds of finding search terms that match the propensity of the flu but are structurally unrelated, and so do not predict the future, were quite high. GFT developers, in fact, report weeding out seasonal search terms unrelated to the flu but strongly correlated to the CDC data, such as those regarding high school basketball. This should have been a warning that the big data were overfitting the small number of cases—a standard concern in data analysis. This ad hoc method of throwing out peculiar search terms failed when GFT completely missed the nonseasonal 2009 influenza A–H1N1 pandemic.

The Science authors have a larger point to make as well:

“Big data hubris” is the often implicit assumption that big data are a substitute for, rather than a supplement to, traditional data collection and analysis. Elsewhere, we have asserted that there are enormous scientific possibilities in big data. However, quantity of data does not mean that one can ignore foundational issues of measurement and construct validity and reliability and dependencies among data. The core challenge is that most big data that have received popular attention are not the output of instruments designed to produce valid and reliable data amenable for scientific analysis.

The quality of the data matters very, very, much, and quantity is no substitute. You can make a very large and complex structure out of toothpicks and scraps of wood, because those units are well-defined and solid. You cannot do the same with a pile of cotton balls and dryer lint, not even if you have an entire warehouse full of the stuff. If the individual data points are squishy, adding more of them will not fix your analysis problem; it will make it worse.

Since 2011, GFT has missed (almost invariably on the high side) for 108 out of 111 weeks. As the authors show, even low-tech extrapolation from three-week-lagging CDC data would have done a better job. But then, the CDC data are a lot closer to being real numbers. Something to think about next time someone's trying to sell you on a BIg Data project. Only trust the big data when the little data are trustworthy in turn.

Update: a glass-half-full response in the comments.

Comments (18) + TrackBacks (0) | Category: Biological News | Clinical Trials | Infectious Diseases

March 11, 2014

Always Insist on Error Bars

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Posted by Derek

That's the take-home of this post by Adam Feuerstein about La Jolla Pharmaceuticals and their kidney drug candidate GCS-100. It's a galectin inhibitor, and it's had a rough time in development. But investors in the company were cheered up a great deal by a recent press release, stating that the drug had shown positive effects.

But look closer. The company's bar-chart presentation looks reasonably good, albeit with a binary dose-response (the low dose looks like it worked; the high dose didn't). But scroll down on that page to see the data expressed as means with error bars. Oh dear. . .

Update: it's been mentioned in the comments that the data look better with standard error rather than standard deviations. Courtesy of a reader, here's the graph in that form. And it does look better, but not by all that much:

Comments (39) + TrackBacks (0) | Category: Business and Markets | Clinical Trials

March 10, 2014

Repurposing for Cervical Cancer

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Posted by Derek

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

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

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

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

March 4, 2014

More Good PD-1 News in Cancer

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Posted by Derek

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

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

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

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

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

February 28, 2014

A Call To Rein In Phase III Trials

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Posted by Derek

Here's a very nice perspective on what gets funded in drug research and why. Robert Kocher and Bryan Roberts bring their venture-capital viewpoint (Venrock) to the readers of the NEJM:

It is not mysterious why projects get funded. As venture-capital investors, we evaluate projects along four primary dimensions: development costs, selling costs, differentiation of the drug relative to current treatments, and incidence and prevalence of the targeted disease (see table). For a project to be attractive, it needs to be favorably reviewed on at least two of these dimensions. Many drugs designed for orphan diseases and cancers are good investments of scarce capital, since they tend to have relatively low development costs and selling costs and to be strongly differentiated from the current treatment options. Conversely, investors are less likely to fund drugs with much higher development and selling costs (e.g., drugs for type 2 diabetes or psychiatric disorders) and drugs that cannot be strongly differentiated from current treatment options — often because low-cost generics are available to treat the targeted condition — despite the condition's high incidence and prevalence (e.g., drugs for hypertension or hypercholesterolemia).

Since improving the rate of discovery is a rather knotty, multivariate problem, the authors turn to the economic back end of the process. They make the case for the FDA to move more towards conditional approvals, since no Phase III trial can be large enough (or long-running enough) to pick up on all the "long tail" adverse events that might be waiting out there. Current Phase III trials, they say, are often overpowered for efficacy but are still underpowered for rare events, so we're spending a lot of money rather inefficiently.

I think they've got a good point, but the FDA already gets enough flak as it is. Changing things in this way, if done too quickly (and frankly, if done too openly) would be seen by many as a bean-counting technique to shift the risk onto the paying customers. Can't you hear it now? But the world they describe would be a good one, if it's feasible:

We estimate that development costs for drugs could be reduced by as much as 90%, and the time required by 50%, if the threshold for initial approval were defined in terms of efficacy and fundamental safety. Cutting costs and time, while requiring high-quality and transparent patient registries for independent safety monitoring, would be a more informative and cost-effective approach. With the widespread adoption of electronic health records and the introduction of many low-cost data-analysis tools, it is now feasible to develop mandatory postmarketing surveillance programs that make thousand-patient trials obsolete. Large data sets would also inoculate drug makers against spurious claims such as the false association of pancreatitis with the glucagon-like peptide 1 (GLP-1) and dipeptidyl peptidase 4 (DPP-4) inhibitors. At the same time, it is essential to empower the FDA to quickly remove or restrict the use of drugs when safety signals emerge from the improved data and safety monitoring.

This moves beyond clinical science and into politics, which (as the cliché has it) is the art of the possible. Even if we agree that this move is desirable, is it possible, or not?

Comments (36) + TrackBacks (0) | Category: Clinical Trials

February 25, 2014

InterMune Comes Through

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Posted by Derek

Back in 2010, I wrote about InterMune's drug for idiopathic pulmonary fibrosis, pirfenidone. The company's stock shot up on hopes that the compound would make it through the FDA, and then went straight back down when those proved ill-founded. The agency asked them for more data, and I wondered at the time if they'd be able to raise enough cash to generate it.

Well, they did, and the effort appears to have been worth it: the company says it met all its endpoints in Phase III, and is headed back to the FDA with what appears to be a solid story. Note that this press release, as opposed to the Pfizer one that I was mentioning earlier today, is full of data.

The company's stock has shot up, once again. If you've been an InterMune investor over the last few years, your fingernails are probably in bad shape and your combover is no longer plausible. The stock has had wild moves on rumors of takeovers (or lack of same) and anticipation of these clinical results. But good for them: they stuck with their compound, and it looks like it's paid off. And, just as a side note, good for people with fibrosis, too, eh?

Comments (4) + TrackBacks (0) | Category: Business and Markets | Clinical Trials

January 28, 2014

Dacomitinib Doesn't Come Through

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Posted by Derek

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

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

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

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

January 24, 2014

PTC's Latest Ataluren Woes

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Posted by Derek

I wrote here about PTC Therapeutics and their drug candidate for Duchenne muscular dystrophy (ataluren, PTC124). Opinion has been divided, to put it mildly, about how it works and whether it works at all.

Well, the saga continues. The company is having a rough time with that program these days, though. PTC applied to the European Medicines Agency for conditional approval of ataluren, but that request has just been firmly rejected.

Ataluren failed both a Phase IIb study for DMD as well as a Phase III study for cystic fibrosis, yet the biotech went on to wrap one of 2013's hottest IPOs in the resurgent biotech field, grabbing $125 million from investors. And over the last month its stock price jumped 37%.

Peltz has argued for years now that even though ataluren hasn't produced statistically significant results in later stage studies, the improvements in walking distance warranted an approval. But the EMA has now formally said no, leaving the drug's fate to be decided by a late-stage study the biotech describes as "confirmatory."

Hey, they might be right in that description - the Phase III might confirm the Phase II results and show that the drug truly does not work. And it looks like the regulatory agencies are thinking the same way. . .

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

January 23, 2014

Alzheimer's Therapies: A Reasonably Gloomy Update

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Posted by Derek

The New England Journal of Medicine has publications from Pfizer / J&J and Lilly on their multiple phase III trials of anti-amyloid antibodies (bapineuzumab and solanezumab, respectively). As the world knows, neither of them hit their primary endpoints. How optimistic one can be after that is a matter for fine distinctions.

Medscape has a look-on-the-bright-side article here. There's some evidence that the antibodies were affecting amyloid, which is (presumably) at least a start:

. . .an analysis of apolipoprotein E (APOE) 4 carriers found a decreased rate of accumulation of amyloid in the brain in a subset of patients taking bapineuzumab who had positron emission tomography (PET) imaging using Pittsburgh compound B, although the difference was smaller than that seen in phase 2 studies using a higher dose of the drug. And, among carriers, bapineuzumab was associated with reduced concentrations of cerebrospinal fluid (CSF) phospho-tau, a marker of neurodegeneration.

"We were getting some target engagement and that's encouraging," said Dr. Salloway. "But we were limited in our ability to lower amyloid because of the dose-related side effects."

Those side effects were signs of edema in the brain imaging of the bapineuzumab patients who carried the APOE4 gene. Their dose was lowered to half a milligram per kilo, while the other patients got up to 1 mpk. The Phase II trials had gone up to 2 mpk, but that dose was dropped completely. At any rate, I think that bapineuzumab has also been dropped completely; I'm unaware of any further work with it. That's as opposed to solanezumab, where Lilly is famously pressing on.

It's at least better-tolerated than bapineuzumab, perhaps because it doesn't specifically target amyloid fibrils, but goes more after the soluble forms. And that, conceivably, is connected with the hints of efficacy that were seen in the patients with milder forms of Alzheimer's, and on this outcropping of solid bedrock rests Eli Lilly's Alzheimer's strategy. It's a tough place to be, but Lilly is already in a tough place, so a roll of the dice like this might be their best shot at this point.

There's a quote in the Medscape piece saying that we've "entered the era of prevention studies" in the disease, but that's too sunny even for an optimistic guy like me. We still have no clear idea of that actual early mechanisms that lead to Alzheimer's. The amyloid hypothesis, though it has a fair amount of evidence on its side, remains unproven, and every attempt to target it pharmacologically has either failed or (if you squint hard) just about failed. The only reason we're running prevention trials with the agents we have is that they failed to do anything in treatment trials. We have staggered into an era of prevention trials because we have nothing else to offer.

That doesn't mean I'm hoping for solanezumab or anything else to fail - far from it. A preventative agent for Alzheimer's would be a great advance. It's just that I'm not hopeful that any of the current therapies will work that way. If one does, it'll be a real long shot bet that's come through, and it's going to be five to ten years before we'll even know enough to say that. So I hope that I don't see too many "Alzheimer's Prevention Trials Underway!" headlines in the general press. The occasional mentions of a "cure by 2025" make a person wonder, though.

There's also a lot of talk about combination therapies, a monoclonal antibody, plus a secretase inhibitor, plus something for tau, and so on. That may well be the way to go, eventually. But it's worth remembering that previous cocktail regimens like this, in other disease areas, combined agents that showed much more robust effects than anything has in Alzheimer's so far. They were good enough, usually, to be approved on their own. In Alzheimer's, as it stands now, we'd be looking at combining two or three drugs that have all struck out in the clinic, and maybe one or two that we don't even have yet, and hoping for the best. I don't see that as a realistic strategy until something works a bit better. Or works at all.

Comments (24) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

January 16, 2014

Should Drug Industry Research All Get Rejected For Publication?

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Posted by Derek

If you work in the drug industry, and for some reason you feel that your blood pressure isn't quite high enough today, a look at this debate at the British Medical Journal should fix that up for you. "Should journals stop publishing research funded by the drug industry?" is the title - there, doesn't that constrict your blood vessels already?

Taking the "Yes, they should" side are Richard Smith (former editor of the journal, now with a British organization called "Patients Know Best", and Peter C. Gøtzsche of the Nordic Cochrane Center. Here's their opening statement, and Gøtzsche's recent opinion piece in the same journal is a good harbinger, as it turns out:

The BMJ and its sibling journals have stopped publishing research funded by the tobacco industry for two main reasons: the research is corrupted and the companies publish their research to advance their commercial aims, oblivious of the harm they do. But these arguments apply even more strongly to research funded by the drug industry, and we suggest there is a better way to communicate the results of trials that would be safer for patients.

Prescribed drugs are the third leading cause of death, partly because of flaws in the evidence published in journals. We have long known that clinical trials funded by the drug industry are much more likely than publicly funded trials to produce results favourable to the company. The reason is obvious. The difference between an honest and a less than honest data analysis can be worth billions of euros, and the fraudulent trials of some cyclo-oxygenase-2 inhibitors for arthritis and selective serotonin reuptake inhibitors for depression are good examples

They're absolutely right about the financial motivations, and a first-rate moral hazard it is, too. But the comparison with the tobacco companies is a real pencil-snapper (as they no doubt intended it to be). They go on about prescription drugs being the "third largest cause of death", about "drug industry crimes", and so on. To be fair, and first let me brush these pencil fragments off my desk, the pharmaceutical companies have laid themselves wide open to these sorts of attacks, painting huge fluorescent bulls-eye targets on themselves again and again. But still.

This piece casually mentions that "olanzapine (Zyprexa), has probably caused 200 000 deaths", footnoting a book by one of the two authors. I seem to have missed that. Many antipsychotic drugs are associated with QT prolongation, which can lead to fatal heart arrythmias, but the worst of them have long been taken out of use. The FDA is investigating two deaths following injection of long-acting olanzapine, not two hundred thousand. Olanzapine has plenty of side effects, though, including weight gain (which can exacerbate Type II diabetes), and it has a warning label in the US about giving it to elderly patients under any conditions. But two hundred thousand deaths? I can't find any support for any such figure; it appears in Gøtzsche's book and apparently nowhere else, so citing it in this article as if it were a well-established fact is a nice move.

Taking the "No" side is Trish Groves of the BMJ itself. She rejects the analogy with the tobacco industry - as she should, because it's offensive and ridiculous. She goes on to detail the problems with industry-reported results and what the journal is doing about them. As opposed to the "Yes" side, it's a pretty reasonable piece. One of the things she mentions is that investigator-led trials have their own sources of bias. Very few people organizing an effort the size of a useful clinical trial will be disinterested in its results, unfortunately.

How much can we trust the evidence base for drugs in current use? It’s hard to tell, given the woeful legacy of widespread non-registration, non-publication, and selective reporting of clinical trials. Much of this reporting bias also applies to investigator led trials, and the many steps now being taken to mandate prospective trial registration, ensure reporting of all results, and access patient level data on interventions’ benefits and harms, as called for by the AllTrials campaign, must apply to them as much as to industry led trials. Moreover, new rules on transparency need to be applied retrospectively: laudable plans to provide access to data on new drugs aren’t enough.

That’s why the BMJ is keen to publish papers from the RIAT (Restoring Invisible and Abandoned Trials) initiative, through which academics who find previously unreported trials can write them up and publish them if the original investigators decline to do so. We also welcome “negative” trials that find no evidence of benefit, as long as their research questions are important and their methods robust, and we’re particularly interested in publishing trials of comparative effectiveness. Both these types of study can be much more useful to clinical practice than the placebo controlled trials that regulators demand. . .

It should be no great task to guess which side of this debate I favor - after all, I'm one of those evil drug company scientists who mow down the customers by the hundreds of thousands. I do wish that Groves' response had strayed a bit from the topic at hand and addressed those accusations of mass murder (that's what they are). I realize that it must be hard to tell a former editor to tone things down and go back for a rewrite. But still.

Comments (48) + TrackBacks (0) | Category: Clinical Trials | The Scientific Literature | Why Everyone Loves Us

January 10, 2014

A New Look At Clinical Attrition

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Posted by Derek

Thanks to this new article in Nature Biotechnology, we have recent data on the failure rates in drug discovery. Unfortunately, this means that we have recent data on the failure rates in drug discovery, and the news is not good.

The study is the largest and most recent of its kind, examining success rates of 835 drug developers, including biotech companies as well as specialty and large pharmaceutical firms from 2003 to 2011. Success rates for over 7,300 independent drug development paths are analyzed by clinical phase, molecule type, disease area and lead versus nonlead indication status. . .Unlike many previous studies that reported clinical development success rates for large pharmaceutical companies, this study provides a benchmark for the broader drug development industry by including small public and private biotech companies and specialty pharmaceutical firms. The aim is to incorporate data from a wider range of clinical development organizations, as well as drug modalities and targets. . .

To illustrate the importance of using all indications to determine success rates, consider this scenario. An antibody is developed in four cancer indications, and all four indications transition successfully from phase 1 to phase 3, but three fail in phase 3 and only one succeeds in gaining FDA approval. Many prior studies reported this as 100% success, whereas our study differentiates the results as 25% success for all indications, and 100% success for the lead indication. Considering the cost and time spent on the three failed phase 3 indications, we believe including all 'development paths' more accurately reflects success and R&D productivity in drug development.

So what do they find? 10% of all indications in Phase I eventually make it through the FDA, which is in line with what most people think. Failure rates are in the thirty-percent range in Phase I, in the 60-percent range in Phase II, thirty to forty percent in Phase III, and in the teens at the NDA-to-approval stage. Broken out by drug class (antibody, peptide, small molecule, vaccine, etc.), the class with the most brutal attrition is (you guessed it) small molecules: slightly over 92% of them entering Phase I did not make it to approval.

If you look at things by therapeutic area, oncology has the roughest row to hoe with over 93% failure. Its failure rate is still over 50% in Phase III, which is particularly hair-raising. Infectious disease, at the other end of the scale, is merely a bit over 83%. Phase II is where the different diseases really separate out by chance of success, which makes sense.

Overall, this is a somewhat gloomier picture than we had before, and the authors have reasonable explanations for it:

Factors contributing to lower success rates found in this study include the large number of small biotech companies represented in the data, more recent time frame (2003–2011) and higher regulatory hurdles for new drugs. Small biotech companies tend to develop riskier, less validated drug classes and targets, and are more likely to have less experienced development teams and fewer resources than large pharmaceutical corporations. The past nine-year period has been a time of increased clinical trial cost and complexity for all drug development sponsors, and this likely contributes to the lower success rates than previous periods. In addition, an increasing number of diseases have higher scientific and regulatory hurdles as the standard of care has improved over the past decade.

So there we have it - if anyone wants numbers, these are the numbers. The questions are still out there for all of us, though: how sustainable is a business with these kinds of failure rates? How feasible are the pricing strategies that can accommodate them? And what will break out out of this system, anyway?

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

December 6, 2013

Outcomes, Expensive Outcomes

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Posted by Derek

Well, to go along with that recent paper on confounding cell assays, here's a column by John LaMattina on the problem of confounding clinical results. For some years now, the regulatory and development trend has been away from surrogate markers and towards outcome studies. You'd think that lowering LDL would be helpful - is it? You'd think that combining two different mechanisms to lower blood pressure would be a good thing - is it? The only way to answer the questions is by looking at a large number of patients in as close to a real-world setting as possible.

And in many cases, we're finding out that some very reasonable-sounding ideas don't, in fact, work out in practice. These aren't just findings with new or experimental drugs, either - as LaMattina shows, we're finding out things about drugs that have been on the market for years. This illustrates several important points: (1) There's a limit to what you can find out in clinical trials. (2) There is a limit to what reasonable medical hypotheses are worth. (3) We do not understand as much as we need to about human biology, in either the healthy or diseased state. (4) A drug, even when it's been approved, even when it's been on the market for years, is always an experimental medication.

LaMattina also points out just how crazily expensive the outcomes trials are that can generate the data that we really need. He's hoping that companies that spend that sort of money will emerge with a compelling enough case to be able to recoup it. I certainly hope that, too - but I'm absolutely 50/50 on whether I think it's true.

Comments (16) + TrackBacks (0) | Category: Clinical Trials | Drug Prices

December 3, 2013

Merck's Drug Development in The New Yorker

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Posted by Derek

The New Yorker has an article about Merck's discovery and development of suvorexant, their orexin inhibitor for insomnia. It also goes into the (not completely reassuring) history of zolpidem (known under the brand name of Ambien), which is the main (and generic) competitor for any new sleep drug.

The piece is pretty accurate about drug research, I have to say:

John Renger, the Merck neuroscientist, has a homemade, mocked-up advertisement for suvorexant pinned to the wall outside his ground-floor office, on a Merck campus in West Point, Pennsylvania. A woman in a darkened room looks unhappily at an alarm clock. It’s 4 a.m. The ad reads, “Restoring Balance.”

The shelves of Renger’s office are filled with small glass trophies. At Merck, these are handed out when chemicals in drug development hit various points on the path to market: they’re celebrations in the face of likely failure. Renger showed me one. Engraved “MK-4305 PCC 2006,” it commemorated the day, seven years ago, when a promising compound was honored with an MK code; it had been cleared for testing on humans. Two years later, MK-4305 became suvorexant. If suvorexant reaches pharmacies, it will have been renamed again—perhaps with three soothing syllables (Valium, Halcion, Ambien).

“We fail so often, even the milestones count for us,” Renger said, laughing. “Think of the number of people who work in the industry. How many get to develop a drug that goes all the way? Probably fewer than ten per cent.”

I well recall when my last company closed up shop - people in one wing were taking those things and lining them up out on a window shelf in the hallway, trying to see how far they could make them reach. Admittedly, they bulked out the lineup with Employee Recognition Awards and Extra Teamwork awards, but there were plenty of oddly shaped clear resin thingies out there, too.

The article also has a good short history of orexin drug development, and it happens just the way I remember it - first, a potential obesity therapy, then sleep disorders (after it was discovered that a strain of narcoleptic dogs lacked functional orexin receptors).

Mignot recently recalled a videoconference that he had with Merck scientists in 1999, a day or two before he published a paper on narcoleptic dogs. (He has never worked for Merck, but at that point he was contemplating a commercial partnership.) When he shared his results, it created an instant commotion, as if he’d “put a foot into an ants’ nest.” Not long afterward, Mignot and his team reported that narcoleptic humans lacked not orexin receptors, like dogs, but orexin itself. In narcoleptic humans, the cells that produce orexin have been destroyed, probably because of an autoimmune response.

Orexin seemed to be essential for fending off sleep, and this changed how one might think of sleep. We know why we eat, drink, and breathe—to keep the internal state of the body adjusted. But sleep is a scientific puzzle. It may enable next-day activity, but that doesn’t explain why rats deprived of sleep don’t just tire; they die, within a couple of weeks. Orexin seemed to turn notions of sleep and arousal upside down. If orexin turns on a light in the brain, then perhaps one could think of dark as the brain’s natural state. “What is sleep?” might be a less profitable question than “What is awake?”

There's also a lot of good coverage of the drug's passage through the FDA, particularly the hearing where the agency and Merck argued about the dose. (The FDA was inclined towards a lower 10-mg tablet, but Merck feared that this wouldn't be enough to be effective in enough patients, and had no desire to launch a drug that would get the reputation of not doing very much).

few weeks later, the F.D.A. wrote to Merck. The letter encouraged the company to revise its application, making ten milligrams the drug’s starting dose. Merck could also include doses of fifteen and twenty milligrams, for people who tried the starting dose and found it unhelpful. This summer, Rick Derrickson designed a ten-milligram tablet: small, round, and green. Several hundred of these tablets now sit on shelves, in rooms set at various temperatures and humidity levels; the tablets are regularly inspected for signs of disintegration.

The F.D.A.’s decision left Merck facing an unusual challenge. In the Phase II trial, this dose of suvorexant had helped to turn off the orexin system in the brains of insomniacs, and it had extended sleep, but its impact didn’t register with users. It worked, but who would notice? Still, suvorexant had a good story—the brain was being targeted in a genuinely innovative way—and pharmaceutical companies are very skilled at selling stories.

Merck has told investors that it intends to seek approval for the new doses next year. I recently asked John Renger how everyday insomniacs would respond to ten milligrams of suvorexant. He responded, “This is a great question.”

There are, naturally, a few shots at the drug industry throughout the article. But it's not like our industry doesn't deserve a few now and then. Overall, it's a good writeup, I'd say, and gets across the later stages of drug development pretty well. The earlier stages are glossed over a bit, by comparison. If the New Yorker would like for me to tell them about those parts sometime, I'm game.

Comments (28) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Drug Industry History | The Central Nervous System

November 15, 2013

Zafgen's Epoxide Clears A Hurdle

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Posted by Derek

I wrote here about Zafgen and their covalent Met-Ap2 inhibitor beloranib. Word is out today that the compound has passed its first Phase II trial handily, so score one for covalent epoxides as drug candidates.

Zafgen has followed up promising results from early-stage work on its weight drug beloranib with a stellar Phase II study that tracked rapid weight loss among the severely obese, with one group shedding an average of 22 pounds in 12 weeks. CEO Tom Hughes says the mid-stage success clears a path to a Phase IIb trial that can fine tune the dose while taking more time to gauge the longterm impact of its treatment on weight. And the data harvest sets the right tone for ongoing talks with investors about a new financing round for the biotech.

Efficacy, though, doesn't seem to have been in much doubt with this compound. Phase III will be the big one, because the worry here will be some sort of funny longer-term toxicity. No one's quite sure what inhibiting that enzyme will do (other than this pretty impressive weight loss), and a covalent drug (even a relatively benign and selective one like an epoxide) is always going to have questions around it until it's proven itself in human tox. But so far, so good.

One thing that beloranib has going for it is that patients would presumably take for a relatively limited course of therapy and then try to keep the weight off on their own. That's a big distinction, toxicologically. On one end of the spectrum, you've got your one-time-use drugs, like an anesthetic, and then there are the anti-infectives that you might take for two weeks or (at most) a few months. But at the other end, you have the cardiovascular and diabetes drugs that your patient population is going to be taking every morning for the rest of their lives, and the safety profile is clearly going to have to clearer in those cases.

Critics of the industry never fail to mention that we, supposedly, are not looking for cures, but rather for drugs in that latter category so we can reap the big, big profits. They haven't thought this through well enough: for one thing, a cure is worth more money up front. And there is that tiny little factor of patent lifetime. To hear some people talk, you'd think that a drug's discoverers continue to reap the gains forever, but it ain't so. Ask Eli Lilly right now how that's going - most of their revenue is in the process of packing up and leaving for the generics companies. It doesn't matter if a company finds a drug that people need to take for fifty years; they're not going to be selling it that long.

Back to Zafgen, though. They've got an interesting program going here, and I'm very curious to see how it works out. Going after obesity from the metabolic end is something that a lot of people have tried, through various mechanisms, but it's still probably a better bet than trying to affect appetite. And I'll be glad to see an epoxide-based drug prove itself in the clinic, because I think that evidence suggests that they're better drug candidates than we give them credit for (see the link in the first line of this post for more on that). We medicinal chemists need all the options we can get. From the way things look, I'd bet on beloranib going fine through the rest of Phase II - and then begins the finger-crossing and rabbit's-footing.

Comments (16) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity

November 14, 2013

Nasty Odor as a Drug Side Effect

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Posted by Derek

If you read the publications on the GSK compound (darapladib) that just failed in Phase III, you may notice something odd. These mention "odor" as a side effect in the clinical trial subjects. Say what?

If you look at the structure, there's a para-fluorobenzyl thioether in there, and I've heard that this is apparently not oxidized in vivo (a common fate for sulfides). That sends potentially smelly parent compound (and other metabolites?) into general circulation, where it can exit in urine and feces and even show up in things like sweat and breath. Off the top of my head, I can't think of another modern drug that has a severe odor liability. Anyone have examples?

Update: plenty of examples in the comments!

Comments (49) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Pharmacokinetics

November 13, 2013

Sarepta's Approval Woes

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Posted by Derek

I briefly mentioned Sarepta and etiplirsen, their proposed therapy for Duchenne muscular dystrophy (DMD) in September. In that post, I made reference to the "delirious fun of investing in biotech". Well, the company recently got some regulatory news that illustrates that point even more clearly. The FDA told Sarepta that it would not get accelerated approval for the drug, and that sent the stock into a mineshaft (and infuriated the DMD community, as you might well think).

Matthew Herper at Forbes has some good background on the story here Etiplirsen is one of these drugs aimed at a small market (one particular DMD mutation). And the clinical data were pretty thin:

It can be hard to imagine saying no to a plea like that – but sometimes that is the FDA’s job. As one muscular dystrophy expert told me when I wrote about Sarepta’s results earlier this year, it was always possible that it might be “too much to hope for” to think that eteplirsen could be approved based on the data so far. Eteplirsen was studied in only twelve boys, half of whom received the medicine immediately, the other half of whom initially got placebo but then switched to taking the drug. Those who started on the medicine earlier have higher levels of dystrophin, at least according to muscle biopsies, and appeared to be able to walk a greater distance in six minutes, a sign that their muscles are deteriorating less quickly.

Unfortunately, great results from small trials have a history of not bearing out in larger studies. Even for rare disease drugs, this study was tiny. Worse, the Sarepta results only look good when two of the 12 patients are excluded – two boys were too sick to be helped by the drug. The FDA usually insists that clinical trials be presented in what is known as an “intent-to-treat” analysis, which means that if you even thought about treating a patient they need to be included when you do the math on the study’s results. This is intended to keep scientists from lying to themselves, convincing themselves that a drug works when it doesn’t. One biotech executive with a great deal of experience in rare diseases told me recently that this issue meant the data “would never fly” with the FDA. The recent failure of a similar, but less effective, drug from Prosensa and GlaxoSmithKline GSK -1.64% made the odds dimmer.

And Adam Feuerstein of, who thought that the company would get the accelerated designation, has a look at the decision here. He spoke with a bearish investor who made this case:

The FDA's issues with trial design are so wide-ranging that it seems like wishful thinking that Sarepta will be able to agree on a study design and start enrolling by the second quarter 2014.

Major questions with dystrophin quantitative assay. Questions with results of anything less than two years. Need for a larger study to power the six-minute walk test (6MWT) data. Possible need to expand study population both high and low and go beyond 6MWT as primary endpoint. The FDA is very deeply skeptical and Sarepta will have a difficult time coming to a study design that the company thinks they can do and that the FDA will be satisfied with.

And any trial seems likely to last 2 years. Seems to me that even if all goes well, approval would get pushed out much more than two years. They're going to spend 9 months arguing over study design and probably won't start enrolling until early 2015. Two-year trial plus filing and approval. Sounds like early 2018 approval at best.

I have to say, this is consistent with worries resulting from the Prosensa trial that the market ignored. But it's actually even more negative that I expected. I thought the FDA would just say, do a larger trial along the same lines. What they're saying is much more confused than that. What is a valid marker and what do you need to get the data to support it?

It makes you wonder whether the FDA really changed their minds lately or if Sarepta misrepresented (through wishful thinking or worse) what the FDA had been telling them all along.

The agency really did made things much trickier than most people had been expecting. They're talking about completely new endpoints, rather than just shoring up the data collected so far (which was already more than the company's boosters were willing to think about, in some cases). I don't envy the folks at the FDA, but then, I never do. They get to look like heartless bureaucrats, bleating about numbers while children are suffering. The flip side, though, is trying to keep people from raising their hopes for something that does no good. If we approve things that just look as if they might work, all sorts of charlatans will rush in, human nature being what it is.

But we're not talking about approval here, just an accelerated protocol for it. Surely they could have at least agreed to fast-track this one? I think, though, that the FDA saw itself being put into an untenable position. They did not think that there was enough solid evidence to approve the drug as it stood, and accelerated approval would ensure that no more was going to be forthcoming. All that would do would be to get everyone's hopes up even more, for what still would looked very much like a rejection based on insufficient data. And in that case, why not tell the company now and get it over with?

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

November 12, 2013

Darapladib Misses Its Endpoint

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Posted by Derek

Well, yesterday Reuters had a preview of GlaxoSmithKline's expected release of Phase III data on their phospholipase A2 inhibitor darapladib:

In theory, darapladib could become a $10 billion-a-year seller, industry analysts believe, making it GSK's biggest-ticket pipeline bet.

In practice, there are major doubts about its prospects, after mixed evidence to date, and current consensus forecasts point to annual sales of only $605 million in 2018, according to Thomson Reuters Pharma.

Barclays analysts see just a 10 percent probability of the drug succeeding, which they say points to a potential 12 percent boost to GSK's valuation if Phase III trial results are positive, with a modest 2 percent downside if it fails.

We'll now see how well that last forecast works out, because the Phase III data are out today, and things don't look good. The compound missed its primary endpoint. GSK picked this one up by acquiring Human Genome Sciences, in a move that doesn't seem quite as slick as it might have once.

But that's hindsight - there's no way to know if a new cardiovascular drug works without recruiting thousands and thousands of people into a huge Phase III trial, and that's just what GSK did here (16,000 patients!) And there's another 13,000 patient trial still waiting to report. How much money has been spent, we'll never know, but it's a lot. Maybe that alone is reason enough to stay out of that therapeutic area - other companies have come to just that conclusion here and there.

Update: in response to some of the comments, I've changed the title and some text of this post. There was one primary endpoint in this trial, but it was a composite: time to first occurrance(s) of any major cardiovascular event: MI (heart attack), stroke, or "cardiovascular death". And it's true that the company is saying that the compound did make some of its secondary endpoints, but until the data are presented, we don't know which ones, nor how important they are. There's no way that this can be anything but bad news, however.

Comments (24) + TrackBacks (0) | Category: Clinical Trials

November 11, 2013

Another Pain Drug Wipes Out

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Posted by Derek

Pain has been a horrendous therapeutic area for drug discovery. That might be because there are a number of very old compounds (opiates, etc.) that most certainly can knock down many kinds of pain, but at the cost of many undesirable side effects. Trying to (1) find drugs without those problems and (2) find drugs that treat other kinds of pain has been nightmarish.

Add another company to the list of blowups in this field. Zalicus (formerly CombinatoRx, which had its own problems) has announced today that two Phase II trials have completely come up empty for them. Z160 was a calcium channel blocker, and it does not work. Coming on the heels of a big clinical failure last year for them, the company's stock is getting driven down into the ground, and that's after a recent 1-for-6 reverse split they did to keep the company listed.

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

November 5, 2013

Compassionate Access: No Good Answer

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Posted by Derek

Here's a very good look (via the New York Times magazine) at the area of "compassionate use" medications - the practice of allowing desperate patients access to an investigational drug long before it's approved by the FDA. At first look, you'd think that this would be a simple question to answer: if someone's going to die shortly, they should be able to take a crack at whatever investigational drug they want, because what's to lose? But it's not that simple, unfortunately:

But not all companies willingly allow compassionate access to drugs in their pipelines, and ImClone’s and AstraZeneca’s reluctance makes sense on some level. Only 6 percent of early-stage cancer drugs ever come to market, because many are found to have severe side effects or simply don’t work. Given those odds, companies hesitate to do anything to jeopardize a product too soon. If they give drugs away, a disastrous side effect or other poor outcome could spur bad publicity and extra scrutiny from regulators. Even more important, if doctors simply let people take untested medicines without going through all the clinical trials, drug companies would most likely never get anyone to enroll in them, never get the data on safety and efficacy for F.D.A. approval and never pass the gateway to big sales. “Even if patients with cancer are willing buyers,” writes George Annas, a Boston University expert on medical law, “drug manufacturers are not willing sellers.”

As a public-health advocate, I know that if we simply let people have access to untested medicines without those trials, we will never learn which ones are effective and how best to use them. But to a physician coming face to face with frightened and desperate patients in the clinic, the case for the greater good seems less compelling. After all, the promising drug may be the patient’s last and only chance. Every now and then, desperation leads to success. . .

The article does go on to say that there would seem to be room for a more organized approach to compassionate access than we have now. There really aren't all that many requests, compared to what you might think, which suggests that most people don't know that it's even a possibility. But if everyone storms the gates, it's quite true that we won't be able to make sense of many of these new therapies at all. There are even worse outcomes, too:

Still, access to unproven medicines cannot be an absolute right; it must depend on review by an experienced doctor, like Shaw, who can weigh complex medical data to make educated guesses for treatment. Otherwise, patients are too vulnerable to charlatans. Recently, Shinya Yamanaka, who won the 2012 Nobel Prize in Medicine for his work on human stem cells, described to me the pleas he and his colleagues receive. His work has created the possibility of one day growing new organs, and patients come to him asking for all sorts of unproven treatments. When they’re inevitably denied, they may seek out people like the Beijing neurosurgeon who treats paralysis by injecting aborted fetal tissue into the spine, even though there is no conclusive testing to suggest it works.

One might imagine a sort of widely-distributed clinical effort, where plenty of patients around the world get the drug in question by request, and the data are collected to find out if it works. That, in fact, seems to be how many people outside the industry imagine clinical trials work, but that's not usually the case. That's asking for a lot of heterogeneity in your data. It'll come from the different patients, who may well not have all been diagnosed the same way to start with, and who surely have varying other conditions that could affect the results. The scatter will also come from the different physicians and clinics who would be administering the drug, because you're not going to be able to train them or monitor them enough to make sure that they're storing and dispensing the stuff exactly the same way as everyone else is. And then there's the monitoring of the patients and the way the endpoints of the trial are measured in them - that's an absolutely crucial part of the process, and it's one of the big reasons that you try to keep everything under control as much as possible. The nightmare is having a drug that actually worked, but whose benefits were obscured because the patients were all worked up differently, and the signal sank into the noise. The alternate nightmare, which is also on offer in some therapeutic areas, is a false signal of efficacy for something that's actually not helping.

The entire disciplines of clinical trial design and execution are set up to try to keep these things from happening. And even when all those variables are supposed to be controlled, you can get bad data. In almost all cases, that makes the plan of turning every patient around the world loose on an investigational drug the exact opposite of what you want to do. There's also the not-very-minor problem that such an approach would add huge amounts to the cost of running the trial, if you were seriously proposing to collect serious data. I'm not just saying that because of some reflexive aversion to spending precious cash - clinical trial costs are one of the biggest factors in the whole industry, so if you want to make them more costly, there will be plenty of effects.

So while there's probably room for us to be doing a better job with this than we are now, it's not going to be anyone's ideal setup, no matter what.

Comments (44) + TrackBacks (0) | Category: Clinical Trials

October 30, 2013

The FDA: Too Loose, Or Appropriately Brave?

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Posted by Derek

The topic of the various "accelerated review" options at the FDA has come up here before. Last month JAMA ran an opinion piece suggesting that the agency has gone too far. (Here's the Pharmalot take on the article). This, of course, is the bind the agency is always in. Similar to the narrow window with an anticoagulant drug (preventing clots versus encouraging hemorrhages), the FDA is constantly getting complaints that they're stifling innovation by setting regulatory barriers too high, and that they're killing patients by letting too many things through. It's an unwinnable situation - under what conditions could neither camp feel wronged?

The FDA defended its review procedures at the time, but now (according to BioCentury Extra, a more emphatic statement has been made:

FDA's Richard Pazdur, director of CDER's Office of Hematology & Oncology Products (OHOP), made it clear at an FDA briefing on personalized medicine on Monday that the agency is willing to take risks to get drugs for serious and life-threatening diseases to patients quickly. Pazdur said, "If we are taking appropriate risks in accelerated approval, some drugs will come off market, some will have restricted labeling." If that doesn't ever happen, "we probably aren't taking the appropriate risks," he said.

It reminds me of the advice that if your manuscripts are all getting accepted, then you aren't sending them to good enough journals. I agree with Pazdur on this one, and I wish that this attitude was more widely circulated and understood. Every new drug is an experimental medication. No clinical trial is ever going to tell us as much as we want to know about how a drug will perform in the real world, because there is no substitute and no model for the real world. (Anyone remember the old Steven Wright joke about how he'd just bought a map of the US - actual size? Down in the corner, it says "One mile equals one mile".)

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

October 16, 2013

The First PCSK9 Phase III

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Posted by Derek

Some long-awaited clinical data has appeared in the cardiovascular area: Sanofi and Regeneron have the first Phase III numbers for their PCSK9-blocking antibody alirocumab. (Here's some background on this area from John LaMattina).

This was a monotherapy trial, run head-to-head against Merck/Schering-Plough's Zetia (ezetimibe). Patients in the alirocumab arm started at a low dose, injected every two weeks, and had to the option to increase it if their LDL had not hit the target levels. Three quarters of them didn't have to. Their LDL levels went down 47% on average, compared to 15.6% in the daily Zetia group, so I think we can call that one a solid success. There are other Phase III trials ongoing in different patient populations and with different regimens (for example, taking alirocumab along with a statin), but these results bode well. No significant toxicity has been observed, which, needless to say, also bodes well.

That's the thing to watch. This is a new mechanism of action, and if there's one thing that the history of drug discovery tells us, it's that we don't know as much as we need to about mechanisms of action (both good and bad). It's good news that PCSK9-blocking therapies have been as clean as they have so far, but everyone in the field (Amgen is right behind Sanofi and Regeneron, and others are behind them) will be scrutinizing the data closely as more and more patient reports come in. These drugs could be used very widely indeed, and for many years at a time, so it's important to look for all sorts of things that might be down in the weeds. But so far, so good.

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

September 25, 2013

Sugammadex's Problems: Is the Merck/Schering-Plough Deal the Worst?

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Posted by Derek

That didn't take long. Just a few days after Roger Perlmutter at Merck had praised the team that developed Bridon (sugammadex), the FDA turned it down for the second time. The FDA seems to be worried about hypersensitivity reactions to the drug - that was the grounds on which they rejected it in 2008. Merck ran another study to address this, but the agency apparently is now concerned about how that trial was run. What we know, according to FiercePharma, is that they "needed to assess an inspection of a clinical trial site conducting the hypersensitivity study". Frustratingly for Merck, their application was approved in the EU back in that 2008 submission period.
It's an odd compound, and it had a nomination in the "Ugliest Drug Candidate" competition I had here a while back. That's because it works by a very unusual mechanism. It's there to reverse the effects of rocuronium, a neuromuscular blockade agent used in anaesthesia. Sugammadex is a cyclodextrin derivative, a big cyclic polysaccharide of the sort that have been used to encapsulate many compounds in their central cavities. It's the mechanism behind the odor-controlling Febreze spray - interestingly, I've read that when that product was introduced, its original formulation failed in the market because it had no scent of its own, and consumers weren't ready for something with no smell that nonetheless decreased other odors). The illustration is from the Wikipedia article on sugammadex, and it shows very well how it's designed to bind rocuronium tightly in a way that it can no longer at at the acetylcholine receptor. Hats off to the Organon folks in Scotland who thought of this - pity that all of them must be long gone, isn't it?

You see, this is one of the drugs from Schering-Plough that Merck took up when they bought the company, but it was one of the compounds from Organon that Schering-Plough took up when they bought them. (How much patent life can this thing have left by now?) By the way, does anyone still remember the ridiculous setup by which Schering-Plough was supposed to be taking over Merck? Did all that maneuvering accomplish anything at all in the end? At any rate, Merck really doesn't seem to have gotten a lot out of the deal, and this latest rejection doesn't make it look any better. Not all of those problems were (or could have been) evident at the time, but enough of them were to make a person wonder. I'm willing to nominate it as "Most Pointless Big Pharma Merger", and would be glad to hear the case for other contenders.

Comments (29) + TrackBacks (0) | Category: Business and Markets | Clinical Trials | Pharmacokinetics | Regulatory Affairs | Toxicology

September 20, 2013

Prosensa: One Duchenne Therapy Down

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Posted by Derek

In the post here the other day about Duchenne Muscular Dystrophy (DMD) I mentioned two other companies that are looking at transcriptional approaches: Prosensa (with GSK) and Sarepta. They've got antisense-driven exon-skipping mechanisms, rather than PTC's direct read-through one.

Well, Sarepta still does, anyway. Prosensa and GSK just announced clinical data on their agent, drisapersen, and it appears to have missed completely. The primary endpoint was a pretty direct one, total distance walked over six minutes, and they didn't make statistical significance versus placebo. This was over 48 weeks of treatment, and none of the secondary measures showed any signs either, from what I can see. I can't think of any way to spin this in any positive direction at all.

So drisapersen is presumably done. What does this say about Sarepta's candidate, eteplirsen? One the one hand, their major competitor has just been removed from the board. But on the other, their complete failure with such a closely related therapy can't help but raise doubts. I don't know enough about the differences between the two (PK?) to speculate, but it'll be interesting to see if Sarepta's stock zips up today, sells off, or (perhaps) fights to a draw between two groups of investors who are taking this news in very different ways.

That's the delirious fun of biotech investing. And that's just for the shareholders - you can imagine what it feels like to bet your whole company on this sort of thing. . .

Comments (4) + TrackBacks (0) | Category: Business and Markets | Clinical Trials | Drug Development

August 15, 2013

Mannkind's Latest Data

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Posted by Derek

I haven't written much about Mannkind recently. This has been a long, long, expensive saga to develop an inhaled-insulin delivery system (Afrezza), which is an idea that all by itself has seems to have swallowed several billion dollars and never given anything back yet. (That link above will send you to some of the story, and this one will tell you something about the disastrous failure of the only inhaled insulin to reach the market so far).

In 2011, Mannkind looked as if they were circling the drain. But (as has been the case many times before), more money was heaved into what might still turn out to be an incinerator, and they kept going. Just in the last few days, they've released another batch of Phase III data, which looked positive. You can see from the year-to-date stock chart that people have been anticipating this, which might account for the way that MNKD hasn't exactly taken off on the news. The stocked jumped at the open yesterday, then spent the rest of the day wandering down, and opened today right back where it was before the news came out.

People might be worried about possible effects on lung function, which show up in the data (FEV1 as well as a side effect of coughing). But there are potentially even bigger concerns in the number for HbA1c and fasting glucose. A closer look at the data shows that Mannkind's product may not have clearly established itself versus the injected-insulin competition. As that FiercePharma story says, this might not keep the product from being approved, but it could give it a rough time in the marketplace (and give Mannkind a rough time finding a big partner).

I wonder if there are any investors - other than Al Mann - who have stuck with this company all the way? If so, I wonder what effect that's had on their well-being? It has been a long, bizarre ride, and no one knows how many more curves and washed-out bridges might still be out there.

Comments (25) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity

July 30, 2013

Apparently, Ads Make Antihistamines Work Better

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Posted by Derek

This PNAS paper's title certainly caught my attention: "Advertisements impact the physiological efficacy of a branded drug". The authors, from the University of Chicago, are digging into the business end of the placebo effect. After giving a set of subjects a skin-test panel to common allergans, here's what happened:

We conducted two randomized clinical trials to measure the impact of direct-to-consumer advertising on the objective, physiological effect of Claritin (Merck & Co.), a leading antihistamine drug. A pilot study assessed the efficacy of Claritin across subjects exposed to advertisements for Claritin, advertisements for Zyrtec (McNeil), or control advertisements. . .Among subjects with allergies, the efficacy was the same across the three advertisement conditions, but among subjects without allergies, efficacy was significantly greater in the Claritin advertisements condition than in the Zyrtec advertisements condition.

The heterogeneity of the treatment effect based on the allergy status was discovered only ex post facto, so we conducted a follow- up trial to replicate these initial findings. To maximize statistical power, the follow-up trial used a larger sample, assigned subjects only to Claritin advertisements or Zyrtec advertisements, and block-randomized subjects based on their allergy status. In ad- dition, we elicited subjects’ beliefs about the efficacy of Claritin to examine whether any difference in impact of the advertisements across the two subpopulations is driven by the relative malleability of their beliefs. . .

This reminds me of the various experiences that people have had with blind taste testing of wines. In the follow-up trial, they used a histamine challenge in the skin test, which will give a red reaction no matter what you're allergic to. The effect repeated:

In the subpopulation without allergies, we find that the efficacy of Claritin at 120 min is substantially higher for subjects who were exposed to Claritin advertisements. Claritin advertisements have no significant impact on efficacy 60 min after the drug is taken. This pattern is consistent with the observed changes in the subjects’ beliefs. Exposure to Claritin advertisements in this subpopulation greatly increases the belief in the efficacy of Claritin. At the same time, the realized efficacy of Claritin at 120 min (but not at 60 min) is strongly correlated with the change in beliefs.
In the subpopulation with allergies, we find no relationship between exposure to Claritin advertisements and the change in beliefs. Moreover, the advertisements have no impact on the efficacy of Claritin at 120 min. We do find a curious negative impact of Claritin advertisements on Claritin’s efficacy at 60 min in this subpopulation, but this effect cannot be mediated by the (nonexistent) impact of advertisements on beliefs.

Oh, boy. I truly wonder why this experiment hasn't been run before, but look for a lot of follow-ups now that it's out. As the authors themselves detail, there are several unanswered questions that could be addressed: does seeing the Claritin advertisements make the Claritin work better, or does seeing the Zyrtec ads make Claritin work more poorly? Why does this seem to work only in people without specific allergies in the first place? What's the physiological pathway at work here, in any case?

Here's the big one: does direct-to-consumer advertising actually increase the efficacy of the drugs it advertises? That is, does the effect shown in this experiment translate to real-world conditions? For how many compounds is this the case, and in what therapeutic classes is the effect most likely to occur? Is there an actual economic or public health benefit to this effect, should it prove to be robust? If so, how large is compared to the money spent on the advertising itself? And if people internalize the idea that advertisements make a drug work better, will advertisements continue to do that at all?

Comments (20) + TrackBacks (0) | Category: Business and Markets | Clinical Trials

July 26, 2013

More Behind-the-Scenes Maneuvering. How Wonderful.

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Posted by Derek

This is exactly the kind of headline the drug industry does not need. Via FierceBiotech, here's a story in The Guardian on the recent efforts to get companies to disclose more about the clinical trial results for investigational drugs. GSK is the company that seems to have done the most in this regard, but the European Medicines Agency (EMA) is proposing mandatory disclosure of trial results into a public database. That's a lot further than most companies are willing to go - so what to do?

The strategy was drawn up by two large trade groups, the Pharmaceutical Research and Manufacturers of America (PhRMA) and the European Federation of Pharmaceutical Industries and Associations (EFPIA), and outlined in a memo to senior industry figures this month, according to an email seen by the Guardian.

The memo, from Richard Bergström, director general of EFPIA, went to directors and legal counsel at Roche, Merck, Pfizer, GSK, AstraZeneca, Eli Lilly, Novartis and many smaller companies. It was leaked by a drugs company employee.

The email describes a four-pronged campaign that starts with "mobilising patient groups to express concern about the risk to public health by non-scientific re-use of data". Translated, that means patient groups go into bat for the industry by raising fears that if full results from drug trials are published, the information might be misinterpreted and cause a health scare.

That's what. Other parts of the strategy include "discussions with scientific associations" about the risks of data sharing and getting other companies in other industries that might be affected by similar proposals to lobby against this as well. None of this is to be done, it seems, under the banner of "Here's why the drug industry opposes this idea". It's all a spontaneous upwelling.

Now, I don't want to seem too shocked: this sort of thing is done all the time in politics. Every time some big regulatory or legislative idea comes along that might cramp some large group's style, you'll see all kinds of organizations pop up with serious-sounding names: "Public Coalition For XYZ" "United Citizens For QRS" and so on. Use of these "instant grassroots" fronts has earned the term "astroturfing" (which also means that any time some actual group of people comes together for real, their political opponents will always accuse them of being an astroturfed gang of shills).

Some of the patient advocacy groups the Guardian talks about are probably in this category. But many of them are real organizations that have been around for some time. There's an evolutionary dance going on, though: while the advocacy groups want to get enough influence with the drug companies to steer their decisions, the drug companies want to get enough influence with the advocacy groups to steer theirs, for just the reasons we're seeing now. And in that second half of the process, the pharma industry has a powerful offer to make: we'll fund you. At that point, every advocacy group (in any industry) has some big decisions to make about what they're trying to do and how best to do it. Will taking the money compromise them? Or will that be outweighed by what they can do with the funding?

But just because this is a common practice doesn't mean that it's right. Or a good idea. Or, at the very least, the sort of thing that the industry should be seen to be doing. Secret memos detailing a behind-the-scenes campaign of influence to avoid disclosing data? The people at PhRMA and EFPIA should apply a simple test to ideas like this: if it sounds like a bad movie plot, if it sounds like something made up by people who hate you. . .maybe it's not such a good plan.

Update: here's more on an effort to pull out unpublished clinical trial data. "Publish or be published" is their motto. The editors of the British Medical Journal and PLoS Medicine have endorsed the idea.

Comments (12) + TrackBacks (0) | Category: Clinical Trials | Why Everyone Loves Us

July 24, 2013

More Details on T-Cell Leukemia Therapy

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Posted by Derek

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

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

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

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

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

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

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

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

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

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

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

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

July 23, 2013

One GSK China Scandal Blends Into Another

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Posted by Derek

According to the New York Times, the problems with GSK's China operations have been going on for a while. It's worth distinguishing two types of trouble, though: there's the bribery scandal, where the company's representatives have been paying off people up and down the Chinese health system, and there's the scientific scandal at the Shanghai R&D site, which has led to a very public retraction and dismissal of employees. I make this distinction because the research end and the commercial end of a given drug company are usually quite far apart from each other; you have to go very high up the chain to find someone who's in charge of both.

What the Times has bears on the R&D problems, and it's not good. THey've obtained a confidential document dated November 2011:

Executives at the British drug maker GlaxoSmithKline were warned nearly two years ago about critical problems with the way the company conducted research at its drug development center in China, exposing it to potential financial risk and regulatory action, an internal audit found. . .

Auditors found that researchers did not report the results of animal studies in a drug that was already being tested in humans, a breach that one medical ethicist described as a “mortal sin” in the world of drug research. They also concluded that workers at the research center did not properly monitor clinical trials and paid hospitals in ways that could be seen as bribery.

That last part refers to a practice of paying clinical trial coordinators a flat fee for their services, regardless of how many people were enrolled at their site. This could be a way of paying someone for supposedly doing a full-time job when they're actually doing nothing of the kind. And that, I have to say, sort of mixes the paint together for all these stories: if even the clinical development group was paying people off, where does it end? Now we have a scientific scandal, a bribery scandal, and a scientific bribery scandal - if this goes on, I'm going to have to make a chart to keep it all straight.

I've been saying unkind and cynical things about the Chinese government while writing about the bribery scandal, and I don't plan on taking any of that back. But there are unkind things to say about GlaxoSmithKline, too. With all the information that's coming out, you have to wonder how well GSK was keeping an eye on things. The Chinese market is so huge, and so potentially lucrative, that some companies might just be tempted to say "OK, you folks are the XYZ Corporation's Chinese branch. Do what you need to do to stay competitive over here, but don't tell us about it, OK?" But I don't think that's something you can get away with, not forever. It catches up with you, especially when dealing with a government like China's that has no problem pitching high and inside when they feel the need.

GSK is a big company, full of people who understand how the world works. The Times document shows that they were aware of what was going on, and what could happen. And here it is, happening. Anyone on the inside who was sounding the alarm probably isn't getting much satisfaction about saying "I told you so", though.

Comments (31) + TrackBacks (0) | Category: Clinical Trials | The Dark Side

July 22, 2013

The NIH's Drug Repurposing Program Gets Going

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Posted by Derek

Here's an update on the NIH's NCATS program to repurpose failed clinical candidates from the drug industry. I wrote about this effort here last year, and expressed some skepticism. It's not that I think that trying drugs (or near-drugs) for other purposes is a bad idea prima facie, because it isn't. I just wonder about the way the way the NIH is talking about this, versus its chances for success.

As was pointed out last time this topic came up, the number of failed clinical candidates involved in this effort is dwarfed by the number of approved compounds that could also be repurposed - and have, in fact, been looked at for years for just that purpose. The success rate is not zero, but it has not been a four-lane shortcut to the promised land, either. And the money involved here ($12.7 million split between nine grants) is, as that Nature piece correctly says, "not much". Especially when you're going after something like Alzheimer's:

Strittmatter’s team is one of nine that won funding last month from the NIH’s National Center for Advancing Translational Sciences (NCATS) in Bethesda, Maryland, to see whether abandoned drugs can be aimed at new targets. Strittmatter, a neuro­biologist at Yale University in New Haven, Connecticut, hopes that a failed cancer drug called saracatinib can block an enzyme implicated in Alzheimer’s. . .

. . .Saracatinib inhibits the Src family kinases (SFKs), enzymes that are commonly activated in cancer cells, and was first developed by London-based pharmaceutical company Astra­Zeneca. But the drug proved only marginally effective against cancer, and the company abandoned it — after spending millions of dollars to develop it through early human trials that proved that it was safe. With that work already done, Strittmatter’s group will be able to move the drug quickly into testing in people with early-stage Alzheimer’s disease.

The team plans to begin a 24-person safety and dosing trial in August. If the results are good, NCATS will fund the effort for two more years, during which the scientists will launch a double-blind, randomized, placebo-controlled trial with 159 participants. Over a year, the team will measure declines in glucose metabolism — a marker for progression of Alzheimer’s disease — in key brain regions, hoping to find that they have slowed.

If you want some saracatanib, you can buy some, by the way (that's just one of the suppliers). And since AZ has already taken this through phase I, then the chances for it passing another Phase I are very good indeed. I will not be impressed by any press releases at that point. The next step, the Phase IIa with 159 people, is as far as this program is mandated to go. But how far is that? One year is not very long in a population of Alzheimer's patients, and 159 patients is not all that many in a disease that heterogeneous. And the whole trial is looking at a secondary marker (glucose metabolism) which (to the best of my knowledge) has not demonstrated any clinical utility as a measure of efficacy for the disease. From what I know about the field, getting someone at that point to put up the big money for larger trials will not be an easy sell.

I understand the impulse to go after Alzheimer's - who dares, wins, eh? But given the amount of money available here, I think the chances for success would be better against almost any other disease. It is very possible to take a promising-looking Alzheimer's candidate all the way through a multi-thousand-patient multiyear Phase III and still wipe out - ask Eli Lilly, among many others. You'd hope that at least a few of them are in areas where there's a shorter, more definitive clinical readout.

Here's the list, and here's the list of all the compounds that have been made available to the whole effort so far. Update: structures here. The press conference announcing the first nine awards is here. The NIH has not announced what the exact compounds are for all the grants, but I'm willing to piece it together myself. Here's what I have:

One of them is saracatanib again, this time for lymphangioleiomyomatosis. There's also an ER-beta agonist being looked at for schizophrenia, a J&J/Janssen nicotinic allosteric modulator for smoking cessation, and a Pfizer ghrelin antagonist for alcoholism (maybe from this series?). There's a Sanofi compound for Duchenne muscular dystrophy, which the NIH has studiously avoided naming, although it's tempting to speculate that it's riferminogene pecaplasmide, a gene-therapy vector for FGF1. But Genetic Engineering News says that there are only seven compounds, with a Sanofi one doubling up as well as the AZ kinase inhibitor, so maybe this one is the ACAT inhibitor below. Makes more sense than a small amount of money trying to advance a gene therapy approach, for sure.

There's an endothelin antagonist for peripheral artery disease. Another unnamed Sanofi compound is being studied for calcific aortic valve stenosis, and my guess is that it's canosimibe, an ACAT inhibitor, since that enzyme has recently been linked to stenosis and heart disease. Finally, there's a Pfizer glycine transport inhibitor being looked at for schizophrenia, which seems a bit odd, because I was under the impression that this compound had already failed in the clinic for that indication. They appear to have some other angle.

So there you have it. I look forward to seeing what comes of this effort, and also to hearing what the NIH will have to say at that point. We'll check in when the time comes!

Update: here's more from Collaborative Chemistry. And here's a paper they published on the problems of identifying compounds for initiatives like this:

In particular, it is notable that NCATS provides on its website [31] only the code number, selected international non-proprietary names (INN) and links to more information including mechanism of action, original development indication, route of administration and formulation availability. However, the molecular structures corresponding to the company code numbers were not included. Although we are highly supportive of the efforts of NCATS to promote drug repurposing in the context of facilitating and funding proposals, we find this omission difficult to understand for a number of reasons. . .

They're calling for the NIH (and the UK initiative in this area as well) to provide real structures and IDs for the compounds they're working with. It's hard to argue against it!

Comments (8) + TrackBacks (0) | Category: Academia (vs. Industry) | Clinical Trials | Drug Development

July 17, 2013

More on the NIH and Its Indian Clinical Trials

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Posted by Derek

Steve Usdin of BioCentury sends along word that they've managed to get a tiny bit more out of the NIH on the Indian clinical trials business. As opposed to the happy-talk that they gave FiercePharma the day before, the agency was now willing to confirm that enrollment has been stopped in some Indian trials, while others have been postponed. No numbers, though. They said that they hoped that "future changes will enable studies to resume", which is a bit of a telling statement in itself, suggesting that the current situation will not allow that at all.

The most detailed account of the situation remains the report in the Live Mint newspaper, an Indian source affiliated with the Wall Street Journal. That article mentions the "unstable regulatory environment" as the big factor, but according to BioCentury, this might be the biggest problem:

The new regulations require clinical trial sponsors to provide compensation to patients who suffer injury or death during or as a result of the trial, including as a result of the "failure of investigational product to provide intended therapeutic effect"

Oh, boy. If companies find themselves having to compensate everyone - in unspecified amounts - that joins a Phase II trial where the compound turns out not to work, that'll mount up fast. We have high failure rates around here, as everyone knows, and everyone involved (investors, patients, clinical trial participants) should be aware of that going in and act accordingly. I believe that both companies and granting agencies feel as if they're paying quite enough money already for the way that many drugs don't work in the clinic.

Comments (3) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs

July 15, 2013

Does That Answer Your Question? Not Quite, No.

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Posted by Derek

John Carroll at Fierce Biotech contacted the NIH, wanting to know more about a newspaper report that the NIH had terminated dozens of clinical trials in India as new regulations come in. What sort of answer did he get? Authentic frontier gibberish, for sure, the sort of thing you'd expect from a UN press release, a State Department briefing, or other such sources of natural gas. He's trying to pressure Francis Collins and the agency to come up with something substantial, which would be most anything compared to what he's gotten so far, and I'm glad to help out in any way I can.

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

July 12, 2013

Lilly Goes All In on Solanezumab

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Posted by Derek

So Eli Lilly is going to double down on solanezumab, their antibody treatment for Alzheimer's that did not show impressive results in earlier trials. The company is going into an even bigger Phase III, with a more carefully selected patient population, in hopes of showing a benefit.

Yikes. On one level, I sort of admire this - it's a decision that takes a lot of nerve to make, will cost a huge amount of money, and is attacking one of the most intractable clinical problems we have. But on that ever-present other hand, what are the odds? If I'm an investor in Lilly stock, am I happy about this move, or not? The only thing I can see to calm the nerves this time, if there's such a thing in an Alzheimer's clinical trial, is better diagnostic criteria from the start:

Eric Siemers, senior medical director of Lilly's Alzheimer's program, said an estimated 25 percent of patients in the two earlier Expedition trials might not actually have had beta-amyloid deposits or Alzheimer's disease, so solanezumab could not have helped them.

He said many patients were enrolled in those trials on the basis of symptoms, without undergoing sophisticated diagnostic procedures now available to confirm the presence of beta-amyloid deposits.

In the new study, Lilly's recently approved radioactive imaging agent, called Amyvid, will be used to screen patients, Siemers said. Biochemical measures in the spinal fluid can also help assess whether patients have Alzheimer's, he said.

I'll say this for them: this trial, you'd think, is going to be the answer. It's going to cost hundreds of millions by the time it's all over, but by gosh, Lilly (and the rest of us) should know if solanezumab is of any use in Alzheimer's. Unless, of course, another bath of equivocal coulda-maybe-worked numbers come out of this one, too. But that's also an answer. Under these conditions, "sort of worked" is going to mean "did not work". I don't see what else is left.

And given Lilly's patent positions and sales forecasts, it looks like they are, to a significant extent, betting the company on this. Drama, this industry could do with less drama. But we seem to be stuck with it.

Comments (31) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

Clinical Trial Fraud Uncovered

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Posted by Derek

Hmmm. This article from Bloomberg says that the BMS/Pfizer anticoagulant Eliquis (apixaban), a Factor Xa inhibitor approved late last year by the FDA, was delayed for months because of misconduct in its Chinese clinical trials. (Its clinical trials had not been without incident even before this). Documents posted by the FDA have the details. Says the article:

In the Eliquis trial, Bristol-Myers hired Pharmaceutical Product Development Inc., a closely held, Wilmington, North Carolina, company known as PPD, to help oversee it.

The Eliquis trial was questioned on two issues, according to the FDA documents first cited by the journal Pharmaceutical Approvals Monthly. One was the improper manipulation of records at a study site for 35 patients at the Shanghai 9th Peoples Hospital in China. The second involved the high percentage of the 9,000 patients who were supposed to be getting Eliquis, and instead were either given the wrong drug, or the wrong dose.

There was a broad list of issues at the Shanghai hospital, according to FDA documents. They included failure to report four potential adverse medical events, late reports on three others and three medical outcomes that weren’t included in the data. Additionally, some patient names and dates were wrong, and Chinese and English records didn’t match in some cases. The FDA also reported that some patient records disappeared just ahead of a site visit by agency inspectors.

I wonder if the Bloomberg reporter was tipped off to this himself, because you have to dig into this PDF (which is one of many) to find the goods (do a search for the words "Shanghai" and "fraud"). Here are some quotes from the document itself:

Although BMS contracted with a Contract Research Organization, PPD, to provide site monitoring for ARISTOTLE, PPD did not have a presence in the People’s Republic of China when the trial was initiated in PRC; BMS initially used its own employees for monitoring. One BMS employee along with at least one other individual altered subject records after being notified the site would be inspected by OSI. OSI inspected eight clinical sites worldwide after becoming aware of this action. Additionally, after errors in dispensing study drug became an issue, BMS and PPD, a CRO involved in conducting and monitoring ARISTOTLE, were inspected specifically to review the issue of trial oversight and monitoring. OSI concludes that the study appears to have been conducted and monitored adequately. They did recommend that data from sites in China be excluded because the employee who committed the GCP violation in China was involved in the conduct of the trial at all Chinese sites.

This came to light because a contract worker went to his or her supervisors with a problem: this person had been asked to change data and documentation on a hard drive before an FDA inspection, and the supervisor making the request (who was later fired) had worked at 18 other trial locations in China. This led the FDA, naturally enough, to say that it was worried about what else might have been going on, and to complain about broad problems with oversight.

As shown in the FDA documents, the agency went on to run the data with that specific site excluded, and then with all the other Chinese site data excluded, and the analysis still came out in favor of apixaban (although not as robustly in some categories). So the approval of the drug seems to have been the right call; the conclusions of the trial don't seem to have been switched by the misconduct. Still, you don't want this sort of thing.

Elliot Levy of BMS is quoted several times in the Bloomberg article, generally playing down the problems mentioned by the FDA: "not exceptional", "appropriately documented and reported", and so on. But if everything was normal, why did things stall for nine months? The lead outside investigator on the trial, Christopher Granger of Duke, has a different perspective:

“There is a greater likelihood of some of this impropriety in certain regions,” Granger said in a telephone interview. “We’ve had experiences in India and China where we’ve had more than we would have expected.”

Unfortunately, I think that's a fair assessment. But it doesn't have to be that way. There are vast numbers of ethical, hard-working scientists and staff in both India and China; it's not like these entire countries are full of cheaters and corner-cutters. But international companies go to these countries to get work done for lower cost, so the incentives are there to keep those costs down by whatever means come to hand. There are underhanded shortcutters in every country in the world, but some business environments give these people more scope to exercise their talents.

I'm actually glad when this sort of thing comes to light. Although it's not like Bristol-Myers Squibb or Lilly were rushing to do that, were they? I think that the only way to clean up this kind of behavior is to make it public, so that it has as many consequences as possible. If a country's reputation for doing fast, cost-effective clinical trials is compromised by a reputation for regulatory trouble and unreliable data, well, that's another set of incentives at work, but this time in the right direction. Throwing a towel over these incidents does no one any good in the long run. Make it public; make it sting.

Comments (10) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | The Dark Side

July 11, 2013

The Last PPAR Compound?

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Posted by Derek

Roche has announced that they're halting trials of aleglitazar, a long-running investigational drug in their diabetes portfolio. I'm noting this because I think that this might be the absolute last of the PPAR ligands to fail in the clinic. And boy howdy, has it been a long list. Merck, Lilly, Kyorin, Bristol-Myers Squibb, Novo Nordisk, GlaxoSmithKline, and Bayer are just the companies I know right off the top of my head that have had clinical failures in this area, and I'm sure that there are plenty more. Some of those companies (GSK, for sure) have had multiple clinical candidates go down, so the damage is even worse than it appears.

That why I nominated this class in the Clinical Futility Awards earlier this summer. Three PPAR compounds actually made it to market, but the record has not been happy there, either. Troglitazone was pulled early, Avandia (rosiglitazone) has (after a strong start) been famously troubled, and Actos (pioglitazone) has its problems, too.

The thing is, no one knows about all this, unless they follow biomedical research in some detail. Uncounted billions have been washed through the grates; years and years of work involving thousands of people has come to nothing. The opportunity costs, in retrospect, are staggering. So much time, effort, and money could have been spent on something else, but there was no way to know that without spending it all. There never really is.

I return to this theme around here every so often, because I think it's an important one. The general public hears about the drugs that we get approved, because we make a big deal out of them. But the failures, for the most part, are no louder than the leaves falling from the trees. They pass unnoticed. Most people never knew about them at all, and the people who did know would rather move on to something else. But if you don't realize how many of these failures there are, and how much they cost, you can get a completely mistaken view of drug discovery. Sure, look at the fruit on the branches, on those rare occasions when some appears. But spare a glance at that expensive layer of leaves on the ground.

Comments (32) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | Drug Development

June 14, 2013

A Beta-Secretase Inhibitor Hits the Skids in Alzheimer's

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Posted by Derek

The brutal drumbeat of Alzheimer's clinical failure continues at Eli Lilly. After the Phase III failure of their gamma-secretase inhibitor semagacestat, and a delusional attempt to pretend that the anti-amyloid antibody solanezumab succeeded, now comes word that the company has halted studies of a beta-secretase inhibitor.

This one wasn't for efficacy, but for tox. The company says that LY2886721 led to abnormalities in liver function, which is the sort of thing that can happen to anyone in Phase II. There is that thioamidine thing in it, but overall, it's not a bad-looking compound, particularly by the standards of beta-secretase inhibitors. But what does that avail one? We'll never find out what this one would have done in a real Phase III trial, although (unfortunately) I know how I'd lay the odds, considering what we know about Alzheimer's drug in the clinic. Beta-secretase inhibitors are an even higher-stakes bet than usual in this field, because mechanistically they have pretty strong support when it comes to inhibiting the buildup of amyloid protein, but they also have clear mechanistic liabilities: the enzyme seems to be important in the formation of myelin sheaths, which is not the sort of thing you'd want to touch in a patient population that's already neurologically impaired. Which effect wins out in humans? Does a BACE inhibitor really lower amyloid in the clinic? And does lowering amyloid in this way really affect the progression of Alzheimer's disease? Extremely good questions, all of those, and the only way to answer them is to round up a plausible drug candidate (not so easy for this target), half a billion dollars (for starters) and try it out.

This failure makes Lilly perhaps the first company to achieve a dread milestone, the Amyloid Trifecta. They have now wiped out on beta-secretase, on gamma-secretase, and on antibody therapy. And you know, I have to salute them for it. They've been making a determined effort against a terrible disease, trying all the most well-founded means of attack, and they're getting hammered into the ground like a tent peg for it. Alzheimer's. At the rate things are going, Lilly is going to end up in a terrible position, and a lot of it has to do with battering themselves against Alzheimer's. Remember this next time someone tells you about how drug companies are just interested in ripping off each other's baldness cures or something.

Comments (30) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

June 4, 2013

AstraZeneca, As Expected, Pulls the Plug

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Posted by Derek

Late last year came word that the AstraZeneca/Rigel compound, fostamatinib, had failed to show any benefit versus AbbVie's Humira in the clinic. Now they've gritted their corporate teeth and declared failure, sending the whole program back to Rigel.

I've lost count of how many late-stage clinical wipeouts this makes for AZ, but it sure is a lot of them. The problem is, it's hard to say just how much of this is drug discovery itself (after all, we have brutal failure rates even when things are going well), how much of it is just random bad luck, or what might be due to something more fundamental about target and compound selection. At any rate, their CEO, Pascal Soriot, has a stark backdrop against which to perform. Odds are, things will pick up, just by random chance if by nothing else. But odds are, that may not be enough. . .

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

May 15, 2013

And The Award For Clinical Futility Goes To. . .

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Posted by Derek

I was talking with someone the other day about the most difficult targets and therapeutic areas we knew, and that brought up the question: which of these has had the greatest number of clinical failures? Sepsis was my nomination: I know that there have been several attempts, all of which have been complete washouts. And for mechanisms, defined broadly, I nominate PPAR ligands. The only ones to make it through were the earliest compounds, discovered even before their target had been identified. What other nominations do you have?

Comments (32) + TrackBacks (0) | Category: Clinical Trials | Drug Industry History

May 2, 2013

Aveo Gets Bad News on Tivozanib

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Posted by Derek

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

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

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

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

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

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

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

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

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

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

April 22, 2013

Cancer: Back to N-of-One

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Posted by Derek

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

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

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

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

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

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

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

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

March 27, 2013

A Therapy Named After You?

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Posted by Derek

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

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

Update: here's more on the story.

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

March 26, 2013

The Wyeth/Elan Insider Trading Case Resolves

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Posted by Derek

You may remember this insider trading scandal from last year, involving a lead investigator for Wyeth/Elan's trials of bapineuzumab for Alzheimer's.

Here's the sequel. The hedge fund involved has agreed to pay $600 million dollars to settle the charges, although this does not get the manager himself off the hook (litigation in his case continues). Dr. Sidney Gilman, the investigator who leaked the information, has already been required to give back all his own gains, with interest and penalties.

Comments (6) + TrackBacks (0) | Category: Business and Markets | Clinical Trials | The Dark Side

March 22, 2013

Good News in Oncology: More Immune Therapy for Leukemia

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Posted by Derek

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

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

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

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

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

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

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

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

Eight days later, his leukemia was gone

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

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

Good News in Oncology: Oncolytic Virus Therapy

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Posted by Derek

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

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

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

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

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

March 21, 2013

NeuroSearch's Decline

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Posted by Derek

If you looked at the timelines of a clinical trial, you'll notice that there's often a surprisingly long gap between when the trial actually ends and when the results of it are ready to announce. If you've ever been involved in working up all that data, you'll know why, but it's usually not obvious to people outside of medical research why it should take so long. (I know how they'd handle the scene in a movie, were any film to ever take on such a subject - it would look like the Oscars, with someone saying "And the winner is. . ." within the first few seconds after the last patient was worked up).

The Danish company NeuroSearch unfortunately provided everyone with a lesson in why you want to go over your trial data carefully. In February of 2010, they announced positive results in a Phase III trial of a drug (pridopidine, Huntexil) for Huntington's (a rare event, that), but two months later they had to take it back. This move cratered their stock price, and investor confidence in general, as you'd imagine. Further analysis, which I would guess involved someone sitting in front of a computer screen, tapping keys and slowly turning pale and sweaty, showed that the drug actually hadn't reached statistical significance after all.

It came down to the varying genetic background in the patients being studied, specifically, the number of CAG repeats. That's the mutation behind Huntington's - once you get up to too many of those trinucleotide repeats in the middle of the gene sequence, the resulting protein starts to behave abnormally. Fewer than 36 CAGs, and you should be fine, but a good part of the severity of the disease has to do with how many repeats past that a person might have. NeuroSearch's trial design was not predicated on such genetic differences, at least not for modeling the primary endpoints. If you took those into account, they reached statistical significance, but if you didn't, you missed.

That's unfortunate, but could (in theory) be worse - after all, their efficacy did seem to track with a clinically relevant measure of disease severity. But you'll have noticed that I'm wording all these sentences in the past tense. The company has announced that they're closing. It's all been downhill since that first grim announcement. In early 2011, the FDA rejected their New Drug Application, saying that the company needed to provide more data. By September of that year, they were laying off most of their employees to try to get the resources together for another Phase III trial. In 2012, the company began shopping Huntexil around, as it became clear that they were not going to be able to develop it themselves, and last September, Teva purchased the program.

This is a rough one, because for a few weeks there in 2010, NeuroSearch looked like they had made it. If you want to see the fulcrum, the place about which whole companies pivot, go to clinical trial design. It's hard to overstate just how important it is.

Comments (7) + TrackBacks (0) | Category: Clinical Trials | The Central Nervous System

March 4, 2013

von Eschenbach Takes Another Whack at Phase III Trials

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Posted by Derek

Here's a new editorial on clinical trials and drug development by Tomas Philipson and Andy von Eschenbach (former head of the FDA). It continues his earlier theme of scaling back Phase III trials (which I commented on here).

These Phase 3 clinical trials served us well in the past. Today, in an era of precision or personalized-drug development, when medicines increasingly work for very specific patient groups, the system may be causing more harm than good for several reasons.

First, because of their restrictive design and the way the FDA interprets their results, Phase 3 trials often fail to recognize the unique benefits that medicines can offer to smaller groups of patients than those required in trials.

Second, information technologies have created improvements in our ability to monitor and improve product performance and safety after medicines are approved for sale. Post-market surveillance can and should reduce dependence on pre-market drug screening in Phase 3 trials.

Third, reducing reliance on Phase 3 trials is unlikely to introduce an offsetting harm induced by more dangerous drugs, since evidence supporting safety is produced in earlier phases. Manufacturers also have powerful incentives to maintain drug safety, since they take enormous financial hits -- well beyond the loss of sales -- when drugs are withdrawn after approval.

I'm still of two minds about this proposal. The idea of moving to less preclinical study and more post-marketing surveillance is not a ridiculous one, but our current system (and the expectations it generates) do make a good fit with it. The nasty details I noticed being glossed over earlier are still with us: how will health insurance companies deal with this change? How do we keep unscrupulous gaming of the system, with companies rushing things to market and spinning out the postmarketing studies as thinly and cheaply as possible? What would keep the real bottom-of-the-barrel types from pumping out high-priced placebos for demanding diseases like Alzheimer's, which compounds would fly through safety studies and reap big profits until they (slowly) were proved ineffective? What would be the legal aspect of all this - that is, when would a patient have the right to sue if something goes badly wrong, and when would they have to just realize that they're taking an investigational drug and that they're part of a research study?

These are real problems, but you wouldn't imagine that they even exist when you read these editorial pieces. I'm a fairly libertarian guy, but these are the sorts of things that occur to me within the first few minutes of thinking about such proposals, which means that there must be many other wrinkles I haven't thought of yet. I agree that increasing the research productivity of the drug industry would be an excellent thing, but I'm really not sure that this is the way to do it.

Comments (9) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs

February 15, 2013

ABT-199 Clinical Trial Suspended (Updated)

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Posted by Derek

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

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

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

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

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

February 7, 2013

DUCTS: Down with Useless Clinical Trial acronymS

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Posted by Derek

I'm not the first person to complain about these things, of course. Even by 2003, there were sixteen different clinical trials in the literature with the acronym HEART. It appears that the cardiovascular field picked up the acronym bug early, probably due to the size and length of their clinical programs. It also may been the first field to think up the jazzy clinical trial name first, and find something half-sensible to match it afterwards. But who can doubt that this is what goes on most of the time now? For those who still want to run the algorithm the other way, there's the Acronym Generator, which, wouldn't you know it, is run out of a cardiac hospital unit in Liverpool.

I wonder if the FDA would ever consider requiring drug companies and other research organizations to tone all this down, in the interest of sanity. If you're studying a drug called, say, kevorkirol (a generic name I invented a few years back, and hereby give freely to the scientific community), couldn't the clinical studies just be named "Kevorkirol Efficacy Trial #1", and "Kevorkirol Expanded Efficacy Trial #2" and so on? That would actually help people to keep them straight, instead of having to make a chart of bizarre trial names and their actual purpose. Anyone up for this idea?

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

February 5, 2013

Not Working Out So Well at Merck?

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Posted by Derek

Here's a rather grim analysis from the AP of Merck's current status. The company's stock was recently downgraded by two analysts after last Friday's earnings call didn't go very well (links added by me below):

Future sales of Vytorin, a controversial combination drug on sale since 2004 that includes Zocor, and prospects for a crucial experimental osteoporosis drug called odanacatib were thrown into question Friday as Merck announced its fourth-quarter results. Company executives made some cryptic comments, suggesting significant problems with both drugs. . .

Merck said Friday that it won't apply for approval of odanacatib, a new type of osteoporosis drug, until 2014 instead of by this June. Management said it was reviewing safety and efficacy data from one study and now won't apply for approval until they have longer-term data from an extension study.

Executives also said a committee monitoring its 18,000-patient study of Vytorin, called IMPROVE-IT, had requested a new interim analysis of patient data in March. The study is meant to determine whether Vytorin reduces risk of heart attack, stroke and death in heart disease patients — the ultimate purpose of cholesterol drugs — but Merck executives, grilled by analysts on a conference call, wouldn't say that they're confident the study will show that benefit.

I wouldn't, either, if I were in their shoes. The Vytorin story has been long and complex, and that complexity comes from two sources: the drug's unique mechanism of action (at least the ezetimibe part), and the uncertainties of human lipid handling and its relationship to cardiovascular outcomes. Honestly, these things could go any way at all, and the same goes for Merck's high-profile push in CETP. A lot of the company is riding on some very uncertain science.

But I wonder, as I was speculating on in that last link, if that isn't where the whole industry is these days. By now, we've attacked all the things that we believe we really know something solid about. What's left is often big, important, potentially very profitable. . .and risky enough to make you leave fingernail marks in the armrests of your chair. The higher up you sit, and the nicer the material that chair is made of, the more damage is being done to it.

Comments (14) + TrackBacks (0) | Category: Business and Markets | Clinical Trials

January 31, 2013

Mipomersen Approved (Bonus Antisense Roundup Included)

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Posted by Derek

So Isis and their partner Sanofi have received FDA approval for mipomersen (branded as Kynamro). Late last year, the European Medicines Agency turned them down, which has people wondering about the drug's future, but here they are, albeit with a warning on the label about liver toxicity.

Mipomersen is designed to lower the Apo-B lipoprotein in people with the most severe (homozygous) form of familial hypercholesterolemia. That's a small patient population, but they're definitely in need of help. The really significant thing about this approval, in my mind, is that it's a pure antisense therapy, and it comes about twenty years after there was supposed to be a world-changing flood of them. (Isis did get one through the process back in 1996, fomivirsen, but it's never had much of an impact). It was a standing joke back in the late 1980s/early 1990s that everyone had heard from a headhunter recruiting for one antisense company or another. (Sheesh, those were the days, eh? There still are search firms, right? When's the last time a headhunter rang your phone?)

I don't think that mipomersen will ever reach the heights that Isis thought it might a few years ago; the liver tox problems will see that it's only used in life-threatening situations. (I note that one time when I wrote about the drug, fans of ISIS showed up rolling their eyes at the mistaken notion that liver tox could ever be a problem). But I'm divided between congratulating them on finally getting something onto the market, and wondering about how difficult it's been to get there. As far as I know, the liver tox seen in this case is largely (completely?) thought to be due to the mechanism of action on lipid handling in the liver itself.

So how about the other antisense compounds in the clinic? As of that 2010 link above, we had trabedersen, for TGF-beta2, which is actively being tried against pancreatic cancer. Alicaforsen, for Crohn's et al., has shown disappointing efficacy in Crohn's, but is still alive for ulcerative colitis.. Aganirsen, for various vascular conditions in the eye, is still in development, with more funding having arrived recently. Oblimersen has shown some effects in the clinic, but CLL is a crowded area, and its current status is unclear, at least to me. And custirsen is in Phase III, with mixed results in Phase II trials.

Actually, that lineup looks a lot like drug development in the rest of the industry, to be honest. Some stuff looks OK and is moving along, some not so OK, and some has wiped out. It's important to realize that even if liver tox is not some general feature of the mipomersen-generation antisense compounds, that we still have efficacy failures. Oh, that we do. The indications where we can really laser right in on a key target do not make a long list. Many of those are orphans, too. In contrast, the list of giant-unmet-medical-need indications where we can laser right in on a key target is, I think, waiting for something, anything, to be written on it.

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

January 25, 2013

CETP, Alzheimer's, Monty Hall, and Roulette. And Goats.

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Posted by Derek

CETP, now there's a drug target that has incinerated a lot of money over the years. Here's a roundup of compounds I posted on back last summer, with links to their brutal development histories. I wondered here about what's going to happen with this class of compounds: will one ever make it as a drug? If it does, will it just end up telling us that there are yet more complications in human lipid handling that we didn't anticipate?

Well, Merck and Lilly are continuing their hugely expensive, long-running atempts to answer these questions. Here's an interview with Merck's Ken Frazier in which he sounds realistic - that is, nervous:

Merck CEO Ken Frazier, speaking in Davos on the sidelines of the World Economic Forum, said the U.S. drugmaker would continue to press ahead with clinical research on HDL raising, even though the scientific case so far remained inconclusive.

"The Tredaptive failure is another piece of evidence on the side of the scale that says HDL raising hasn't yet been proven," he said.

"I don't think by any means, though, that the question of HDL raising as a positive factor in cardiovascular health has been settled."

Tredaptive, of course, hit the skids just last month. And while its mechanism is not directly relevant to CETP inhibition (I think), it does illustrate how little we know about this area. Merck's anacetrapib is one of the ugliest-looking drug candidates I've ever seen (ten fluorines, three aryl rings, no hydrogen bond donors in sight), and Lilly's compound is only slightly more appealing.

But Merck finds itself having to bet a large part of the company's future in this area. Lilly, for its part, is betting similarly, and most of the rest of their future is being plunked down on Alzheimer's. And these two therapeutic areas have a lot in common: they're both huge markets that require huge clinical trials and rest on tricky fundamental biology. The huge market part makes sense; that's the only way that you could justify the amount of development needed to get a compound through. But the rest of the setup is worth some thought.

Is this what Big Pharma has come to, then? Placing larger and larger bets in hopes of a payoff that will make it all work out? If this were roulette, I'd have no trouble diagnosing someone who was using a Martingale betting system. There are a few differences, although I'm not sure how (or if) they cancel out For one thing, the Martingale gambler is putting down larger and larger amounts of money in an attempt to win the same small payout (the sum of the initial bet!) Pharma is at least chasing a larger jackpot. But the second difference is that the house advantage at roulette is a fixed 5.26% (at least in the US), which is ruinous, but is at least a known quantity.

But mentioning "known quantities" brings up a third difference. The rules of casino games don't change (unless an Ed Thorp shows up, which was a one-time situation). The odds of drug discovery are subject to continuous change as we acquire more knowledge; it's more like the Monty Hall Paradox. The question is, have the odds changed enough in CETP (or HDL-raising therapies in general) or Alzheimer's to make this a reasonable wager?

For the former, well, maybe. There are theories about what went wrong with torcetrapib (a slight raising of blood pressure being foremost, last I heard), and Merck's compound seems to be dodging those. Roche's failure with dacetrapib is worrisome, though, since the official reason there was sheer lack of efficacy in the clinic. And it's clear that there's a lot about HDL and LDL that we don't understand, both their underlying biology and their effects on human health when they're altered. So (to put things in terms of the Monty Hall problem), a tiny door has been opened a crack, and we may have caught a glimpse of some goat hair. But it could have been a throw rug, or a gorilla; it's hard to say.

What about Alzheimer's? I'm not even sure if we're learned as much as we have with CETP. The immunological therapies have been hard to draw conclusions from, because hey, it's the immune system. Every antibody is different, and can do different things. But the mechanistic implications of what we've seen so far are not that encouraging, unless, of course, you're giving interviews as an executive of Eli Lilly. The small-molecule side of the business is a bit easier to interpret; it's an unrelieved string of failures, one crater after another. We've learned a lot about Alzheimer's therapies, but what we've mostly learned is that nothing we've tried has worked much. In Monty Hall terms, the door has stayed shut (or perhaps has opened every so often to provide a terrifying view of the Void). At any rate, the flow of actionable goat-delivered information has been sparse.

Overall, then, I wonder if we really are at the go-for-the-biggest-markets-and-hope-for-the-best stage of research. The big companies are the ones with enough resources to tackle the big diseases; that's one reason we see them there. But the other reason is that the big diseases are the only things that the big companies think can rescue them.

Comments (4) + TrackBacks (0) | Category: Alzheimer's Disease | Cardiovascular Disease | Clinical Trials | Drug Development | Drug Industry History

January 21, 2013

That Many Compounds in Development? Really?

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Posted by Derek

So PhRMA has a press release out on the state of drug research, but it's a little hard to believe. This part, especially:

The report, developed by the Analysis Group and supported by PhRMA, reveals that more than 5,000 new medicines are in the pipeline globally. Of these medicines in various phases of clinical development, 70 percent are potential first-in-class medicines, which could provide exciting new approaches to treating disease for patients.

This set off discussion on Twitter and elsewhere about how these number could have been arrived at. Here's the report itself (PDF), and looking through it provides a few more details Using figures that show up in the body of the report, that looks like between 2164 compounds in Phase I, 2329 in Phase II, and 833 in Phase III. Of those, by far the greatest number are in oncology, where they have 1265, 1507, and 288 in Phase I, II, and III, respectively. Second is infectious disease (304/289/135), and third is neurology (256/273/74). It's worth noting that "Psychiatry" is a separate category all its own, by the way.

An accompanying report (PDF) gives a few more specific figures. It claims, among other things, 66 medicines currently in clinical trials for Hepatitis C, 61 projects for ALS, and 158 for ovarian cancer. Now, it's good to have the exact numbers broken down. But don't those seem rather high?

Here's the section on how these counts were obtained:

Except where otherwise noted, data were obtained from EvaluatePharma, a proprietary commercial database with coverage of over 4,500 companies and approximately 50,000 marketed and pipeline products (including those on-market, discontinued, and in development), and containing historical data from 1986 onward. Pipeline information is available for each stage of development, defined as: Research Project, Preclinical, Phase I, II, III, Filed, and Approved. EvaluatePharma collects and curates information from publicly available sources and contains drug-related information such as company sponsor and therapy area. The data were downloaded on December 12, 2011.

While our interest is in drugs in development that have the potential to become new treatment options for U.S. patients, it is difficult to identify ex ante which drugs in development may eventually be submitted for FDA approval – development activity is inherently global, although regulatory review, launch, and marketing are market-specific. Because most drugs are intended for marketing in the U.S., the largest drug market in the world, we have not excluded any drugs in clinical development (i.e., in Phases I, II, or III). However, in any counts of drugs currently in regulatory review, we have excluded drugs that were not filed with the FDA.

Unless otherwise noted, the analysis in this report is restricted to new drug applications for medicines that would be reviewed as new molecular entities (NMEs) and to new indications for already approved NMEs. . .

Products are defined as having a unique generic name, such that a single product is counted exactly once (regardless of the number of indications being pursued).

That gives some openings for the higher-than-expected numbers. For one, those databases of company activities always seem to run on the high side, because many companies keep things listed as development compounds when they're really ceased any work on them (or in extreme cases, never even really started work at all). Second, there may be some oddities from other countries in there, where the standards for press releases are even lower. But we can rule out a third possibility, that single compounds are being counted across multiple indications. I think that the first-in-class figures are surely pumped up by the cases where there are several compounds all in development for the same (as yet unrealized) target, though. Finally, I think that there's some shuffling between "compounds" and "projects" taking place, with the latter having even larger figures.

I'm going to see in another post if I can break down any of these numbers further - who know, maybe there are a lot more compounds in development than I think. But my first impression is that these numbers are much higher than I would have guessed. It would be very helpful if someone at PhRMA would release a list of the compounds they've counted from one of these indications, just to give us an idea. Any chance of that?

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

January 18, 2013

A Short Rise Out of Depression

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Posted by Derek

Here's another one to file under "What we don't know about brain chemistry". That's a roomy category for sure, which (to be optimistic about it) leaves a lot of room for discovery. In that category are the observations that ketamine seems to dramatically help some people with major depression. It's an old drug, of course, still used in some situations as an anesthetic, and also used (or abused) by people who wish to deliberately derange themselves in dance clubs. Chemists will note the chemical resemblance to phencyclidine (PCP), a compound whose reputation for causing derangement is thouroughly deserved. (Ketamine was, in fact, a "second-generation" version of PCP, many years on).

Both of these compounds are, among other things, NMDA receptor antagonists. That had not been considered a high-priority target for treating depression, but you certainly can't argue with results (not, at least, when you know as little about the mechanisms of depression as we do). There are better compounds around, fortunately:

AZD6765, an inhibitor of the N-methyl-D-aspartate (NMDA) receptor, a glutamate signaling protein involved in cellular mechanisms for learning and memory, was originally developed as a treatment for stroke. It was shelved in 2000 by the drug's manufacturer, AstraZeneca, after phase 2 trials failed to show signs of efficacy. In the decade that followed, however, small clinical reports started to emerge showing that ketamine, an analgesic that also blocks the NMDA receptor, produced rapid responses in people who didn't benefit from any other antidepressants. And unlike most therapies for major depression, which usually take weeks to kick in, ketamine's mood-lifting effects could be seen within two hours, with a therapeutic boost that often lasted for weeks following a single infusion. Ketamine treatment also came with a number of debilitating side effects, though, including psychosis and detachment from reality. Fortunately for AstraZeneca, the company had a cleaner drug on its shelves that could harness ketamine's benefits with fewer problems.

Note that AZD6765 (lanicemine) has a rather simple structure, further confirmation (if anyone needed any) that things this size can be very effective drugs. Here's the clinical study that Nature Medicine news item refers to, and it makes clear that this was a pretty tough patient cohort:

This double-blind, placebo-controlled, proof-of-concept study found that a single intravenous infusion of a low-trapping nonselective NMDA channel blocker in patients with treatment-resistant MDD rapidly (within minutes) improved depressive symptoms without inducing psychotomimetic effects. However, this improvement was transitory. To our knowledge, this is the first report showing rapid antidepressant effects associated with a single infusion of a low-trapping nonselective NMDA channel blocker that did not induce psychotomimetic side effects in patients with treatment-resistant MDD.

More specifically, patient depression scores improved significantly more in patients receiving AZD6765 than in those receiving placebo, and this improvement occurred as early as 80 min. This difference was statistically significant for the MADRS, HDRS, BDI, and HAM-A. These findings are particularly noteworthy, because a large proportion of study participants had a substantial history of past treatment that was not efficacious. The mean number of past antidepressant trials was seven, and 45% of participants had failed to respond to electroconvulsive therapy.

The problem is the short duration. By one evaluation scale, the effects only lasted about two hours (by another less stringent test, some small effect could still be seen out to one or two days). Ketamine lasts longer, albeit at a cost of some severe side effects. This doesn't seem to be a problem with high clearance of AZD6765 (its PK had been well worked out when it was a candidate for stroke). Other factors might be operating:

These differences could be due to subunit selectivity and trapping blockade. It is also possible that the metabolites of ketamine might be involved in its relatively sustained antidepressant effects, perhaps acting on off-site targets; a recent report described active ketamine metabolites that last for up to 3 days. It is also important to note that, although trapping blockade or broadness of antagonist effects on the NMDA subunit receptors might be key to the robustness of antidepressant effects, these same properties might be involved in the dissociative and perceptual side effects of ketamine. Notably, these side effects were not apparent at the dose of AZD6765 tested.

If that last part is accurate, this is going to be a tricky target to work with. I doubt if AZD6765 itself has a future as an antidepressant, but if it can help to understand that mode of action, what the downstream effects might be, and which ones are important, it could lead to something very valuable indeed. The time and effort that will be needed for that is food for thought, particularly when you consider the patients in this study. What must it be like to feel the poison cloud of major depression lift briefly, only to descend again? The Nature Medicine piece has this testimony:

(David) Prietz, 48, a scheduling supervisor at a sheet-metal manufacturer in Rochester, New York, who has been on disability leave for several years, started to feel his head clear from the fog of depression within days of receiving AZD6765. After his second infusion, he vividly began noticing the fall foliage of the trees outside his doctor's office—something he hadn't previously appreciated in his depressed state. “The greens seemed a lot greener and the blue sky seemed a lot bluer,” he says. Although the lift lasted only a couple months after the three-week trial finished and the drug was taken away, the experience gave Prietz hope that he might one day get better. “I can't recall feeling as well I did at the time,” he says.

Fall foliage for Algernon? I hope we can do something for these people, because as it is, a short-duration effect is scientifically fascinating but emotionally cruel.

Comments (44) + TrackBacks (0) | Category: Clinical Trials | The Central Nervous System

January 3, 2013

Overselling p53 Drugs

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Posted by Derek

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

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

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

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

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

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

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

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

December 21, 2012

Merck's Tredaptive Comes to a Halt

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Posted by Derek

Merck's Tredaptive (formerly Cordaptive) has had a long and troubled history. It's a combination of niacin and Laropiprant, which is there to try to reduce the cardiovascular (flushing) side effects of large niacin doses, which otherwise seem to do a good job improving lipid profiles. (Mind you, we don't seem to know how that works, and there's a lot of reason to wonder how well it works in combination with statins, but still).

The combination was rejected by the FDA back in 2008, but approved in Europe. Merck has been trying to shore up the drug ever since, and since the FDA told them that they would not approve without more data, the company has been running a 25,000-patient trial (oh, cardiovascular disease. . .) combining Tredaptive with statin therapy. In light of the last link in the paragraph above, one might have wondered how that was going to work out, since the NIH had to stop a large niacin-plus-statin study of their own. Well. . .

The European Medicines Agency has started a review of the safety and efficacy of Tredaptive, Pelzont and Trevaclyn, identical medicines that are used to treat adults with dyslipidaemia (abnormally high levels of fat in the blood), particularly combined mixed dyslipidaemia and primary hypercholesterolaemia.

The review was triggered because the Agency was informed by the pharmaceutical company Merck, Sharp & Dohme of the preliminary results of a large, long-term study comparing the clinical effects of adding these medicines to statins (standard medicines used to reduce cholesterol) with statin treatment alone. The study raises questions about the efficacy of the medicine when added to statins, as this did not reduce the risk of major vascular events (serious problems with the heart and blood vessels, including heart attack and stroke) compared with statin therapy alone. In addition, in the preliminary results a higher frequency of non-fatal but serious side effects was seen in patients taking the medicines than in patients only taking statins.

So much for Tredaptive, and (I'd say) so much for the idea of taking niacin and statins together. And it also looks like the FDA was on target here when they asked for more evidence from Merck. Human lipid biology, as we get reminded over and over, is very complicated indeed. The statin drugs, for all their faults, do seem to be effective, but (to repeat myself!) they also seem, more and more, to be outliers in that regard.

Comments (13) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology

December 20, 2012

CNS Drug Development Claims Another Victim

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Posted by Derek

Tiny Allon Therapeutics had an ambitious plan to go after progressive supranuclear palsy, a kind of progressive brain deterioration, and thence (they hoped) to other neurodegenerative disorders. The lead compound was davunetide, an oligopeptide derived from activity-dependent neuroprotective protein, ADNP.

It was a reasonable idea, but neurodegeneration is not a reasonable area. The drug has now completely wiped out in the clinic, failing both primary endpoints in its pivotal trial. This is one example of the sort of research that most people don't ever hear about, from a small company that most people will never have heard of at all. But this is the background activity of drug research (with an all-too-common outcome), and if more people were aware of it, perhaps that would be a good thing (see today's other post).

Comments (8) + TrackBacks (0) | Category: Clinical Trials | The Central Nervous System

December 13, 2012

Asking the Tough Questions: Doomsday in the Clinic

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Posted by Derek

Now, here's something useful for all of us in drug discovery and development: "The Mayan Doomsday’s effect on survival outcomes in clinical trials":

There is a great deal of speculation concerning the end of the world in December 2012, coinciding with the end of the Mesoamerican Long Count calendar (the “Maya calendar”). Such an event would undoubtedly affect population survival and, thus, survival outcomes in clinical trials. Here, we discuss how the outcomes of clinical trials may be affected by the extinction of all mankind and recommend appropriate changes to their conduct. In addition, we use computer modelling to show the effect of the apocalypse on a sample clinical trial

I especially like the comparative survival curves, with and without the destruction of all life factored in. I wonder if a Bayesian trial design would be able to handle the End of Days more gracefully?

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

Rheumatoid Arthritis Wins A Couple of Rounds

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Posted by Derek

No one told me that it was "Rheumatoid arthritis clinical disaster day for companies that have enough to worry about already", but apparently that's what it is. AstraZeneca doesn't have an awful lot in its late-stage pipeline, but one of the things in it is a Syk inhibitor licensed in from Rigel, Fostamatinib. (More accurately, that's a phosphate ester prodrug of the Rigel compound - check out the structure and you'll see why a prodrug approach might have been necessary).

That's positioned as an orally active anti-inflammatory, to go up against Humira and the like. Back in Phase IIa it looked promising, although there have been concerns about blood pressure effects (disclosure of which has led to some hard feelings among some investors). But a new trial head-to-head against Humira in rheumatoid arthritis patients, it definitely comes up short. A Phase III trial will report next year, but what are the odds that it'll turn this one into a success?

And Eli Lilly is another company that doesn't need any more bad news, but they're stopping an RA therapy, too. Tabalumab, an antibody against B-cell activating factor, is also targeting the TNF pathway. This trial was in RA patients who were not responsive to methotrexate therapy, and was halted for sheer lack of efficacy, which is disturbing, since the antibody had (up until now) shown reasonable data. Lilly says that they're suspending enrollment in the clinic until they see the results (next year) of their ongoing trials.

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

December 12, 2012

Eli Lilly's Brave Alzheimer's Talk

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Posted by Derek

I'm a bit baffled by Eli Lilly's strategy on Alzheimer's. Not the scientific side of it - they're going strongly after the amyloid hypothesis, with secretase inhibitors and antibody therapies, and if I were committed to the amyloid hypothesis, that's probably what I'd be doing, too. It is, after all, the strongest idea out there for the underlying mechanism of the disease. (But is it strong enough? Whether or not amyloid is the way to go is the multibillion dollar question that can really only be answered by spending the big money in Phase III trials against it, unfortunately).

No, what puzzles me is the company's publicity effort. As detailed here and here, the company recently made too much (it seemed to me and many others) of the results for solanezumab, their leading antibody therapy. Less hopeful eyes could look at the numbers and conclude that it did not work, but Lilly kept on insisting otherwise.

And now we have things like this:

"We are on the cusp here of writing medical history again as a company, this time in Alzheimer's disease," Jan Lundberg, Lilly's research chief, said in an interview.

Just as the Indianapolis-based company made history in the 1920s by producing the first insulin when type 1 diabetes was a virtual death sentence, Lundberg said he is optimistic that the drugs Lilly is currently testing could significantly slow the ultimately fatal memory-robbing disease.

"It is no longer a question of 'if' we will get a successful medicine for this devastating disease on the market, but when," said Lundberg, 59.

Ohhh-kay. The problems here are numerous. For one thing, as Lundberg (an intelligent man) well knows, insulin-for-diabetes is a much straighter shot than anything we know of for Alzheimer's. It was clear, when Lilly got their insulin business underway, that the most devastating symptoms of type I diabetes were caused by lack of insulin production in the body, and that providing that insulin was the obvious remedy. Even if it did nothing for the underlying cause of the disease (and it doesn't), it was a huge step forward. As for Alzheimer's, I understand that what Lundberg and Lilly are trying to get across here is the idea of a "successful medicine", rather than a "cure". Something that just slows Alzheimer's down noticeably would indeed be a successful medicine.

But "when, not if"? With what Lilly has in the clinic? After raising hopes by insisting that the Phase III results for solanezumab were positive, the company now says that. . .well, no, it's not going to the FDA for approval. It will, instead, conduct a third Phase III trial. This decision came after consulting with regulators in the the US and Europe, who no doubt told them to stop living in a fantasy world. So, sometime next year, Lilly will start enrolling for another multiyear shot at achieving some reproducible hint of efficacy. Given the way solanezumab has performed so far, that's about the best that could be hoped for, that it works a bit in some people, sometimes, for a while, as far as can be told in a large statistical sample. Which sets up this situation, I fear.

And this is "on the cusp. . .of writing medical history"? Look, I would very much like for Lilly, for anyone, to write some medical history against Alzheimer's. But saying it will not make it so.

Comments (19) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

December 4, 2012

Merck Presses Ahead on Alzheimer's:

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Posted by Derek

One Alzheimer's compound recently died off in the clinic - Bristol-Myers Squibb's avagacestat, a gamma-secretase inhibitor, has been pulled from trials. The compound "did not establish a profile that supported advancement" to Phase III, says the company. Gamma-secretase has been a troubled area for some time, highlighted by the complete failure of Lilly's semagacestat. I wondered, when that one cratered, what they were thinking at BMS, and now we know.

But Merck is getting all the attention in Alzheimer's today. They've announced that their beta-secretase inhibitor, MK-8931, is moving into Phase III, and the headlines are. . .well, they're mostly just not realistic. "Hope for Alzheimer's", "Merck Becomes Bigger Alzheimer's Player", and so on. My two (least) favorites are "Merck Races to Beat Lilly Debut" and "Effective Alzheimer's Drug May Be Just Three Years Away." Let me throw the bucket of cold water here: that first headline is extremely unlikely, and the second one is insane.

As I've said here several times, I don't think that there's going to be any big Lilly debut into Alzheimer's therapy with their lead antibody candidate, solanezumab. (And if there is, we might regret it). The company does have a beta-secretase (BACE) inhibitor, but that's not what these folks are talking about. And looking at Merck's compound, you really have to wonder if there's ever going to be one there, either. I like Fierce Biotech's headline a lot better: "Merck Ignores Red Flags and Throws Dice on PhII/III Alzheimer's Gamble". That, unfortunately, is a more realistic appraisal.

It's interesting, though, that Merck is testing this approach in a patient population that includes patients with moderate cases. After solanezumab and bapineuzumab appears to have hit that target without any clear signal that they had improved symptoms for patients with more fully developed cases, there has been a growing move to shift R&D into earlier-stage patients, whose brains have not already been seriously damaged by the disease. Merck is likely to face growing skepticism that it can succeed with the amyloid hypothesis when tackling the same population that hasn't delivered positive data.

And BACE has been a rough place to work in over the years. The literature is littered with oddities, since finding a potent compound that will also be selective and get into the brain has been extremely difficult. I actually applaud Merck for having the nerve to try this, but it really is a big roll of the dice, and there's no use pretending otherwise. I wish that the headlines would get that across, as part of a campaign for a more realistic idea of what drug discovery is actually like.

Comments (17) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

November 21, 2012

TauRx Goes Into Phase III For Alzheimer's

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Posted by Derek

I can't even count the number of e-mails I've gotten over the last few years asking about TauRx and their Alzheimer's program, which made a big splash back in 2008. Finally, there's some news to report. The company is starting Phase III clinical trials, and has announced new financing to see these through. The company is based in Singapore, and they're getting money from a large multinational company in the region.

Good for them. The tau-based therapy they're working on is a very interesting idea, and (of course) extremely significant if it actually works. I'm happy to see that it's going to get a real chance to prove itself, and I look forward to seeing the results. Their earlier compound ("Rember") was reformulated methylene blue, but they now seem to have an improved version to go ahead with (and not just in Alzheimer's, apparently).

I know I'll get more mail about this, but let me save time by telling those interested to go here, to a site run by TauRx about their clinical trials. It seems that they have started enrolling patients in North America.

Comments (19) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

November 20, 2012

And Since We're Talking About Insider Trading

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Posted by Derek

Here's something from just this morning, a whopping large case on illegal trading in Wyeth and Elan stock. This one involves a hedge fund manager, Mathew Martoma, and (quite disturbingly), Dr. Sidney Gilman of the University of Michigan, who was the lead investigator on a very large bapineuzumab trial for Alzheimer's. His conduct appears, from the text of the complaint, to be completely inexcusable, just a total, raw tipoff of confidential information.

I blogged at the time about the trial results, not knowing, of course, that someone had been pre-warned and was trading 20 per cent of Elan's stock volume on the news (and at least ten per cent of Wyeth's). So I take back anything I said about insider trading cases becoming more small-time over the years; this case has jerked the average right back up.

Update: Adam Feuerstein on Twitter: "Gilman's presentation of bapi data at 2008 ICAD meeting was so poorly done. It was shockingly bad. Now we know why."

Comments (18) + TrackBacks (0) | Category: Alzheimer's Disease | Business and Markets | Clinical Trials | The Dark Side

November 12, 2012

Oh Yeah, Now That You Mention It, They're Dead

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Posted by Derek

The overhyped nature of stem cell therapies is a topic that's come up here several times. In the latest developments, Pluristem, Inc., is threatening to sue Bloomberg New for their recent report, titled "Girl Dies As Pluristem Sells On Gains With Miracle Cells". Gosh, it's hard to see why the company would take exception to a headline like that, but here's how the piece leads off, in case things weren't clear:

Pluristem Therapeutics Inc.’s (PSTI) stock doubled in Nasdaq trading from May through September, helped by three news releases announcing that patients’ lives had been saved by injections of the company’s experimental stem cells.
After the stock soared on the positive news, two top executives profited by selling shares at the highest price in more than four years as part of a pre-determined program. When the first of those patients, a 7-year-old girl with a bone- marrow disease, died four months after the company said her life had been saved, Pluristem was silent. The company raised $34 million selling shares a week later.

Not so good. But as that link in the first paragraph shows, Pluristem's response has not cleared things up very much. In the same press release in which they demanded a correction from Bloombert, they revealed that another of their three initial patients had also died after four months, which also had not been announced before. The earlier press releases for all three patients are well-stocked with phrases like "medical miracle" and "life-saving". As long as this sort of thing is going on, the stem cell field will continue to have problems.

Update: interestingly, this post seems to have brought a lot of Pluristem's stock market fans flocking. And I mean this in the best possible way, but their appearance here does not inspire confidence.

Comments (29) + TrackBacks (0) | Category: Clinical Trials | Press Coverage

October 31, 2012

The Coming Battle Over Alzheimer's Disease

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Posted by Derek

Solanezumab is a story that won't go away. Eli Lilly's antibody therapy for Alzheimer's is the subject of a lot of arguing among investors: some people (and I'm one of them) think that there is no strong evidence for its efficacy, not yet, and that the amount of time and effort devoted to finding that out means that there likely isn't any meaningful efficacy to be found. Others are more optimistic, which is why Lilly's stock has risen in recent months.

The latest point of contention is an independent analysis of biomarker data which came out this week at a conference in Monaco. This suggests that there was a meaningful change in the amount of circulating beta-amyloid after treatment, which could mean that the antibody was working as planned to increase clearance of soluble amyloid, thus altering the amyloid balance in the CNS. It should be noted that this line of attack depends on several factors - first among them, that amyloid is a causative factor in Alzheimer's, and secondly, that clearing it from the periphery can affect its concentration and distribution inside the brain. There's evidence for both of these, and there's evidence against both of them. Such questions can only be answered in the clinic, and I'm glad that Lilly, Roche/Genentech, and others are trying to answer them.

What I want to focus on today, though, is an issue that comes up in passing in the Fierce Biotech link above:

Biomarkers and pooled data may help support further studies of the drug, as well as other programs that rest on the beta amyloid hypothesis, but they don't prove that solanezumab works as hoped. Nevertheless, the first sign of success in this field has fueled tremendous enthusiasm that something in the pipeline could eventually work--perhaps even pushing regulators to approve new therapies with something less than clear efficacy data. And any newly approved drug would find a massive market of millions of desperate patients.

That's a big "perhaps", one that's worth tens of billions of dollars. What I worry about is pressure building for the FDA to approve an Alzheimer's therapy (solanezumab or something else) based on these hints of mechanistic efficacy. The problem is, solanezumab hasn't shown much promise of improving the lives of actual Alzheimer's patients. Lilly's own trials showed a possible improvement in a measure of cognitive decline, but this did not show up again in a second patient group, even when they specifically modified the endpoints of the trial to look for it. And neither group showed any functional effects at all, which I think are what most Alzheimer's patients (and their family members) would really want to see.

But there really is such a huge demand for something, anything, with any hint of hope. People would line up to buy anything that got FDA approval, no matter how tenuous the evidence was. And that puts the agency in a very tough position, similar to the one it was in with the Avastin breast cancer issue. Update: there was, to be sure, more of a safety question with Avastin at the same time. You can argue that one of the main purposes of the agency is to make sure that medicines that people can be prescribed in this country will actually do some good, rather than raise hopes for nothing. You could also argue that responsible adults - and their physicians, and their insurance companies - should be able to make such choices for themselves, and should be able to spend their time and money in the ways that they best see fit. You could argue that companies with marginally effective (or ineffective) therapies face a huge moral hazard, in that their incentives are to get such treatments onto the market whether they do anyone else any good or not. None of these are foolish positions, but they are also, in places, mutually incompatible. Alzheimer's disease might well turn into the next place in which we thrash them out.

Comments (17) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Drug Prices | Regulatory Affairs

October 26, 2012

"Basically, They're A Bunch of Lemmings"

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Posted by Derek

True, but that's unfair to lemmings. This is Raghuram Selveraju of Aegis Capital, talking about deal-making executives in the big pharma companies and the string of costly blowups so far this year. That link has the list, and it's quite an impressive string of fireballs.

“What all of these deals had in common was the desperation of big pharma, because its R&D productivity has been dropping and we’ve known that for a long time,” he said.

That desperation leads to the repetition of familiar mistakes which derive from the predictable thinking of too many business development executives at big pharma, Selveraju opined. First, when looking for licensing opportunities, pharmas very often seek out their comfort zone – a potential product for which they can deploy an existing sales force or promote to doctors they already know and communicate with. Also, to be confident in an experimental drug’s preclinical and clinical data, pharmas often want to go into areas where their competitors also have a compound as well as into validated targets.

“Basically, they’re a bunch of lemmings,” Selveraju said. “As soon as a target becomes hot, they all have to have a molecule in that space, hitting that target."

But who could blame them? Going out into areas that haven't been explored, or haven't worked out for others, can get you slaughtered, too (ask Eli Lilly about Alzheimer's). And when that happens, you have nowhere to hide. If everyone else was rushing into a given therapeutic area and it turns out to be a disaster, well, you yourself might be able to get by, because that's just one of those things, and it happened to everyone at the same time. It reminds me of something I saw years ago about investment managers. If you go out and buy a bunch of (say) IBM for your clients and it drops, people might say "Man, what's wrong with IBM?" But if you go out and buy a bunch of WhoZat, Inc., and it drops, people will ask what's wrong with you.

My own biases make me think that if the chances for failure are high both ways, then maybe you should go ahead and strike out for the unknown territory, because the payoff is larger if you succeed. Selveraju himself has a much more cautious (and perhaps outright dispiriting) recommendation:

What then is Selveraju’s prescription for better business development practices? It might disappoint those who want pharma to be in the vanguard of innovation. He recommends incremental innovation – using FDA’s 505b2 pathway to develop products with already defined efficacy and safety – as well as biosimilars and re-purposing. Pharma also should focus on niche and specialty indications, and largely eliminate primary care products and the large commercial operations that come with them.

That's cranking up the dial even more on the Bernard Munos strategy. Munos also recommends getting out of the big, expensive areas and going more for niche and specialty ones, but mainly because of the cost of the clinical trials (and the validation step inherent in them). Alzheimer's, for example, scores big on innovation, but very, very poorly on the risk/cost ratio, since it's going to take you years and years in huge clinical trials to see if you've got something.

But that "develop products with already defined efficacy and safety" line is Selveraju’s own, and doesn't that sound like loads of fun? Coming up with new formulations and dosing schedules of existing drugs is what a 505(b)(2) strategy amounts to, and it brings up thoughts of alternative careers - going off to trucking school and learning to drive the big rigs, for example. Actually, as a drug-discovery chemist, that's probably what I'd end up doing if everyone switched to that plan, since you certainly don't need people like me if you're five-oh-five-bee-twoing.

Comments (21) + TrackBacks (0) | Category: Business and Markets | Clinical Trials | Regulatory Affairs

October 18, 2012

The Generic Wellbutrin Problem: Whose Fault Is It?

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Posted by Derek

One of the questions I get asked most often, by people outside of the drug industry, is whether generic medications really are the same as the original branded ones. My answer has always been the same: that yes, they are. And that's still my answer, but I'll have to modify it a bit, because we're seeing an exception right now. Update: more exceptions are showing up in the comments section.

Unfortunately, "right now" turns out, in this case, to mean "over the last five years". The problem here is bupropion (brand name Wellbutrin), the well-known antidepressant. A generic version of it came on the market in 2006, and it went through the usual FDA review. For generic drugs, the big question is bioequivalence: do they deliver the same ingredient in the same way as the originally approved drug and formulation? The agency requires generic drug applications to show proof of this for their own version.

For bupropion/Wellbutrin, the case is complicated by the two approved doses, 150mg and 300mg. The higher dose is associated with a risk of seizures, which made the FDA grant a waiver for its testing - they extrapolated from the 150mg data instead. And right about here is where the red flags began to go up. The agency began to receive reports, almost immediately, of trouble with the 300mg generic dose. In many cases, these problems (lack of efficacy and/or increased side effects) resolved when patients switched back to the original branded formulation. That link also shows the pharamacokinetic data comparing the two 150mg dosages (branded and generic), which turned out to have some differences, mostly in the time it took to reach the maximum concentration (the generic came on a bit faster).

At the time, though, as that link shows, the FDA decided that because of the complicated clinical course of depression (and antidepressant therapy) that they couldn't blame the reported problems on a difference between the two 300mg products. A large number of patients were taking each one, and the number of problems reported could have been explained by the usual variations:

The FDA considers the generic form of bupropion XL 300 mg (Teva Pharmaceuticals) bioequivalent and therapeutically equivalent to (interchangeable with) Wellbutrin XL 300 mg. Although there are small differences in the pharmacokinetic profiles of these two formulations, they are not outside the established boundaries for equivalence nor are they different from other bupropion products known to be effective. The recurrent nature of (major depression) offers a scientifically reasonable explanation for the reports of lack of efficacy following a switch to a generic product. The adverse effects (e.g., headache, GI disorder, fatigue and anxiety) reported following a switch were relatively few in number and typical of adverse drug events reported in drug and placebo groups in most clinical trials. . .

But they seem to have changed their minds about this. It appears that reports continued to come in, and were associated most frequently with the generic version marketed by Teva (and produced by Impax Pharmaceuticals). That FDA page I've quoted above is not dated, but appears to come from late 2007 or so. As it turns out, the agency was at that time asking Teva to conduct that missing bioequivalence study with their 300mg product. See Q12 on this page:

FDA continued to review postmarketing reports throughout 2007. In November 2007, taking into consideration reports of lack of efficacy, FDA requested that Impax/Teva conduct a bioequivalence study directly comparing Budeprion XL 300 mg to Wellbutrin XL 300 mg. The study protocol stipulated the enrollment of patients who reported problems after switching from Wellbutrin XL 300 mg to Budeprion XL 300 mg. Impax/Teva began the study, but terminated it in late 2011, reporting that despite efforts to enroll patients, Impax/Teva was unable to recruit a significant number of affected patients.

The agency apparently was continuing to receive reports of problems, because they ended up deciding to run their own study, which is an uncommon move. This got underway before Teva officially gave up on their study, which gives one the impression that the FDA did not expect anything useful from them by that point:

In 2010, because of the public health interest in obtaining bioequivalence data, FDA decided to sponsor a bioequivalence study comparing Budeprion XL 300 mg to Wellbutrin XL 300 mg. The FDA-sponsored study enrolled 24 healthy adult volunteers and examined the rate and extent of absorption of the two drug products under fasting conditions. In that study, the results of which became available in August 2012, Budeprion XL 300 mg failed to demonstrate bioequivalence to Wellbutrin XL 300 mg.

That FDA-sponsored study is what led to the recent decision to pull the Imapax/Teva 300mg product from the market. Their 150mg dosage is still approved, and doesn't seem to have been associated with any increased reports of trouble (despite the small-but-real PK differences noted above). And it's also worth noting that there are four other generic 300mg bupropion/Wellbutrin products out there, which do not seem to have caused problems.

How big a difference are we talking about here? There are several measurements that are used for measuring blood levels of a drug. You have Cmax, the maximum concentration that is seen at a given dosage, and there's also Tmax, the time at which that maximum concentration occurs. And if you plot blood levels versus time, you also get AUC (area under the curve), which is a measure of the total exposure that a given dose provides. There are a lot of ways these measurements can play out: a very quickly absorbed drug will have an early Tmax and a large Cmax, for example, but that concentration might come back down quickly, too, which could lead to a lower AUC than a formulation of the same drug (at the same nominal dose) that came on more slowly and spread out over a longer time period. To add to the fun, some drugs have efficacy that's more driven by how high their Cmax values can get, while others are more driven by how large the AUCs are. And in the case of bupropion/Wellbutrin, there's an additional complication: some of the drug's efficacy is due to a metabolite, a further compound produced in the liver after dosing, and such metabolites have their own PK profiles, too.

So in this case, it turns out that the AUC just missed on the low side. The FDA wants the statistical 90% confidence interval to fall between 80 and 125% compared to the original drug, and in this case the 90% CI was 77-96%. The Cmax was definitely lower, too - 90% CI was 65-87% of the branded product. And while the agency doesn't provide numbers for the metabolite, they also state that it missed meeting the standards as well. There are drugs, it should be said, that would still be effective at these levels, but Wellbutrin clearly isn't one of them.

My own take is that the FDA was willing to consider the adverse reports as just the usual noisy clinical situation with an antidepressant until the other generics were approved, at which point it became clear that the problems were clustering around the Impax/Teva product. Here's how the FDA addresses the "Why didn't we find out about this earlier?" question:

Q17. In retrospect, were FDA’s decisions regarding the approval and ongoing monitoring of Budeprion XL 300 mg appropriate?

A17. A less cautious approach in studying the bioequivalence of Budeprion XL 300 mg could have brought the data to light earlier. The FDA-sponsored study was completed only weeks ago, which is a very short time for data from a clinical experiment to be announced to the public.

Bupropion is associated with a risk for seizures, which was the basis of the Agency's cautious approach with regard to the early Budeprion XL bioequivalence studies, in which data were extrapolated from Budeprion XL 150 mg in patients to the projected consequences of exposure to Budeprion 300 mg. In retrospect, it is clear that this extrapolation did not provide the right conclusion regarding bioequivalence of Budeprion XL 300 mg. FDA also has much more knowledge today of the seizure-associated risk of bupropion-containing drugs. The trial design of the sponsor-initiated study of 2007 could have been successful, had it been replaced by the trial design employed in the recent FDA-sponsored study.

Of course, the trial design in the sponsor-initiated study of 2007 was that requested by the FDA. But Teva, for their part, does not appear to have been a ball of fire in getting that study recruited and completed, either. It's quite possible, though, that they couldn't round up enough patients who'd had trouble with the generic switch and were also willing to go back and experience that again in the cause of science. Overall, I think that the FDA is more on the hook here for letting things go on as long as they did, but there's plenty of blame to go around.

Still, I find this post at Forbes to be full of unnecessary hyperventilation. You wouldn't know, from reading it, that the FDA initially waived the requirement for 300mg testing in this case because of the risk of seizures. There's a line in there about how the agency is making patients their guinea pigs by not testing at the higher dose, but you could have scored the same debating points after a 300mg study that harmed its patients, which is what it looked at the time would happen. You also wouldn't know that the other generic 300mg formulations don't seem to have been associated with increased adverse-event reports, either.

And that post makes much of the way that these bioequivalence tests are left up the manufacturers. That they are: but if you want to change that, you're going to have to (1) fund the FDA at a much higher level, and (2) wait longer for generic switches to occur. The generic manufacturers will run these tests at the absolute first possible moment, since they want to get onto the market. The FDA will run them when they get around to it; they don't have the same incentives at all. Their incentives, in fact, oscillate between "Don't approve - there might be trouble" and "Definitely approve - we might be missing out on benefit". The winds of fortune blow the line between those two around all the time.

In this case, I think the FDA should have exercised its court-of-last-resort function earlier and more forcefully. But that's easy for me to say, sitting where I am. I don't have to see the mass of noisy adverse event reports coming in over the transom day after day. If the agency acted immediately and forcefully on every one, we'd have no drugs on the market at all. There's a middle ground, but boy, is it hard to find.

Comments (44) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs | The Central Nervous System

October 12, 2012

Another Prospective Alzheimer's Trial

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Posted by Derek

I wrote here about a prospective Alzheimer's trial that's starting soon among a population in Colombia, and now comes word of another large effort along the same lines. DIAN, the Dominantly Inherited Alzheimer's Network, will test several current Alzheimer's candidates in groups of people around the world with genetic mutations that make them susceptible to the disease. The hope is that these different mutations will provide a fast-forward-button look at the progress of Alzheimer's in the general population, and help to settle the question of which mechanisms (if any) are appropriate to fight it. They'll go two years of clinical observation (memory tests and brain imaging), and then the plan is to switch everyone to the most efficacious therapy and continue monitoring for real-world benefits.

Currently, it looks like there will be three candidates, with two from Eli Lilly: their beta-secretase inhibitor LY2886721, and their circulating-amyloid antibody Solanezumab, currently the subject of controversy about its efficacy or lack of same. The Roche antibody gantenerumab, which appears to bind more to amyloid that's already precipitated, completes the trio.

This is an excellent idea, and I'm very glad to see so much work being done on prospective trials like these. There's always the danger that working in genetic-mutation populations will give you an answer that's not generally applicable, but I think that we know enough about the specific mutations to make a call on that, should anything stand out. The worry, naturally, is that nothing will stand out. The DIAN trial and the Roche crenezumab trial in Colombia are all aimed at various parts of the amyloid hypothesis, which has been the dominant strain of thought in Alzheimer's etiology for decades. If nothing distinctive comes out of these efforts, that hypothesis will have taken some major hits - but they'll have to be major hits to damage it in the first place.

The best result will be if something looks useful in preventative or early-stage Alzheimer's. Second best would be a painful realization that the amyloid hypothesis is insufficient. And way down at the bottom would be a bunch of "Well, maybe. . ." clinical data showing that some of the agents seemed to help some of the patients, some of the time, to an extent, but maybe not enough to be effective by real-world standards. Anything but that, please.

Comments (10) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

October 11, 2012

GSK Opens Up Its Trial Data

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Posted by Derek

GlaxoSmithKline took an unusual step today: they announced that they're opening up clinical trial data:

"GSK is fully committed to sharing information about its clinical trials. It posts summary information about each trial it begins and shares the summary results of all of its clinical trials – whether positive or negative – on a website accessible to all. Today this website includes almost 4,500 clinical trial result summaries and receives an average of almost 10,000 visitors each month. The company has also committed to seek publication of the results of all of its clinical trials that evaluate its medicines – regardless of what the results say – to peer-reviewed scientific journals.

Expanding further on its commitments to openness and transparency, GSK also announced today that the company will create a system that will enable researchers to access the detailed anonymised patient-level data that sit behind the results of clinical trials of its approved medicines and discontinued investigational medicines. To ensure that this information will be used for valid scientific endeavour, researchers will submit requests which will be reviewed for scientific merit by an independent panel of experts and, where approved, access will be granted via a secure web site. This will enable researchers to examine the data more closely or to combine data from different studies in order to conduct further research, to learn more about how medicines work in different patient populations and to help optimise the use of medicines with the aim of improving patient care."

I very much applaud this step, and I very much hope that the rest of the industry follows suit. We're getting a lot of flack - and we deserve it - for the way that we handle clinical trial data, with accusations of cherry-picking, data-burying, and all the associated sins. (Ben Goldacre has a book out on the drug industry, which I'm going to read more of before posting on, and he's taken the industry to task on this very point in it). The only cure for this will be to open the books as much as possible - saying "Trust us" will not cut it, and (unfortunately), neither will trying to say "None of your business".

Here's a look at this idea from John Carroll at FierceBiotech. So, Pfizer, Novartis, Merck, all the rest of you? What's the response?

Comments (14) + TrackBacks (0) | Category: Clinical Trials | Why Everyone Loves Us

October 9, 2012

Lilly's Solanezumab: Did It Actually Work?

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Posted by Derek

"Hope Rises For Alzheimer's Treatment, Scientists Say". Not this scientist. That's a composite of headlines, but it captures the unfortunate tone.

We're talking about solanezumab, Eli Lilly's antibody therapy. The company presented analysis of their trial data yesterday, and put a very optimistic face on things. But wait, you say, didn't Lilly already report on this? And didn't the drug miss all its endpoints? Yes, indeed it did. But this is a secondary analysis by the Alzheimer's Disease Cooperative Study, a third-party look at the data. It's hard for me to imagine an optimistic take on the numbers that Lilly itself didn't find, to be honest, but here we have it:

But after a secondary analysis of the first study showed that there was a 42% reduction in the rate of cognitive decline among a subpopulation of patients in the solanezumab arm with only a mild form of the disease, investigators decided to hunt for confirmation of that endpoint in a second Phase III. They didn't find it, seeing the numbers fall short of statistical significance after switching from one measure (ADAS- Cog11) to another (ADAS-Cog14). But by "pooling" the data they came up with a 34% reduction in cognitive decline in that particular group. None of the data indicated a significant reduction in the rate of functional decline.

This looks to me like grasping at straws. I understand that people want to see any tiny edge of possible efficacy as an avenue for further research, but I can't help but think that the path to an effective Alzheimer's therapy would announce itself a bit more clearly than this. Anything should. Chasing after these sorts of results looks like the path to another Phase III trial that might just manage to miss its endpoints by an even narrower margin. The best one could hope for would be a therapy that might, possibly, help a few patients in the early stage of the disease a bit, for a while. Maybe.

The problem is that the pent-up need for anything effective in Alzheimer's is so great that vast hordes of people will likely rush to take anything - or put their aging relatives on anything - that might offer any shred of hope. And I know just where those people are coming from, and I sympathize greatly. Eli Lilly, for its part, is strongly motivated to have something in its large and expensive Alzheimer's portfolio actually work - the company is facing a very, very rough time with its patent expirations, and something like this is about the only thing that could pull them back from the cliff. On all sides, this is not a situation that encourages sound decision-making.

Comments (21) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

September 21, 2012

Transcelerate: What Is It, Exactly?

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Posted by Derek

A list of big pharma companies have announced that they're setting up a joint venture, Trancelerate, to try to address common precompetitive drug development problems. But that covers a broad area, and this collaboration is more narrowly focused:

Members of TransCelerate have identified clinical study execution as the initiative's initial area of focus. Five projects have been selected by the group for funding and development, including: development of a shared user interface for investigator site portals; mutual recognition of study site qualification and training; development of risk-based site monitoring approach and standards; development of clinical data standards; and establishment of a comparator drug supply model.

Now, that paragraph is hard to get through, I have to say. I understand what they're getting at, and these are all worthy objectives, but I think it could be boiled down to saying "We're going to try not to duplicate each other's work so much when we're setting up clinical trials and finding places to run them. They cost so much already that it's silly for us all to spend money doing the same things that have to be done every time." And other than this, details are few. The initiative will be headquartered in Philadelphia, but that seems to be about it so far.

But this it won't get at the fundamental problems in drug research. Our clinical failure rate of around 90% has very little to do with the factors that Transcelerate is addressing - what they're trying to do is make that failure rate less of a financial burden. That's certainly worth taking on, in lieu of figuring out why our drugs crash and burn so often. That one is a much tougher problem, easily proven by the fact that there are billions of dollars waiting to be picked up for even partial solutions to it.

Comments (18) + TrackBacks (0) | Category: Clinical Trials | Drug Development

September 10, 2012

Geron, And The Risk of Cancer Therapies

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Posted by Derek

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

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

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

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

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

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

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

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

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

August 31, 2012

Eli Lilly's Drumbeat of Bad News

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Posted by Derek

Eli Lilly has been getting shelled with bad news recently. There was the not-that-encouraging-at-all failure of its Alzheimer's antibody solanezumab to meet any of its clinical endpoints. But that's the good news, since that (at least according to the company) it showed some signs of something in some patients.

We can't say that about pomaglumetad methionil (LY2140023), their metabotropic glutamate receptor ligand for schizophrenia, which is being halted. The first large trial of the compound failed to meet its endpoint, and an interim analysis showed that the drug was unlikely to have a chance of making its endpoints in the second trial. It will now disappear, as will the money spent on it so far. (The first drug project I ever worked on was a backup for an antipsychotic with a novel mechanism, which also failed to do a damned thing in the clinic, and which experience perhaps gave me some of the ideas I have now about drug research).

This compound is an oral prodrug of LY404039, which has a rather unusual structure. The New York Times did a story about the drug's development a few years ago, which honestly makes rather sad reading in light of the current news. It was once thought to have great promise. Note the cynical statement in that last link about how it really doesn't matter if the compound works or not - but you know what? It did matter in the end. This was the first compound of its type, an attempt at a real innovation through a new mechanism to treat mental illness, just the sort of thing that some people will tell you that the drug industry never gets around to doing.

And just to round things off, Lilly announced the results of a head-to-head trial of its anticoagulant drug Effient versus (now generic) Plavix in acute coronary syndrome. This is the sort of trial that critics of the drug industry keep saying never gets run, by the way. But this one was, because Plavix is the thing to beat in that field - and Effient didn't beat it, although there might have been an edge in long-term followup.

Anticoagulants are a tough field - there are a lot of patients, a lot of money to be made, and a lot of room (in theory) for improvement over the existing agents. But just beating heparin is hard enough, without the additional challenge of beating cheap Plavix. It's a large enough patient population, though, that more than one drug is needed because of different responses.

There have been a lot of critics of Lilly's research strategy over the years, and a lot of shareholders have been (and are) yelling for the CEO's head. But from where I sit, it looks like the company has been taking a lot of good shots. They've had a big push in Alzheimer's, for example. Their gamma-secretase inhibitor, which failed in terrible fashion, was a first of its kind. Someone had to be the first to try this mechanism out; it's been a goal of Alzheimer's research for over twenty years now. Solanezumab was a tougher call, given the difficulties that Elan (and Wyeth/Pfizer, J&J, and so on) have had with that approach over the years. But immunology is a black box, different antibodies do different things in different people, and Lilly's not the only company trying the same thing. And they've been doggedly pursuing beta-secretase as well. These, like them or not, are still some of the best ideas that anyone has for Alzheimer's therapy. And any kind of win in that area would be a huge event - I think that Lilly deserves credit for having the nerve to go after such a tough area, because I can tell you that I've been avoiding it ever since I worked on it in the 1990s.

But what would I have spent the money on instead? It's not like there are any low-risk ideas crowding each other for attention. Lilly's portfolio is not a crazy or stupid one - it's not all wild ideas, but it's not all full of attempts to play it safe, either. It looks like the sort of thing any big (and highly competent) drug research organization could have ended up with. The odds are still very much against any drug making it through the clinic, which means that having three (or four, or five) in a row go bad on you is not an unusual event at all. Just a horribly unprofitable one.

Comments (26) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development | Drug Industry History | The Central Nervous System

August 24, 2012

Lilly's Solanezumab: A Miss or a Win?

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Posted by Derek

Lilly has reported results from its anti-amyloid antibody, solanezumab, and. . .well, it's mixed. And it's either quite good news, or quite bad. You make the call.

The therapy missed its endpoints (both "cognitive and functional", according to the company) in two clinical trials, so that's clearly bad news. Progression of Alzheimer's disease was not slowed. But I'll let the company's press release tell the tale from there:

The EXPEDITION1 study did not meet co-primary cognitive and functional endpoints in the overall mild-to-moderate patient population; however, pre-specified secondary subgroup analyses in patients with mild Alzheimer's disease showed a statistically significant reduction in cognitive decline. Based on those results, Lilly modified the statistical analysis plan (SAP) for EXPEDITION2 prior to database lock to specify a single primary endpoint of cognition in the mild patient population. This revised primary endpoint did not achieve statistical significance.

Now, this news - what you've just read above - actually is sending Lilly's stock up as I write this, which tells you how beaten-down Eli Lilly investors are, or how beaten-down investors in Alzheimer's therapies are. Or both. The headlines are all about how the drug missed in these trials, but that the company sees some hope. But man, is it ever a faint one.

What I'm taking away from the company's statement is that they had a cognition endpoint defined at the beginning of the trial (as well they should). We can assume that it was not a wildly optimistic one; no one is wildly optimistic in this field. And solanezumab missed it in the first Phase III data. But the patients with milder Alzheimer's, when they looked more closely, showed a trend towards efficacy, so they modified the endpoints (that is, lowered the bar and narrowed down to a select population) in the data for the second Phase III before it finished up. And even then, the antibody missed. So what we have are trends, possible trends, but nothing that really gets to the level of statistical significance.

But note, they're talking cognitive efficacy, and there's nothing said about those functional endpoints. If I'm interpreting this right, that means that there was a trend towards efficacy in tests like remembering words and lists of numbers, but not a trend when it came to actually performing better in real-life circumstances. Am I seeing this correctly? Lilly will be presenting more data in October, and we'll know more then. But I'm not getting an optimistic feeling from all this.

I assume that the company is now talking about going back and rounding up a population of the mildest Alzheimer's patients it can find and giving solanezumab another shot. Given Lilly's pipeline and situation, I suppose I'd do the same thing, but this is really a back-to-the-wall move. I think that you'd want to see something in a functional endpoint to really make a case for the drug, for one thing, and out in the real world, diagnosing Alzheimer's that early is not so easy, as far as I know. Good luck to them, but they are really going to need it.

Comments (59) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

August 14, 2012

Is Ampyra Any Good?

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Posted by Derek

I wrote here about Ampyra, the multiple sclerosis drug from Acorda Therapeutics, one that came close to the record for "simplest chemical matter in a marketed drug". (As it happens, Biogen Idec is making sure that it doesn't even have the title of "simplest drug for multiple sclerosis", and the shadow of valproic acid looms over this entire competition).

That post mentioned some doubts that had been expressed about how effective Ampyra is for its target: improving gait in MS patients. And now those doubts are increasing, because the company has been asked to conduct a trial of a lower 5 mg dose of the drug along with the approved 10 mg one (which was associated with seizures in some patients). And neither one of them met the primary endpoint. As that link shows, the company has several explanations - different endpoint than used before, higher placebo response than usual, wider variety of patients - but those are all ex post facto. Acorda wouldn't have set up the trial like this in the first place if they didn't think that the approved dose would work, and it didn't.

For a drug with a rather narrow symptomatic indication, that's not good news. And it comes as Acorda is still trying to get the compound approved in Europe. The cost/benefit ratio usually can't stand a big hit to the "benefit" term.

Comments (11) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs | The Central Nervous System

August 8, 2012

Does Aveo's Tivozanib Work, or Not?

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Posted by Derek

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

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

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

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

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

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

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

August 7, 2012

Bapineuzumab Still Does Not Work Against Alzheimer's

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Posted by Derek

As expected (by all but the most relentlessly optimistic observers), the anti-Alzheimers antibody bapineuzumab has now failed in its most likely patient population. Results came out last night about from patients who do not carry the ApoE4 mutation, the only group that seemed to offer hope in earlier clinical trials. The therapy missed its endpoints versus placebo, and according to Pharmalot, subgroup analysis offered no hope that there was some further fraction of patients that might be responding. (You would have had to have been a pretty hardy investor to carry on even if something had shown up).

But apparently Pfizer and J&J are those hardy investors, because (as that link shows), they're apparently going on with an already-in-progress Phase II study of the antibody dosed subcutaneously. That baffles me - I don't know enough about antibody dosing to say if that makes a difference, but it seems odd to think that it would. And clinical work on another active immunization therapy is going on as well (as opposed to dosing a pre-made antibody).

Good luck to them on that - I mean that sincerely, because the Alzheimer's field needs any successes it can find. The immunological approach has been a long and hard one, and hasn't delivered much encouragement so far. But on the other hand, it's immunology, which means that it's still a wild black box in many ways and capable of all kinds of unexpected results. But that said, it's still hard to imagine that Eli Lilly's competing antibody solanezumab has much chance of working, at this point. We'll hear about that one soon, and I very much expect to be using the phrase "missed endpoints" again. I might be using the phrase "subgroup analysis", though, in which case the phrase "more money" will also make an appearance.

Comments (18) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

July 25, 2012

When Is A Company Shading the Truth About Its Clinical Trials?

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Posted by Derek

I wanted to point out this fine piece by Adam Feuerstein, "How to Tell When a Drug Company Fibs About Clinical Trial Results". The points he makes apply especially to small companies trying to stay afloat, but they can show up anywhere.

You need to look at when the trial started (and thus how long it took, relative to how long it should have taken), what the stated endpoints were before the trial, the time points at which these benefits (real and otherwise) occurred, and how the current trial results match up with previous ones. One general rule that I have, which Feuerstein also notes, is that when a company makes a big deal out of their investigational drug being safe/well-tolerated in a Phase II trial, that's a red flag. It's certainly a good thing that the drug was tolerated, but finding that out is not the point of Phase II.

But as the article details, clinical endpoints are where a lot of the hand-waving goes on. If a trial is designed well at all, it's run to look for the most clinically relevant signs that the investigators can think up - the ones that are going to make the patients, the physicians, the regulatory agencies, and the investors pay attention. And if a trial concludes and the company starts talking instead about various other benefits and trends that were seen in the data, while not making as big a deal out of the previously stated endpoints, well. . .there's a reason for that. It's not a good reason, and may not even be a very honorable one, but believe it, there is a reason.

Comments (15) + TrackBacks (0) | Category: Clinical Trials | The Dark Side

July 24, 2012

Bapineuzumab Does Not Work Against Alzheimer's

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Posted by Derek

This long, long story may finally be coming to an end. Immune-based therapies against beta-amyloid (and the associated amyloid plaques) have been in development for many years now (an excellent review here), and Elan has been in the thick of it for most of that time. Phase II results for this antibody came out in 2008 (here's the publication), and since then, everyone's been waiting to see if anything good would come of the phase III trials.

But not with a lot of hope. That's because the Phase II data weren't too encouraging, press releases aside. The subset of patients with without the ApoE4 mutation showed what appeared to be some slowing in their rate of deterioration; the patients with have that mutation showed basically no beneficial effects at all (edited, got this reversed at first - DBL). There was a bit of biomarker data released earlier this year, which didn't convince people much one way or another. And now we have the numbers for the first of four Phase III trials.

Endpoints were not met - bapineuzumab seems to have definitely failed to help the patients in this study. Note that these were mild-to-moderate Alzheimer's patients who carry the ApoE4 mutation. There's another study going on with non-carriers, and two similar studies to these going on outside the US, but after this miss, what are the chances that they'll report anything beneficial? No, if we were going to see something, you'd think that we'd have seen it here. Edit: not necessarily so, because the only hints of efficacy in Phase II were in ApoE4 noncarriers. But that wasn't all that convincing, and my own advice is still not to get any hopes up for the results of the next study).

There's another odd feature to this news: Elan was working with Wyeth, who were acquired by Pfizer. They then signed another development deal with J&J (Janssen) to spread the risk around. The trial results that came out yesterday were from the Janssen end of things (Pfizer's paying for the outside-the-US trials). But the press release was from Pfizer - as far as I can see, J&J has not sent out anything yet. And as for Elan, their press release is titled: "Elan Announces Pfizer’s Release of A Top-Line Result In First Of Four Bapineuzumab Phase 3 Trials". It says nothing about what that result might be - just that Pfizer released it, and it reminds people that more results are coming. Hmm. Was it agreed on that Pfizer would be the people to release these results? Or is that the sound of gritted teeth in the distance?

One other question: will this result finally shake the faith of the people who've been buying Elan stock all these years? Or was the failure of patients to respond the fault of hedge funds and short sellers instead? You know, the usual suspects. . .

Comments (21) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

July 16, 2012

AstraZeneca Admits It Spent Too Much Money

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Posted by Derek

Looks like AstraZeneca's internal numbers agree with Matthew Herper's. The company was talking about its current R&D late last week, and this comment stands out:

Discovery head Mene Pangalos told reporters on Thursday that mistakes had been in the past by encouraging quantity over quality in early drug selection.

"If you looked at our output in terms of numbers of candidates entering the clinic, we were one of the most productive companies in the world, dollar for dollar. If you rated us by how many drugs we launched, we were one of the least successful," he said.

Yep, sending compounds to the clinic is easy - you just declare them to be Clinical Candidates, and the job is done. Getting them through the clinic, now, that's harder, because at that point you're encountering things that can't be rah-rah-ed. Viruses and bacteria, neurons and receptors and tumor cells, they don't care so much about your goals statement and your Corporate Commitment to Excellence. In the end, that's one of the things I like most about research: the real world has the last laugh.

The news aggregator Biospace has a particularly misleading headline on all this: "AstraZeneca Claims Neuroscience Shake-Up is Paying Off ; May Advance at Least 8 Drugs to Final Tests by 2015". I can't find anyone from AZ putting it in quite those terms, fortunately. That would be like saying that my decision, back in Boston, to cut costs by not filling my gas tank is paying off as I approach Philadelphia.

Comments (27) + TrackBacks (0) | Category: Business and Markets | Clinical Trials | Drug Development

June 29, 2012

The CETP Rogues Gallery

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Posted by Derek

Has there ever been a less structurally appealing class of drugs than the cholesteryl ester transfer protein (CETP) inhibitors? Just look at that bunch. From left to right, that's Pfizer's torcetrapib (which famously was the first to crash and burn back in 2006), Roche's dalcetrapib (which was pulled earlier this year from the clinic, a contributing factor to the company's huge recent site closure), Merck's anacetrapib (which is forging on in Phase III), Lilly's evacetrapib (which when last heard from was also on track to go into Phase III), and a compound from Bristol-Myers Squibb, recently published, which must be at least close to their clinical candidate BMS-795311.


Man, is that ever an ugly-looking group of compounds. They look like fire retardants, or something you'd put in marine paint formulations to keep barnacles from sticking to the hull. Every one of them is wildly hydrophobic, most are heavy on aromatic rings, and on what other occasion did you ever see nine or ten fluorines on one drug molecule? But, as you would figure, this is what the binding site of CETP likes, and this is what the combined medicinal chemistry talents of some of the biggest drug companies in the world have been driven to. You can be sure that they didn't like it, but the nice-looking compounds don't inhibit CETP.

Will any of these fancy fluorocarbon nanoparticles make it through to the market, just on properties/idiosyncratic toxicity concerns alone? How do their inhibitory mechanisms differ, and what will that mean? Is inhibiting CETP even a good idea in the first place, or are we finding out yet more fascinating details about human lipoprotein handling? Money is being spent, even as you read this, to find out. And how.

Comments (22) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology

May 17, 2012

A Preventative Trial for Alzheimer's: The Right Experiment

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Posted by Derek

Alzheimer's disease is in the news, as the first major preventative drug trial gets underway. I salute the people who have made this happen, because we're bound to learn a lot from the attempt, even while I fear the chances for success are not that good.

A preventative trial for Alzheimer's would, under normal circumstances, be a nightmarish undertaking. The disease is quite variable and comes on slowly, and it's proven very difficult to predict who might start to show symptoms as they age. You'd be looking at dosing a very large number of people (thousands, even tens of thousands?) for a very long time (years, maybe a decade or two?) in order to have a chance at statistical significance. And you would, in the course of things, be giving a lot of drug to a lot of people who (in the end) would have turned out not to need it. No, it's no surprise that no one's gone that route.

But there's a way out of that impasse: find a population with some sort of amyloid-pathway mutation. Now you know exactly who will come down with symptoms, and (unfortunately) you also know that they're going to come down with them earlier and more quickly as well. There are several of these around the world; the "Swedish" and "Dutch" mutations are probably the most famous. There's a Colombian mutation too, with a well-defined patient population that's been studied for years, and that's where this new study will take place.

About 300 people will be given an experimental antibody therapy to amyloid protein, crenezumab. This was developed by AC Immune in Switzerland and licensed to Genentech, and is one of many amyloid-targeted antibodies that have come along over the years. (The best-known is bapineuzumab, currently in Phase III). Genentech (Roche) will be putting up the majority of the money for the trial ($65 million, with $16 million from the NIH and $15 million in private foundation money). Just in passing, weren't some people trying to convince everyone a year ago that it only costs $43 million total to develop a new drug? Har, har.

100 people with the mutation will get the antibody every two weeks, and 100 more will get placebo. There are also 100 non-carriers mixed in, who will all get placebo, because some carriers have indicated that they don't want to know their status. Everyone will go through a continuing battery of cognitive and psychological tests, as well as brain imaging and a great deal of blood work, which (if we're lucky) could furnish tips towards clinical biomarkers for future trials.

So overall, I think that this trial is an excellent idea, and I very much hope that a lot of useful information comes out of it. But I've no firm hopes that it will pan out therapeutically. This will be a direct test of the amyloid hypothesis for Alzheimer's, and although there's a tremendous amount of evidence for that line of thought, there's a lot against it as well. Anyone who really thinks they know what will happen in this situation hasn't thought hard enough about it. But that's the best kind of experiment, isn't it?

Comments (18) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Drug Development

May 7, 2012

The CETP Saga Continues (And It's Not Getting More Entertaining)

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Posted by Derek

Roche has halted trials of its CETP inhibitor dalcetrapib. Many will remember the Pfizer compound in this class, torcetrapib, which went down catastrophically in Phase III back in 2006. In that case, deaths in the treatment group were higher than the placebo group, which will bring you to a screeching halt every time. The generally accepted story is that the compound's effects on blood pressure (and possibly electrolyte balance) negated its beneficial effects on lipoproteins. But was torcetrapib actually working? It certainly raised HDL levels - but is that enough?

You have to wonder. Dalcetrapib wasn't taken out by toxicity - it was dropped because of "a lack of clinically meaningful efficacy". Analysis of several Phase II trials seems to have shown no beneficial outcome in cardiovascular mortality and mobidity. So what is it that we don't know about CETP, about HDL, and about lipoprotein roles in cardiovascular disease in general? Quite a bit, is my guess.

Two companies that are very, very much pondering that question are Merck and Eli Lilly, both with competing CETP inhibitors in the clinic. Expect statement from each of them that they continue to have confidence in their clinical candidates. But behind the scenes, expect a lot of very intense re-evaluation.

Comments (32) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials

April 23, 2012

Making Their Own ALS Drug

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Posted by Derek

We should expect to see more of this sort of thing. The Wall Street Journal headline says it all: "Frustrated ALS Patients Concoct Their Own Drug". In this case, the drug appears to be sodium chlorite, which is under investigation as NP001 by Neuraltus Pharmaceuticals in Palo Alto. (Let's hope that isn't one of their lead structures at the top of their web site).

It is an accepted part of scientific lore that scientists sometimes use themselves in experiments, and cancer patients and others with life-threatening illnesses are known to self-medicate using concoctions of vitamins, special teas, and off-label medications. But the efforts of patients with ALS to come up with a home-brewed version of a drug still in early-stage clinical trials and not approved by the FDA is one of the most dramatic examples of how far the phenomenon of do-it-yourself science has gone.

A number of patients who have been involved in the Phase II trials of NP001 have been sharing information about it, and they and others have dug into the literature enough to be pretty sure that what Neuraltus is investigating is, indeed, some formulation of sodium chlorite. Here's one of them:

Mr. Valor first read about NP001 in a news release. He tracked down published papers that led him to believe the compound was sodium chlorite, a chemical that in various forms is used in municipal water treatment plants. A friend found online the scientists' patent filings. He also consulted an engineer in water treatment to learn more and read environmental reports to get insight into toxicity levels. The chemical is easy to order online and is inexpensive. He estimates he has spent less than $150 total.

Mixed in distilled water, the sodium chlorite is delivered through Mr. Valor's feeding tube three days a week, one week per month. He says he cautions participants that the chemical isn't as efficacious as NP001 and "that this is only to buy time until NP001 is available to all."

This case is the prefect situation for something like this to happen: a terrible disease, with an unfortunately fast clinical course, rare enough for a good fraction of the patient population to be very organized, along with an easily-available active agent. If NP001 were some sort of modified antibody, we wouldn't be having this discussion (although eventually, who knows?) And as much as I agree that Phase II and Phase III trials are necessary to find out if something really works or not, if I had ALS myself, I'd be doing what these people are doing, and if it were a family member affected, I'd be helping them mix the stuff up. With a condition like ALS, honestly, the risk/benefit ratio is pretty skewed.

If NP001 progresses, look for comment along the lines of "How can this little company get a patent on the use of this common chemical for this dread disease?" But as the WSJ article reports, the sodium chlorite mixtures that people are whipping up in their kitchens don't seem to be as effective as whatever NP001 is, for one thing. And Neuraltus is basically much of their existence on whether it works or not; they're taking on the risk and trouble of a proper investigation, and good for them. But it's true that many people who have ALS right now will not be around to see the end of a Phase III trial, and I can't blame them at all for doing whatever they can to try to get some of the benefits of this research in the interim.

Comments (23) + TrackBacks (0) | Category: Clinical Trials | The Central Nervous System

April 10, 2012

Biomarker Caution

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Posted by Derek

After that news of the Stanford professor who underwent just about every "omics" test known, I wrote that I didn't expect this sort of full-body monitoring to become routine in my own lifetime:

It's a safe bet, though, that as this sort of thing is repeated, that we'll find all sorts of unsuspected connections. Some of these connections, I should add, will turn out to be spurious nonsense, noise and artifacts, but we won't know which are which until a lot of people have been studied for a long time. By "lot" I really mean "many, many thousands" - think of how many people we need to establish significance in a clinical trial for something subtle. Now, what if you're looking at a thousand subtle things all at once? The statistics on this stuff will eat you (and your budget) alive.

I can now adduce some evidence for that point of view. The Institute of Medicine has warned that a lot of biomarker work is spurious. The recent Duke University scandal has brought these problems into higher relief, but there are plenty of less egregious (and not even deliberate) examples that are still a problem:

The request for the IOM report stemmed in part from a series of events at Duke University in which researchers claimed that their genomics-based tests were reliable predictors of which chemotherapy would be most effective for specific cancer patients. Failure by many parties to detect or act on problems with key data and computational methods underlying the tests led to the inappropriate enrollment of patients in clinical trials, premature launch of companies, and retraction of dozens of research papers. Five years after they were first made public, the tests were acknowledged to be invalid.

Lack of clearly defined development and evaluation processes has caused several problems, noted the committee that wrote the report. Omics-based tests involve large data sets and complex algorithms, and investigators do not routinely make their data and computational procedures accessible to others who could independently verify them. The regulatory steps that investigators and research institutions should follow may be ignored or misunderstood. As a result, flaws and missteps can go unchecked.

So (Duke aside) the problem isn't fraud, so much as it is wishful thinking. And that's what statistical analysis is supposed to keep in check, but we're got to make sure that that's really happening. But to keep everyone honest, we also have to keep everything out there where multiple sets of eyes can check things over, and this isn't always happening:

Investigators should be required to make the data, computer codes, and computational procedures used to develop their tests publicly accessible for independent review and ensure that their data and steps are presented comprehensibly, the report says. Agencies and companies that fund omics research should require this disclosure and support the cost of independently managed databases to hold the information. Journals also should require researchers to disclose their data and codes at the time of a paper's submission. The computational procedures of candidate tests should be recorded and "locked down" before the start of analytical validation studies designed to assess their accuracy, the report adds.

This is (and has been for some years) a potentially huge field of medical research, with huge implications. But it hasn't been moving forward as quickly as everyone thought it would. We have to resist the temptation to speed things up by cutting corners, consciously or unconsciously.

Comments (14) + TrackBacks (0) | Category: Biological News | Clinical Trials

March 2, 2012

Stem Cells in Texas: Quite the Business

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Posted by Derek

I (and many of the readers here) have long thought that stem cells are perhaps the most overhyped medical technology out there - at least for now. I definitely agree that the possibilities for their use are staggering, and I very much hope that some of these pan out, but the gap between those possibilities and the current reality is just as huge. And it's a gap that really shows how hard medical progress is compared to how hard it is in the public imagination.

Nature has an article that bears on this, and on some other important topics. They've found that stem cell treatments are being sold to patients in Texas.

(The investigation) suggests that (Celltex Therapeutics) has supplied adult stem cells to Texas doctors who offer unproven treatments to patients, and that the company is involved in these treatments. One doctor claims that the treatments are part of a clinical study run by Celltex and that the company pays him US$500 a time to inject the cells into patients, who are charged up to $25,000 for a course. The US Food and Drug Administration (FDA) considers it to be a crime to inject unapproved adult stem cells into patients. David Eller, chief executive of Celltex, denies that the company is involved in treatment procedures, but would not comment on Nature's findings about how its cells are used or answer questions about them.

This makes me wonder about what is going on down there in Texas (and I can tell you, as an Arkansan, I'm willing to believe just about anything in that department). This latest business reminds me of the Burzynski cancer treatment stuff, in the way that definitions of "clinical trial" are stretched like rubber bands. Personally, I think that clinical trials are supposed to follow something very much like Yog's Law in publishing ("Money flows towards the writer"). If you're being asked to put up all kinds of money to get your book edited and published, you're very likely being scammed. And if you're being asked to pay thousands of dollars to be in a "clinical trial", well. . .you're being sold something. Real clinical trials reimburse their patients for time and effort, with money and/or medical care. They do not bill them for 25 long ones at the end of the dosing schedule

I should mention here that Slate also had an article up on Celltex, but there have been some problems. They've taken the piece down, citing editorial problems, but (as you'd figure), the cherchez le lawsuit rule applies here. Nature, though, doesn't seem to be getting sued for what they've written.

Now, back to the stem cell treatments. Among other things, Nature mentions a blog by a woman in Texas, who's written about her experiences being treated with adult stem cells from Celltex. It appears that she's receiving these treatments for multiple sclerosis, and was told that "This method has been successful with auto immune diseases such as Parkinson’s, arthritis, Multiple Sclerosis as well as others." She had apparently had a similar procedure done earlier in Mexico, but then:

". . .a friend told Larry about a doctor in Houston who went to South Korea two years ago for a stem cell transplant to treat the debilitating effects of psoriatic arthritis. He is now able to continue his medical practice, perform surgeries, and live without pain. Because our friends had noticed progress from my first stem cell transplant, they wanted us to know that Dr. Jones was now licensed to perform the procedure in Houston. To say the least, we were both excited about the possibilities and timing."

As that extract illustrates, at no point (that I have found) does this patient mention the phrase "clinical trial". One gets the strong impression, actually, that she believes that she is paying to undergo a new medical procedure, the latest thing, rather than participating in any kind of investigational study for a therapy that has not yet been reviewed by the FDA. The Nature writer, David Cyranoski, was able to speak with the physician involved, who says he's treated a number of people with cells from Celltex:

Lotfi says that most of his patients claim to get better after the treatment, but he admits that there is no scientific evidence that the cells are effective. “The scientific mind is not convinced by anecdotal evidence,” he acknowledges. “You need a controlled, double-blind study. But for many treatments, that's not possible. It would take years, and some patients don't have years.”

“The worst-case scenario is that it won't work,” he adds. “But it could be a panacea, from cosmetics to cancer.” He says that Celltex is conducting a trial in which patients “will be their own control”. “If you can compare before and after and show improvement, there's no need for a placebo,” he explains. “How can you charge people, and then give them a placebo?”

Indeed! Maybe you could try not charging them, and not making them spend their own money to find out whether your treatment is any good. Maybe you could get a large, statistically significant number of people together, who've been given thorough diagnostic workups, and give half of them the best standard of care for multiple sclerosis and half of them the stem cell treatment - at your expense - and see if they get better. How about that? (Oh, and just a little note - the worst case is not that nothing happens at all. It might be good for the people involved to think about that a bit).

This gets back to the discussions we've had around here about rethinking clinical trials. One of the things I'll say for the FDA is that they do force people to be rigorous, and to put new medical ideas to well-controlled tests. My worry about the "sell, then test" ideas was summed up in the first link in this paragraph: "I fear that there are any number of entrepreneurial types who would gladly stretch things out, as long as someone else is paying, in the hopes of finally seeing something useful. No one will - or should - pay for extending fishing expeditions." Read that Celltex article and see if that sounds familiar.

Comments (16) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs | The Central Nervous System | The Dark Side

February 29, 2012

Bias in Industry-Funded Trials in Rheumatoid Arthritis?

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Posted by Derek

The title of this one says it all: "Association of industry funding with the outcome and quality of randomized controlled trials of drug therapy for rheumatoid arthritis". Any number of critics of the drug business will tell you what that association is: we publish the good stuff and bury the bad news, right?

Well, not so much in arthritis, apparently. The authors identified 103 recent clinical trials in the area, over half of them industry-funded. But when it came to outcomes, things were pretty much the same. Trials from the three largest classes of funding (industry, nonprofit, and "unspecified") all tended to strongly favor the tested drug, although the small number (six) of mixed-funding trials ended up with two favoring and four against. The industry-run trials tended to have more subjects, while the nonprofit ones tended to run longer. The industrial trials also tended to have a more complete description of their intent-to-treat and workflow. As you'd figure, the industrial trials tended to be on newer agents, while the others tended to investigate different combinations or treatment regimens with older ones. But the take-home is this:

No association between funding source and the study outcome was found after adjustment for the type of study drug used, number of study center, study phase, number of study subject, or journal impact factor. . .

. . .Though preponderance of data in medical literature shows that industry funding leads to higher chances of pro-industry results and conclusions, we did not find any association between the funding source and the study outcome of "published" (randomized clinical trials) of RA drug therapies.

The one worrying thing they did find was a trend towards publication bias - the industry-sponsored studies showed up less often in the literature. The authors speculate as to whether these were trials with less favorable outcomes, but didn't have enough data to say one way or another. . .

Comments (5) + TrackBacks (0) | Category: Clinical Trials | The Dark Side | The Scientific Literature

February 15, 2012

Eschenbach Says Market, Then Test

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Posted by Derek

Ex-Intel chief Andy Grove's idea to reform clinical trials didn't get much of a reception around here, although (in the end) I was more receptive to the idea than many people were (the comments to the posts here followed similar lines).

So it's quite interesting to see former FDA commissioner Andy Eschenbach making what sounds like a very similar pitch in the Wall Street Journal. It's near the end of an op-ed about reforming the FDA, and it goes like this:

Breakthrough technologies deserve a breakthrough in the wa the FDA evaluates them. Take regenerative medicine. If a company can grow cells that repair the retina in a lab, patients shouldn't have to wait years while the FDA asks the company to complete laborious clinical trials proving efficacy. Instead, after proof of concept and safety testing, the product could be approved for marketing with every eligible patient entered in a registry so the company and the FDA can establish efficacy through post-market studies.

There are several ways to look at that idea. One is to translate it into less editorial language and propose that "Patients (and their insurance companies) should be able to pay to try therapies before they're proven to have worked, as long as that proof is forthcoming". That's not prima facie a crazy idea, but it's subject to the same sorts of objections as Grove's earlier proposal. The post-marketing data will likely be of lower quality than a properly run clinical trial, and it will be harder to use it to establish efficacy. On the other hand, useful therapies would get into the hands of patients faster than happens now, and the expense of drug development would (presumably) go down. But useless therapies would also get into the hands of patients faster than happens now, too, and that's something that we're not currently equipped to deal with.

Any such scheme is going to have to deal with the legal aspect. People don't currently feel as if they're enrolled in a clinical trial when a new drug is offered for sale (although perhaps they should), and it's going to take some doing to make clear that an investigative therapy is just that. Will patients sue, or try to sue, if it doesn't work? If it goes further than that and causes actual harm? I'm thinking of Lilly's gamma-secretase inhibitor that actually seemed to make Alzheimer's worse - how do we handle things like that?

What about the insurers? Will they be happy to have the costs of a Phase III trial offloaded onto them? Not likely. There's also the question of what therapies will get to hop onto this conveyor belt: how much proof-of-concept will be needed? Will that be for the insurers to decide, what investigational drugs they're willing to pay for, so that data can be obtained?

And about that data - it would be of great importance to establish, up front, just what sort of endpoint is being sought. Clear criteria would need to be established (both positive and negative) so that a regulatory decision could be reached in a reasonable time frame. Otherwise, I fear that there are any number of entrepreneurial types who would gladly stretch things out, as long as someone else is paying, in the hopes of finally seeing something useful. No one will - or should - pay for extending fishing expeditions.

Even after all these objections, I can still see some merit in the whole idea. But the question is, after you take all the objections into account (and there are surely more), how much merit is left over? It's not as clear-cut a case as Eschenbach (or Grove) would have a person believe. . .

Some early reactions to Eschenbach's proposal are here and here. There are, I should note, a few other aspects to his op-ed that will be subject of another post.

Update: John LaMattina has similar views.

Comments (30) + TrackBacks (0) | Category: Clinical Trials

January 5, 2012

Reaction to Andy Grove's Clinical Trial Proposals

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Posted by Derek

I should mention that Science is publishing some letters that it received in response to Andy Grove's proposal to rework the clinical trial system for drug development.

Sidney Wolfe and Michael Carome of Public Citizen aren't too happy with the idea, as you might expect. Their take, as I would reword it, could be summarized as "Hey, the existing system allows the drug industry to spew unsafe crap all over the market, and this would make it even worse". Actually, the language in their letter isn't far off:

A. Grove proposes returning to the era before the enactment of the 1938 Federal Food, Drug, and Cosmetic Act, when new drugs were marketed in the United States without evidence that they were safe or effective. His irrational and dangerous proposal, which would limit the Food and Drug Administration's (FDA) premarket review of new drugs to phase 1 clinical trials, is premised on the fundamental misunderstanding that such trials can provide proof of a drug's safety and on the misguided belief that it is not necessary to establish proof of efficacy. . .

Grove's proposal would subject patients on a massive scale to haphazard, uncontrolled, poorly regulated experimentation involving drugs with unknown safety and effectiveness. Such a flawed proposal does not deserve serious consideration.

Norman Marcus of the Virginia Cartilage Institute is more even-tempered, and his view is closer to my own blog post:

. . .Grove's proposed system needs some fine-tuning.

Grove correctly leaves the safety issues to the FDA, but he does not address dosage issues, which should also be determined before distribution. He does not explore how virtual clinical research organizations of the future would monitor issues of compliance and establish fair methods of measuring response. Replacing the heralded phase 3 trial with a self-administered trial would indeed save money and introduce the product much sooner to at least part of the potential market, but pharmaceutical companies would need some shielding of liability to protect them from the increased risks inherent in this plan. Because patients and third-party payers would undoubtedly see the new drugs as experimental, the pharmaceutical companies should be required to offer them at nominal cost.

That said, experimenting (carefully) is exactly what we should be doing. . .

Finally, David Borhani and J. Adam Butts (of DE Shaw Research) go right to what I've named the Andy Grove Fallacy:

. . .Compared to the semiconductor industry's gains over the past 50 years, the pharmaceutical industry's productivity must seem disappointing. There exists, however, an important distinction between engineering integrated circuits and discovering drugs. The semiconductor industry's realization of Moore's Law has always benefited from a fundamental understanding of solid-state physics. Conversely, we still don't know how living organisms work; new “components,” as well as interactions between well-known components, are discovered daily. . .This ignorance is the real reason why 90% of drug candidates fail in clinical trials: They simply don't work. The trial process is doing just what we ask of it.

None of these are unexpected reactions, and I'm sure that Grove himself has heard them before (and anticipated these). So where does this leave us? Status quo ante, with everyone having stated their positions?

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

December 5, 2011

Rexahn Rides Again

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Posted by Derek

You may remember Rexahn Pharmaceuticals being mentioned here in 2010. They're the company whose lead antidepressant drug Serdaxin showed no significance versus placebo in Phase IIa trials, and whose CEO (Dr. Ahn himself) then calmed the investment community by saying that the trial was never designed to show any statistical significance, anyway, and was therefore a success. You know, because it showed that patients could benefit from the drug, even though it didn't show that patients could benefit from the drug. You may think I'm exaggerating, but go back and read Ahn's statement and see if you still think that.

And when you do, you'll discover that Serdaxin is nothing else than clavulinic acid, the beta-lactamase inhibitor, and not the first thing you'd think of as a CNS agent. But Rexahn has pushed on to Phase IIb with it, and this time they seem to actually have been going all the way, looking for a statistically meaningful effect and everything. That hasn't gone so well, although the press release does what it can:

The randomized, double-blind, placebo-controlled study compared two doses of Serdaxin, 0.5 mg and 5 mg, to placebo over an 8-week treatment period. Results from the study did not demonstrate Serdaxin’s efficacy compared to placebo measured by the Montgomery-Asberg Depression Rating Scale (MADRS). All groups showed an approximate -14 point improvement in the protocol defined primary endpoint of MADRS. All groups had a substantial number of patients who demonstrated a meaningful clinical improvement from baseline. The study showed Serdaxin to be safe and well tolerated.

What really attracts me to this follow-up is another quote from Dr. Ahn: "These results contradict findings from previous studies of Serdaxin in depression, which is disappointing", he stated. Those previous studies, of course, are the ones that didn't reach significance, either, so I'd say that the latest results are right in line. But then, I have a different outlook on life. Serdaxin doesn't look like it'll do much for me, though.

Comments (12) + TrackBacks (0) | Category: Clinical Trials | The Central Nervous System

November 8, 2011

Targacept's Antidepressant Fails, And How

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Posted by Derek

Bad news yesterday from Targacept, a small company that's been developing an antidepressant with AstraZeneca. TC-5214 (the S enantiomer of the nicotinic ligand mecamylamine) missed its endpoints in a trial of 295 patients in Europe who had not responded to standard drug therapy - the trial started with more like 700 patients, who received open-label therapy with one of the usual agents, and then they picked out the tough cases for the real trial, adding this compound to the standard regimens.

Seeing results in such a population is a very tall order, but that's why AZ and others were excited about the earlier Targacept data. The Phase II numbers were extraordinary. A compound that followed through on that promise would be huge. This piece by Adam Feuerstein gets across the excitement - people really couldn't believe what they were seeing.

And maybe they shouldn't have. The grumbling today, though, is taking an interesting turn. What you might not realize from reading about those Phase II results is that they were the result of a clinical trial in India. That's added an extra layer of can-we-trust-this-stuff to the usual despairing comments about Phase II/Phase III disconnects. This is an unusually brutal disconnect, because the earlier data were unusually good. So the muttering is not going to go away any time soon.

AstraZeneca says that they're committed to further studies of TC-5214, so we'll see what happens then. Depression is a tricky illness, and getting solid clinical data isn't easy. It's possible that this latest study just had some confounding variable that messed up the numbers - but then, it's possible that the earlier one did, too, and that, sad to say, is probably the way to bet. This is bad news for AZ, a company that needs all the help it can get, and downright catastrophic news for Targacept, as I'm sure their stock price will reflect. And it might even be bad news for India, and Indian clinical research.

Update: to drive the point home, Adam Feuerstein has posted this under the heading of "My punishment for getting TRGT wrong".

Comments (26) + TrackBacks (0) | Category: Clinical Trials | The Central Nervous System

November 3, 2011

Medivation Comes Through With MDV3100

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Posted by Derek

Remember Medivation? That's the small biotech that was trying to develop a Russian compound as an Alzheimer's drug, an effort which blew up completely in early 2010. The company did have one other compound in development, targeting prostate cancer, a ligand for the androgen receptor called MDV3100.

You'll note from that link that it's a rather odd-looking compound, a thiohydantoin, which is a heterocycle that you don't see very often. The discovery of the compound is detailed here, in a collaboration between Michael Jung's group at UCLA and Charles Sawyers' at Sloan-Kettering (here's an interview with him). It's been a long road. The starting point was another known ligand, RU 59063, which comes out of research in France in the early 1990s. The whole left-hand side of MDV3100 (including the thiohydantoin) comes from that scaffold, but it behaves differently on the androgen receptor. Taking advantage of the wild and often intractable complexity of nuclear receptor signaling, it binds in a different mode than other AR ligands, and in a way that the receptor loses its ability to further bind DNA in the nucleus.

Here's the J. Med. Chem. paper (in open-access form) on the development of the series. The compounds were pushed through relatively quickly in cellular assays and in an in vivo model in mice, which allowed MDV3100 and its close analogs to stand out not only for their superior activity on the androgen receptor (which many compounds in the series had), but for their pharmacokinetics. Interestingly, the lead compound for some time seems to have been a spiro-cyclobutyl analog (RD162), but the corresponding gem-dimethyl compound was just as active and a lot easier to make, so that one became the clinical candidate.

Medivation's Phase III trial of the compound came in with data yesterday, and it was startlingly good, so much so that the trial was stopped early and the placebo group switched to the drug. The company's stock is going through the top of the chart in pre-market trading as I write, which shows that the expectations weren't all that high. But MDV3100 certainly seems to have come through, and considering how much failure we live with in drug discovery, it's nice to see something actually outperform. Congratulations to the company, and to Jung and Sawyers as well - they've added another straight-out-of-academia drug to the list, and helped to considerably advance the standard of care in prostate cancer. Good news all around.

Oh, and by the way. . .you have to wonder if this guy stuck around for this result. It all depends on what price he was in at - after today's trading, Medivation's stock might even make it up past where it was back when everyone was hoping that they had an Alzheimer's drug. Expectations!

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

November 1, 2011

Exelixis Fights City Hall, and City Hall Looks Like Winning

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Posted by Derek

So what happens when you and the FDA disagree on the clinical trials needed to show efficacy for your new drug? Well, this happens: your stock opens down 40%. That's what's going on with Exelixis today - here are the details. Basically, the company had a fast clinical path in mind, taking their prostate cancer candidate cabozantinib into late-stage patients and using pain reduction as an endpoint. But the FDA wasn't (and isn't) buying that as a marker.

I see their point. Survival is really what you're looking for, and there doesn't seem to be enough evidence that pain reduction is going to translate to that. As that Adam Feuerstein piece notes, all the other prostate drugs have had to show survival benefits. EXEL was planning to follow up with a second trial to show that, but hoped to jump-start things by getting approval just on the pain data. It appears that they're going to stick with their strategy and hope that the numbers are so dramatic that the agency will reverse course. But is that realistic - both for the chances of getting great data and the chances of persuading the FDA? The market doesn't think so. Neither do I.

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

October 11, 2011

Too Many Cancer Drugs? Too Few? About Right?

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Posted by Derek

According to Bruce Booth (@LifeSciVC on Twitter), Ernst & Young have estimated the proportion of drugs in the clinic in the US that are targeting cancer. Anyone want to pause for a moment to make a mental estimate of their own?

Well, I can tell you that I was a bit low. The E&Y number is 44%. The first thought I have is that I'd like to see that in some historical perspective, because I'd guess that it's been climbing for at least ten years now. My second thought is to wonder if that number is too high - no, not whether the estimate is too high. Assuming that the estimate is correct, is that too high a proportion of drug research being spent in oncology, or not?

Several factors led to the rise in the first place - lots of potential targets, ability to charge a lot for anything effective, an overall shorter and more definitive clinical pathway, no need for huge expensive ad campaigns to reach the specialists. Have these caused us to overshoot?

Comments (22) + TrackBacks (0) | Category: Cancer | Clinical Trials | Drug Development | Drug Industry History

September 28, 2011

Andy Grove's Idea For Opening Up Clinical Trials

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Posted by Derek

The last time I talked here at length about Andy Grove, ex-Intel CEO, I was rather hard on him, not that I imagine that I ruined his afternoon much. And in the same vein, I recently gave his name to the fallacy that runs like this: other high-tech R&D sector X is doing better than the pharmaceutical business is. Therefore the drug industry should do what those other businesses do, and things will be better. In Grove's original case, X was naturally "chip designers like Intel", and those two links above will tell you what I think of that analogy. (Hint: not too much).

But Grove has an editorial in Science with a concrete suggestion about how things could be done differently in clinical research. Specifically, he's looking at the ways that large outfits like Amazon manage their customer databases, and wonders about applying that to clinical trial management. Here's the key section:

Drug safety would continue to be ensured by the U.S. Food and Drug Administration. While safety-focused Phase I trials would continue under their jurisdiction, establishing efficacy would no longer be under their purview. Once safety is proven, patients could access the medicine in question through qualified physicians. Patients' responses to a drug would be stored in a database, along with their medical histories. Patient identity would be protected by biometric identifiers, and the database would be open to qualified medical researchers as a “commons.” The response of any patient or group of patients to a drug or treatment would be tracked and compared to those of others in the database who were treated in a different manner or not at all. These comparisons would provide insights into the factors that determine real-life efficacy: how individuals or subgroups respond to the drug. This would liberate drugs from the tyranny of the averages that characterize trial information today.

Now, that is not a crazy idea, but I think it still needs some work. The first issue that comes to mind is heterogeneity of the resulting data. One of the tricky parts of Phase II (and especially Phase III) trials is trying to make sure that all the patients, scattered as they often are across various trial sites, are really being treated and evaluated in exactly the same way. Grove's plan sort of swerves around that issue, in not-a-bug-but-a-feature style. I worry, though, that rather than getting away from his "tyranny of averages", that this might end up swamping things that could be meaningful clinical signals, losing them in a noisy pile of averaged-out errors. The easier the dosing protocols, and the more straighforward the clinical workup, the better it'll go for this method.

That leads right in to the second question: who decides which patients get tested? That's another major issue for any clinical program (and is, in fact, one of the biggest differences between Phase II and Phase III, as you open up the patient population). There are all sorts of errors to make here. On one end of the scale, you can be too restrictive, which will lead the regulatory agencies to wonder if your drug will have any benefit out in the real world (or to just approve you for the same narrow slice you tested in). If you make that error in Phase II, then you'll go on to waste your money in Phase III when your drug has to come out of the climate-controlled clinical greenhouse. But on the other end, you can ruin your chances for statistical significance by going too broad too soon. Monitoring and enforcing such things in a wide-open plan like Grove's proposal could be tough. (But that may not be what he has in mind. From the sound of it, wide-open is the key part of the whole thing, and as long as a complete medical history and record is kept of each patient, then let a thousand flowers bloom).

A few other questions: what, under these conditions, constitutes an endpoint for a trial? That is, when do you say "Great! Enough good data!" and go to the FDA for approval? On the other side, when do you decide that you've seen enough because things aren't working - how would a drug drop out of this process? And how would drugs be made available for the whole process, anyway? Wouldn't this favor the big companies even more, since they'd be able to distribute their clinical candidates to a wider population? (And wouldn't there be even more opportunities for unethical behavior, in trying to crowd out competitor compounds in some manner?)

Even after all those objections, I can still see some merit in this idea. But the details of it, which slide by very quickly in Grove's article, are the real problems. Aren't they always?

Comments (46) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs

August 5, 2011

Bernard Munos Rides Again

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Posted by Derek

I've been meaning to link to Matthew Herper's piece on Bernard Munos and his ideas on what's wrong with the drug business. Readers will recall several long discussions here about Munos and his published thoughts (Parts one, two, three and four). A take-home message:

So how can companies avoid tossing away billions on medicines that won’t work? By picking better targets. Munos says the companies that have done best made very big bets in untrammeled areas of pharmacology. . .Munos also showed that mergers—endemic in the industry—don’t fix productivity and may actually hurt it. . . What correlated most with the number of new drugs approved was the total number of companies in the industry. More companies, more successful drugs.

I should note that the last time I saw Munos, he was emphasizing that these big bets need to be in areas where you can get a solid answer in the clinic in the shortest amount of time possible - otherwise, you're really setting yourself up with too much risk. Alzheimer's, for example, is a disease that he was advising that drug developers basically stay away from: tricky unanswered medical questions, tough drug development problems, followed up by big huge long expensive clinical trials. If you're going to jump into a wild, untamed medical area (as he says you should), then pick one where you don't have to spend years in the clinic. (And yes, this would seem to mean a focus on an awful lot of orphan diseases, the way I look at it).

But, as the article goes on to say, the next thought after all this is: why do your researchers need to be in the same building? Or the same site? Or in the same company? Why not spin out the various areas and programs as much as possible, so that as many new ideas get tried out as can be tried? One way to interpret that is "Outsource everything!" which is where a lot of people jump off the bus. But he's not thinking in terms of "Keep lots of central control and make other people do all your grunt work". His take is more radical:

(Munos) points to the Pentagon’s Defense Advanced Research Projects Agency, the innovation engine of the military, which developed GPS, night vision and biosensors with a staff of only 140 people—and vast imagination. What if drug companies acted that way? What areas of medicine might be revolutionized?

DARPA is a very interesting case, which a lot of people have sought to emulate. From what I know of them, their success has indeed been through funding - lightly funding - an awful lot of ideas, and basically giving them just enough money to try to prove their worth before doling out any more. They have not been afraid of going after a lot of things that might be considered "out there", which is to their credit. But neither have they been charged with making money, much less reporting earnings quarterly. I don't really know what the intersection of DARPA and a publicly traded company might look like (the old Bell Labs?), or if that's possible today. If it isn't, so much the worse for us, most likely.

Comments (114) + TrackBacks (0) | Category: Alzheimer's Disease | Business and Markets | Clinical Trials | Drug Development | Drug Industry History | Who Discovers and Why

August 1, 2011

Laquinimod Fails For Multiple Sclerosis

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Posted by Derek

If you haven't been reading carefully, you might have had trouble figuring out Teva's oral therapy for multiple sclerosis, laquinimod. After all, earlier this year, the company was blowing the horn for the compound at neurology meetings, touting how safe and effective it was, its advantages over existing therapies, and its potential in the market. You'd hardly know that the compound actually didn't perform as well as many people were hoping. And of course, that very article does mention, near the end, that the company was going to have some more results later in the year. . .

. . .and that day has arrived. Unfortunately. Laquinimod missed its primary endpoint of reducing relapses in MS patients, and unless Teva and its Israeli Swedish partner company (Active Biotech) have some real surprises to unveil, you'd have to presume that the compound is dead. Or if not dead, destined to never make much of an impact in the market, for sure. This program has had a long history, with an earlier version of the structure (roquinimex) running into severe cardiovascular issues ten or twelve years ago.

Teva is a huge player in the generic world, and in recent years has been trying to break into the research end of the drug business. (Their first was Copaxone (glatiramer acetate), also for MS, a compound with a tangled history). Enjoy the experience, guys. If you're used to dealing with compounds whose value has already been proven, this sort of thing must come as even more of a shock than usual.

Comments (19) + TrackBacks (0) | Category: Clinical Trials | The Central Nervous System

July 8, 2011

The Duke Cancer Scandal and Personalized Medicine

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Posted by Derek

Here's a good overview from the New York Times of the Duke scandal. Basically, a team there spent several years publishing high-profile papers, and getting high-profile funding, and treating cancer patients based on their own tumor-profiling biomarker work. Which was shoddy, as it turns out, and useless, and wasted everyone's time, money, and (in some cases) the last weeks or months of people's lives. I think that about sums it up. It was Keith Baggerly at M. D. Anderson who really helped catch what was going on, and Retraction Watch has a good link to his presentation on the whole subject.

The lead investigator in this sordid business, Anil Potti, ended up retracting four papers on the work and left Duke last fall (although he's since resurfaced at a cancer treatment center in South Carolina). That's an interesting hiring decision. Looking over the case (and such details of it as Potti lying about having a Rhodes Scholarship), I don't think I'd consider hiring him to mow my yard. Perhaps that statement will be something for his online reputation management outfit to deal with.

But enough about Dr. Potti himself; I hope I never hear about him again. What this case illustrates are several very important problems with the whole field of personalized medicine, and with its public perception. First off, for some years now, everyone has been hearing about the stuff: the coming age of individual cancer treatment, biomarkers, zeroing in on the right drugs for the right patient, and so on. You'd almost get the impression that this age is already here. But it isn't, not yet. It's just barely, barely begun. By one estimate, no major new cancer biomarker has been approved for clinical use in 25 years. Update: changed the language here to reflect differences of opinion!)

Why is that? What's holding things up? We can read off DNA so quickly these days - what's to stop us from just ripping through every cancer sample there is, matching those up with who responded to which treatment regime and which cancer targets are (over)expressed, and there you have it. That's what all these computers are for, right?

Well, that sort of protocol has, in fact, occurred to many researchers. And it's been tried, over and over, without a whole lot of success. Now, there are some good correlations, here and there - but the best ones tend to be in relatively rare tumor types. There's nowhere near as much overlap as we'd like between the cancers that present the most serious public health problems and the ones that we have good biomarker-driven treatment data for. Breast cancer may be one of the fields where things have moved along the most - treatment really is affected by checking for things like Her-2. But it's not enough, nowhere near enough.

So why, then, is that the case? Several reasons - for one, tumor biology is clearly a lot more complex than we'd like it to be. Many common forms of cancer present as a host of mutated cells, each with a host of mutations (see this breast cancer work for an example). And they're genetically unstable, constantly changing. That's why so many cancers relapse after initially successful treatment - you kill off the tumor cells that can be killed off, but that may just give the ones that are left a free field.

Given this state of affairs, and the huge need (and demand) for something that works, the field is primed for just the sort of trouble that occurred at Duke. Someone unscrupulous would have no problem convincing people that a hot new biomarker was worthwhile - any patients that survived would praise it to the skies, while the ones that didn't would not be around to add their perspective. And even without criminal behavior, it's all too easy for researchers to honestly believe that they're on to something, even what that isn't true. The statistical workup needed to go through data sets like these is not trivial; you really have to know what you're doing. Adding to the problem, a number of judgment calls can be made along the way about what to allow, what to emphasize, and what to ignore.

The other problem is that cancer is such an emotional issue. It's very easy for anyone with a drum to beat to join in at full volume. Do you think that the FDA is letting all sorts of toxic junk through? Or do you think that the FDA is killing people by being stupidly cautious? Are drug companies ignoring dying patients, or ruthlessly profiteering off them? Are there too few good ideas for people to work on, or too many? Come to oncology; you can find plenty of support for whatever position you like. They can't all be right, but when did that ever slow anyone down? Besides, that means that there will invariably be Wrong-Thinking Evil People on the other side of any topic, and that's always stimulating, too.

It is, in fact, a mess. Nor are we out of it. But our only hope to is to keep hacking away. Wish us luck!

Comments (22) + TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs | The Dark Side

June 30, 2011

An Unethical Clinical Trial

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Posted by Derek

Well, here's one from the Archives of Internal Medicine that most certainly did get published. It's an analysis of an old clinical trial, STEPS, which was conducted for Neurontin (gabapentin) during the 1990s.

But that's not quite right. The authors find, by analyzing a large trove of documents released during lawsuit discovery proceedings, that STEPS was not really intended to be a clinical trial. Instead, it was a marketing program:

Documents demonstrated that STEPS was a seeding trial posing as a legitimate scientific study. Documents consistently described the trial itself, not trial results, to be a marketing tactic in the company's marketing plans. Documents demonstrated that at least 2 external sources questioned the validity of the study before execution, and that data quality during the study was often compromised. Furthermore, documents described company analyses examining the impact of participating as a STEPS investigator on rates and dosages of gabapentin prescribing, finding a positive association. None of these findings were reported in 2 published articles.

Here's more at Medscape. STEPS was allegedly a Phase IV post-approval trial, but it was unblinded and pretty much uncontrolled. Instead of taking place at a small number of centers, it seems to have been set up to enroll as many physicians as possible (they ended up with 772!), with each of them bringing in a handful of patients.

This is an extremely foul technique, which brings the companies who use it, the entire drug industry, and the whole idea of clinical research into disrepute. For money. I feel like spitting on the floor.

Comments (14) + TrackBacks (0) | Category: Clinical Trials | The Dark Side

June 27, 2011

Making the Numbers Confess

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Posted by Derek

Adam Feuerstein calls this not just "post hoc data mining", but "extreme post hoc data mining". Take a look and see what you think.

Update: more here.

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

May 27, 2011

Niacin's Unexpected Flop

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Posted by Derek

Let's add to the uncertainty about whether we understand cardiovascular disease, OK? The NIH has been conducting a large statin-plus-niacin trial, which is definitely a combination worth looking at. The statin will lower your LDL, and niacin will raise your HDL and lower your triglycerides (albeit with some irritating side effects). An earlier trial of niacin versus Zetia (ezetimibe) made the former look pretty good (and Zetia look pretty bad) using an endpoint of arterial examination by ultrasound.

But now the NIH trial has been stopped, a full 18 months early. Not only did the addition of niacin show no benefit at all, but that treatment group actually had a slightly higher rate of ischemic stroke. This despite the combination working as planned, from a blood-marker standpoint. No, we really still have a lot to learn, particularly when we're trying to raise HDL and lower triglycerides. These results, together with the fenofibrate data, really make a person wonder.

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

The Ethics of Avastin

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Posted by Derek

When we last spoke about the Avastin-and-breast-cancer story here, the FDA had rescinded its provisional approval for that indication, and a number of people were shouting that here it was, health care rationing based on price, right in front of us. As I said at the time, I think that those worries were misplaced: the reason Avastin was approved for metastatic breast cancer was that it seemed to work (a little). But when the numbers were firmed up with more studies, it turned out that it didn't. The whole point of a provisional approval is that it can be rolled back if things don't work out they way that they looked at first.

Now Genentech is coming back to the FDA next month asking for approval again. Here's an op-ed in the New York Times that I think does a good job of laying out the case against the whole idea:

Genentech presented progression-free survival as a surrogate for better quality of life, but the quality-of-life data were incomplete, sketchy and, in some cases, non-existent. The best that one Genentech spokesman could say was that “health-related quality of life was not worsened when Avastin was added.” Patients didn’t live longer, and they didn’t live better.

It was this lack of demonstrated clinical benefit, combined with the potentially severe side effects of the drug, that led the F.D.A. last year to reject the use of Avastin with Taxol or with the other chemotherapies for breast cancer.

In its appeal Genentech is changing its interpretation of its own data to pursue the case. Last year Genentech argued that the decrease in progression-free survival in its supplementary studies was not due to the pairing of Avastin with drugs other than Taxol. This year, however, in its brief supporting the appeal, Genentech argues that the degree of benefit may indeed vary with “the particular chemotherapy used with Avastin.” In other words, different chemotherapies suddenly do yield different results, with Taxol being superior. The same data now generate the opposite conclusion.

Another problem, as the piece says, is that the whole cancer drug approval process has a tendency to slip into ancedotal form: tearful patients testify that the drug saved their lives. But the plural of anecdote is still not data, and never will be. In oncology, there's really not much way of being sure about any individual patient's response. There are so many different types of cancer, and they occur in so many different kinds of people. The only way to say anything useful is in a well-designed clinical trial setting.

Now, that doesn't mean that you just have to round up thousands of people with all kinds of cancer and let things rip. It's perfectly acceptable - in fact, very useful - to screen the patients that go into the trials so that you're sure that they, as far as can be told, all have the same sort of disease. But you have to do that up front to really trust the conclusions. Data-mining, running things in reverse, is tricky, and if you're going to do it, it should be used to tell you how to run your next trial, not to argue for approval. Only when you've run these kinds of experiments can you say with any certainly that a cancer therapy is useful.

But that's a hard sell, compared to someone who is convinced that they're alive because of cancer drug X (or is convinced that a loved one would be alive, if they'd only been able to get it). If you're trying to persuade a crowd (or a mob), that would be the way to go: Aristotle's appeal to pathos. But keep in mind that Aristotle (and the rest of the Greeks) looked down on that technique, and they were right. Logos, used properly, is what we're after here, mixed in with the ethos of a disinterested observer who's trying to find the truth.

And this gets to the moral dilemma at the heart of the modern drug industry: are we trying to find drugs that work? Or are we trying to sell drugs, whether they work or not? Roche/Genentech has every right to make its case and to petition the FDA for whatever decision they want. But they (and every other drug company out there) owe the rest of us, and the rest of the world, something while they're doing it: to present all the solid data they have, and to let the numbers speak for themselves. But if the numbers can't persuade, then a company should go back and get some more before trying again.

Comments (23) + TrackBacks (0) | Category: Cancer | Clinical Trials | Why Everyone Loves Us

May 18, 2011

Fenofibrate: Good For Much?

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Posted by Derek

Abbott has some difficult times ahead with their fenofibrate franchise. That's TriCor, and its newer formulation, TriLipix. Fenofibrate, as I've mentioned here before, is an oddity among drugs. It was discovered way before anyone had a mechanism of action, and even now, while it's supposed to be a PPAR-alpha ligand, no one's completely happy with that explanation. (For one thing, it's not very potent at that nuclear receptor, while other PPAR-alpha compounds have crashed in clinical trials for various reasons). But it can lower triglycerides and raise HDL, which should both (in theory) be beneficial effects, and it's been a big seller over the years.

But how much good does it do? That's always the big, important, slow question in the cardiovascular field. The data for fenofibrate have always been somewhat messy (although probably positive overall), but a new study has muddied things up. As the FDA puts it, in the documents for an advisory committee meeting tomorrow (PDF):

Over the last 40 years laboratory and clinical data have suggested the potential of fibrates to reduce cardiovascular risk. However, data from large clinical outcomes trials have produced mixed results. The inconsistent outcomes may be a result of differences in pharmacodynamic properties among individual fibrates or study populations or both.

The new data, from a trial called ACCORD-Lipid, is another one looking at fenofibrate plus a statin, which is the usual combination (that way, at least in theory, you go after triglycerides, low HDL, and high LDL simultaneously). But this trial, in a large population of diabetic patients, showed that overall, the rate of major adverse cardiovascular events (MACE) was statistically identical between the statin/fenofibrate and statin/placebo groups. No advantage! It gets trickier with a bit of subgroup analysis: women showed some evidence of worse outcomes with fenofibrate as opposed to statin alone. The group that seemed to benefit, on the other hand, were the patients who started out with the highest triglycerides and the lowest HDL. (See that FDA file above for all the numbers and more).

That's disconcerting. Is fenofibrate only helping the worst-off patients, and doing nothing (or worse) for the others? That a question worth wrestling with for a drug that sold well over a billion dollars last year. And beyond that is the same sort of question that came up when all the ezetimibe data hit: how much do we really know about blood markers versus real cardiovascular outcomes? Can you hit the various numbers by different routes, some of which are beneficial and some of which aren't? What is it that we're not understanding?

Comments (3) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Regulatory Affairs

May 10, 2011

Phase II Failures

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Posted by Derek

We know what clinical trial success rates have been like for the last twenty years or so (hint: not so good). Are things turning around, or not? This Nature Reviews Drug Discovery piece takes a look at the 2008-2010 data. It's not necessarily reassuring:

At present, however, Phase II success rates are lower than at any other phase of development. Analysis by the Centre for Medicines Research (CMR) of projects from a group of 16 companies (representing approximately 60% of global R&D spending) in the CMR International Global R&D database reveals that the Phase II success rates for new development projects have fallen from 28% (2006–2007) to 18% (2008–2009), although these success rates do vary between therapeutic areas and between small molecules and biologics.

There were 108 Phase II failures in 2008-2010, and for 87 of those we have a stated reason. Half of those were good old lack of efficacy, another 19% failed on safety grounds, and the rest failed for "strategic reasons". The best guess there is that the compounds seem to have been targeting areas where there was already competition, and they didn't differentiate themselves enough from the standard of care to be worth continuing. That's worth thinking about in the context of the arguments about "me-too" drugs. To hear some of the industry's critics tell it, there shouldn't be any such failures at all, since they seem to believe that even most marketed drugs really don't differentiate themselves from their competition as it is.

Nearly 70% of those 108 failures, by the way, were in four therapeutic areas: cardiovascular, CNS, metabolics, and oncology. (What we don't have are the failures adjusted for how many drugs were taken into the clinic in the first place in those areas). CNS and oncology are traditional high-risk areas, of course, and I think that a lot of the metabolics failures were in diabetes. That's a tough field - big market, but pretty well-served, making efficacy versus the standard of care a high bar to clear, and this while the FDA's safety requirements have gotten very stiff indeed.

But cardiovascular - that's interesting, since that area has traditionally had one of the better trial success rates. Perhaps that one is also suffering from the standard of care being pretty good (and often generic, or soon to be). So the high-success-rate mechanisms of the old days are well covered, leaving you to try your luck in the riskier ideas, while still trying to beat some pretty good (and pretty cheap) drugs. . .

Update: it's been suggested that some of these "strategic" failures are a sign of what happens during merger/acquisition activity. Could be, but you'd have to run these down company-by-company. I'll see if I can contact the authors of this paper about that idea. . .

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May 3, 2011

Lucentis and Avastin: Results

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Posted by Derek

So the results are in from that Lucentis-vs-Avastin comparison (known as CATT, Comparison of AMD Treatment Trials), and I'd say that they came out the way people were expecting: monthly injections of either antibody give the same end results, as measured by vision testing. There are some slight differences between the two when retinal thickness is measured, but that hasn't shown up in the end result (visual impairment). There's another year of follow-up ongoing, and perhaps that will show something (or perhaps not). For now, the outcome appears to be the same.

Another interesting feature of this study is that it compared regular monthly treatment with either drug to an "as-needed" dosing schedule. In this case Lucentis performed equally well by either schedule, with monthly Avastin equivalent, but (interestingly) as-needed Avastin dosing was, in fact, inferior. These protocols need fewer injections (and less Lucentis), but more imaging of the retina, along with more judgment calls on the part of physicians, so the cost savings there will remain to be seen. Savings on injections into the eyes, though, would surely be welcome - it's too bad that Avastin didn't perform as well that way.

As the editorial in the NEJM summed it up:

Health care providers and payers worldwide will now have to justify the cost of using ranibizumab. Regulators in certain countries will be forced to reconsider their policies that make it illegal to use drugs off-label, particularly when so many of their citizens cannot afford ranibizumab. The CATT data support the continued global use of intravitreal bevacizumab as an effective, low-cost alternative to ranibizumab.

The only thing that could flip this around is if the second year of CATT produces some new data, or if the ongoing European trials turn up some safety data that this study wasn't powered to pick up.

More here at the In Vivo Blog. BioCentury also did a good write-up on this one for their subscribers - they interviewed a number of opthamology practitioners, and the voting looks solidly in favor of using the much less expensive Avastin. One South Carolina practice reported that, because of the state's sales tax on physician-administered drugs, that they pay $140 in tax for every injection of Lucentis, while getting reimbursed $120 by Medicare for doing it, which doesn't sound like much of a way to make a living. Still, as the newsletter points out, off-label Avastin use (which would be legal) involves repackaging what was a single-dose container, and that part is technically in violation of the law. Buthe agency doesn't want to get in the way of freedom of medical practice, and seems to be letting that trump the repackaging/compounding concerns.

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April 4, 2011

Update on Avastin and Lucentis

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Posted by Derek

The Lucentis/Avastin story is going to get more complicated as the year goes on. Next month the results of a head-to-head study of the two drugs (one far less costly than the other) in cases of macular degeneration will be revealed, and it's widely thought that they'll come up as basically equivalent in efficacy.

But as this Wall Street Journal article makes clear, they may not be equal in safely. The same meeting that will see the trial results presented will also feature an analysis of Medicare claims for both drugs, which looks like it'll show that Lucentis has a better safety profile. This is exactly what Roche/Genentech would like to hear, naturally. We'll have to wait until May to see which message wins out. . .

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March 24, 2011

More on KV and Makena's Pricing

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Posted by Derek

I wanted to do some follow-up on the Makena story - the longtime progesterone ester drug that has now been newly FDA-approved and newly made two order of magnitude more expensive. (That earlier post has the details, for those who might not have been following).

Steve Usdin at BioCentury has, in the newsletter's March 21st issue, gone into some more detail about the whole process where KV Pharmaceuticals stepped in under the Orphan Drug Act to pick up exclusive marketing rights to the drug. The company, he says, "arguably has played a marginal role" in getting the drug back onto the market.

Here's the timeline, from that article and some digging around of my own: in 1956, Squibb got FDA approval for the exact compound (progesterone caproate) for the exact indication (preventing preterm labor), under the brand name Delalutin. But at that time, the FDA didn't require proof of efficacy, just safety. There were several small, inconclusive academic studies during the 1960s. In 1971, the FDA noted that the drug was effective for abnormal uterine bleeding and other indications, and was "probably effective" for preventing preterm delivery. In 1973, though, based on further data from the company, the agency went back on that statement, and said that there was now evidence of birth defects from the use of Delalutin in pregnant women, and removed any of these as approved uses. In the late 1970s, warning language was further added. In 1989, the agency said that its earlier concerns (heart and limb defects) were unfounded, but warned of others. By 1999, the FDA had concluded that progesterone drugs were too varied in their effects to be covered under a single set of warnings, and took the warning labels off.

In 1998, the National Institute of Child Health and Human Development launched a larger, controlled study, but this was an example of bad coordination all the way. By this time, Bristol-Myers Squibb had requested that Delalutin's NDAs be revoked, saying that they hadn't even sold the compound for several years. This seems to have also been a move, though, in response to FDA complaints about earlier violations of manufacturing guidelines and a request to recall the outstanding stocks of the drug. So the NICHD study was terminated after a year, with no results, and the drug's NDA was revoked as of September, 2000.

The NICHD had started another study by then, however, although I'm not sure how they solved their supply problems. This is the one that reported data in 2003, and showed a real statistical benefit for preterm labor. More physicians began to prescribe the drug, and in 2008, the American College of Obstetricians and Gynecologists recommended its use.

So much for the medical efficacy side of the story. Now we get back to the regulatory and marketing end of things. In March of 2006, a company called CUSTOpharm asked the FDA to determine if the drug had been withdrawn for reasons of safety or efficacy - basically, was it something that could be resubmitted as an ANDA? The agency determined that the compound was so eligible.

Meanwhile, another company called Adeza Biomedical was moving in the same direction (as far as I can tell, they and CUSTOpharm had nothing to do with each other, but I don't have all the details). Adeza submitted an NDA in July 2006, under the FDA's provision for using data that that applicant had not generated - in fact, they used the NICHD study results. They called the compound Gestiva, and asked for accelerated approval, since preterm delivery was accepted as a surrogate for infant mortality. An advisory committee recommended this in August of 2006, by a 12 to 9 vote. (Scroll down to the bottom of this page for the details).

The agency sent Adeza an "approvable" letter in October 2006 which asked for more animal studies. The next year, Adeza was bought by Cytec, who were bought by Hologic, who sold the Gestiva rights to KV Pharmaceuticals in January 2008. So that's how KV enters the story: they bought the drug program from someone who bought it from someone who just used a government agency's clinical data.

The NDA was approved by the FDA in February 2011, along with a name change to Makena. By this time, KV and Hologic had modified their agreement - KV had already paid up nearly $80 million, with another $12.5 million due with the approval, and has further payments to make to Hologic which would take the total purchase price up to nearly $200 million. That's been their main expense for the drug, by far. The FDA has asked them to continue two ongoing studies of Makena - one placebo-controlled trial to look at neonatal mortality and morbidity, and one observational study to see if there are any later developmental effects. Those studies will report in late 2016, and KV has said that their costs will be in the "tens of millions". So they paid more for the rights to Makena than it's costing them to get it studied in the clinic.

That only makes sense if they can charge a lot more than the generic price for the drug had been, of course, and that's what takes us up to today, with the uproar over the company's proposed price tag of $1500 per treatment. But the St. Louis Post-Dispatch (thanks to FiercePharma for the link) says that the company has now filed its latest 10-Q with the SEC, and is notifying investors that its pricing plans are in doubt:

The success of the Company’s commercialization of Makena™ is dependent upon a number of factors, including: (i) the Company’s ability to maintain certain net pricing levels for Makena™; (ii) successfully obtaining agreements for coverage and reimbursement rates on behalf of patients and medical practitioners prescribing Makena™ with third-party payors, including government authorities, private health insurers and other organizations, such as HMOs, insurance companies, and Medicaid programs and administrators, and (iii) the extent to which pharmaceutical compounders continue to produce non-FDA approved purported substitute product. The Company has been criticized regarding the list pricing of Makena™ in a number of news articles and internet postings. In addition, the Company has received, and expects to continue to receive, letters criticizing the Company’s list pricing of Makena™ from several medical practitioners and several advocacy groups, including the March of Dimes, American College of Obstetricians and Gynecologists, American Academy of Pediatrics and the Society for Maternal Fetal Medicine. Further, the Company has received one letter from a United States Senator and expect to receive another letter from a number of members of the United States Congress asking the Company to reduce its indicated pricing of Makena™, and the same Senator, together with a second Senator, has sent a letter to the Federal Trade Commission asking the agency to initiate an investigation of our pricing of Makena™.

The Company is responding to these criticisms and events in a number of respects. . .The success of the Company is largely dependent upon these efforts and appropriately responding to both the media and governmental concerns regarding the pricing of Makena™.

Personally, I'm torn a bit by the whole situation. I think that people and companies have the right to charge what the market will bear for their goods and services. But at the same time, I find myself also very irritated by KV in this case, because I truly think that they are taking advantage of the regulatory framework. As I said in the last post, it's not like they took on much risk here - they didn't discover this drug, didn't do the key clinical work on it, and don't even manufacture it themselves. Their business plan involves sitting back and collecting the rent, but that's what the law allows them to do.

In the end, if political pressure forces them to back down on their pricing, this will come down to a poor business decision. Companies should, in fact, charge what the market will bear - but KV may have neglected some other factors when they calculated what that price should be. Before setting a price, you should ask "Will the insurance companies pay?" and "Will Medicare pay?" and "Will people pay out of their own pocket?", but you should also ask "Will this price bring down so much controversy that we won't be able to make it stick?"

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March 11, 2011

Makena's Price: What to Do?

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Posted by Derek

The situation with KV Pharmaceuticals and the premature birth therapy Makena has been all over the news in the last couple of days. Briefly, Makena is an injectable progesterone formulation, given to women at risk of delivering prematurely. It went off the market in the early 1990s, because of side effect concerns and worries about overall efficacy, but since 2003 it's made an off-label comeback, thanks largely to a study at Wake Forest. This seemed to tip the risk/benefit ratio over to the favorable side.

Comes now the FDA and the provisions for orphan drugs. There is an official program offering market exclusivity to companies that are willing to take up such non-approved therapies and give them the full clinical and regulatory treatment. The idea, which is well-intentioned, as so many ideas are, was to bring these things in from the cold and give them more medical, scientific, and legal standing as things that had been through the whole review process. And that's what KV did. But this system says nothing about what the price of the drug will be during the years of exclusivity, in the same way that the approval process for new drugs says nothing about what their price will be when they come to market.

KV has decided that the price will now be about $1500 per patient, as opposed to about $15 before under the off-label regime. The reaction has been exactly what one would expect, and why not? Here, then are some thoughts:

Unfortunately, this should not have come as a surprise. It seems to have, though. The news stories are full of quotes from patients, doctors, and insurance companies saying that they never saw this coming. Look, though, at what happened recently with colchicine. Same situation. Same price jump. Same outrage, understandably. As long as these same incentives exist, any no-name generic company that comes along to adopt an old therapy and bring it into the modern regulatory regime can be assumed to be planning to run the price up to what they think the market will bear. That's why they're going to the trouble.

KV seems to have guessed correctly about the price. You wouldn't think so, with a hundred-fold increase. And the news stories, as I say, are full of (understandably) angry quotes from people at the insurance companies who will now be asked to pay. But (as that NPR link in the first paragraph says), Aetna, outraged or not, is going to pony up. It's going to cost them $20 to $30 million per year, most of which is going to go directly to KV's bottom line, but they're going to pay. And the other big health insurance providers seem to be doing the same. Meanwhile, the company has announced a program to provide low-cost treatment to people without insurance. From what I can see, it looks like basically everyone who had access to the drug before will have it now, the main difference being that the payers with deeper pockets will now be getting hammered on by KV. This is not a nice way to run a business, and it's not something I would sleep well on after having done myself. But there it is.

How much is regulatory approval worth, anyway? That seems to be what we're really arguing about. After all, patients are getting the same drug, in the same formulation, dosed the same way as before. But now it's **FDA Approved**. For new substances, I think regulatory approval is worth quite a bit. There are all kinds of things that can go wrong. But how about drugs that have been dosed in humans for years? And already run through the equivalent of Phase II trials by other people? The main thing that's being added is some confirmation that yes, the dose that everyone's been using is about right, and yes, the effects that are being seen are, in fact, real. And that's not worthless, not at all - but how much is it worth, really? The agency itself seems to place a pretty high value on it - seven years of market exclusivity, to be exact, and we can see by example just what that goes for on the market.

This does the drug industry no good, either. We have a bad enough reputation as it is, wouldn't you think? What's irritating, to someone like me who works at a "find a new drug" type of company, is that these no-name generic outfits (KV in this case, URL Pharma for colchicine) are doing pretty much what critics of the industry think that we all do, all the time. That is, walk up to situations where other people have done a lot of the work, a good amount of it with public/NIH money, and step right in and profit. Now it's true that these companies have to basically run Phase II/Phase III trials to take the data to the FDA, and that's a significant amount of money. But their risks in doing so have been watered down immensely by the history of these drugs in the medical community. When a research company closes its eyes, holds its breath, and jumps into the clinic with a new molecule, that's one thing. And that's where those 90% failure rates come from. But the failure rate of drugs that have been used for years in human patients already, and already studied under clinical conditions, is not anything like 90%. Is it zero per cent? Has anyone failed yet, taking one of these old medications back to the FDA? Even once?

The company picked its target carefully. I will say this, that KV's trials have presumably clarified the question of whether progesterone therapy actually does help. You'd think that the 2003 study would have answered that, and as it turned out, it had. A review of the field in 2006 concluded that it was a worthwhile therapy, from a cost/benefit standpoint, as did another review in 2007. (Mind you, that wasn't at any $1500 a throw, was it?) But a Cochrane review from last year concluded that there still wasn't enough evidence to recommend the whole idea. And progesterone therapy doesn't seem to help with twin or tripletpregnancies or with some other gestational problems. No, the 2003 study seemed fairly strong, and has the greatest relevance to public health, so that's what the company went for. From one viewing angle, the system worked.

My take, though, is that as long as the regulatory environment is set to value FDA's stamp of approval for old drugs this highly, that people will continue to take advantage of it. You subsidize something; you're going to get it. Personally, I don't think that the balance is right, but I'm open to suggestion about what to do about it. A shorter period of market exclusivity would just mean, I think, that the prices go up even higher once a drug gets re-approved. Just throwing up our hands and letting all that old stuff stand is a possibility, but there may well still be some of these things that aren't as effective as we think, or aren't being dosed right, and we have to decide what the cost is of letting those situations stand.

Update: see also Alex Tabarrok's thoughts on the effects of the Orphan Drug Act in general.

Comments (57) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Drug Prices | Regulatory Affairs | Why Everyone Loves Us

March 10, 2011

The Cost to Develop a Drug: Your Own Numbers?

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Posted by Derek

Bruce Booth over at Atlas Venture (a VC fund here in Cambridge) has been following the Light and Warburton drug-cost estimate with interest. And now he's got a form up on his site for people to enter their own estimates of the costs. Take a look - it's bound to come up with a number that's more in tune with reality! For one thing, he's actually asking people who have, you know, developed drugs. . .

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March 8, 2011

That $43 Million R&D Figure

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Posted by Derek

One of the readers in the comments section to the last post noticed Rebecca Warburton trying to clarify that absurd $43-million-per-drug R&D figure. You'll find her response in the comments section to the Slate piece that brought this whole study so much attention. Says Warburton:

. . .Our estimate of $59 million is the median development (the “D” in R&D) cost per average drug, not just NMEs (new chemicals) and does not include basic research costs, for which there is no reasonable estimate available.

But that explanation won't wash, as some of the readers over at Slate noticed as well. If you read the Light and Warburton article itself, you find the authors talking about nothing but "R&D" all the way through. In the one section where they do start to make a distinction, they brush aside expenses for basic research, on the grounds that drug companies hardly do any:

Companies under pressure from quarterly reports have difficulty justifying long searches for breakthrough drugs to investors. . .Little company R&D is devoted to basic research. Although industry association reports, based on unverified numbers from its members, claim that companies invest on average 17–19 per cent of sales in R&D, the most authoritative data come from the long-standing survey by the US National Science Foundation (2003). Its data document that pharmaceutical firms invest 12.4 per cent of gross domestic sales on R&D. Of this, 18 per cent, or 2.4 per cent of sales, went to basic research. More detailed reports from the industry indicate the percentage of R&D going to basic research is even smaller, about 9.3 per cent (or 1.2 per cent of sales) (Light, 2006). Thus the net corporate investment in research to discover important new drugs is about 1.2 per cent of sales, not 17–19 per cent.

So no, claiming that the $43 million figure is only supposed to represent the "D" part of R&D is disingenuous. There's another line from this paper, quoting Marcia Angell, that I think gets to one of the roots of the problem with the way these authors have characterized drug research. Angell is quoted here with approval - everything she and Merril Goozner have to say is quoted with approval:

It is also unclear how far back one should go to count up the costs of discovery, given that often there are several strands of research that are pieced together. In Angell’s view, the critical step in ‘discovering’ a new drug is understanding how the disease works and finding one or two good targets of vulnerability in the defences of a disease for intervention. Basic research ‘is almost always carried out at universities or government research labs, either in this country or abroad’ (Angell, 2004, p. 23).

And there you have it. The critical step is understanding how the disease works, you see, and finding one or two good targets. By that definition, the vast amount of money that gets spent in the drug industry is then non-critical. This is a viewpoint that can only be held by someone who has never tried to discover a drug, or never held a serious conversation with anyone who has.

Let's poke a few holes in that worldview. First off, if we waited to "understand" diseases before trying to develop drugs for them, we'd hardly have a damned thing on the drugstore shelves. Look at Alzheimer's - the medical community is still having fist-waving arguments about its cause, while drug companies continue to sink piles of money into trying to treat it. (Almost all of which has gone down the tubes, I might add, and I helped flush some of it through myself, earlier in my career).

Then you have to find one or two good targets. Peachy! Where do you find those thingies, anyway? And how do you know that they're good targets? I wish that Marcia Angell, Donald Light, or Rebecca Warburton would let the rest of us in on those secrets. As it is, we have to take chances on some pretty tenuous stuff, and often the only way to find out if a target really has any connection to human health is to. . .well, to discover a drug candidate that hits it. And develop it, and get it through tox, and into humans, and through Phase I, and into Phase II, and more likely than not these days, into Phase III before you really find out if, you know, it was actually a good target. We pass on those results to the rest of the world at that point. But that doesn't count as research, apparently.

And how about the drugs that have been developed without good mechanisms or targets at all? Metformin, ezetimibe, rosiglitazone and pioglitazone: none of these had any detailed mechanisms worked out for them while the money was being spent to develop them. These are the sorts of things we do around here in between having meetings to decide what color the package should be, and right after we do that thing where we all jump around in rooms knee-deep in hundred-dollar bills. Exhausting stuff, that money-wading.

But what I'd really like to ask Light and Warburton about is this: if you do think that the Tufts/diMasi estimate is crap, why did you feel as if the antidote was more crap from the opposite direction? Honestly, I'd think that intelligent people of good will might be more interested in decreasing the total amount of crap out there instead. . .

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March 7, 2011

The Costs of Drug Research: Beginning a Rebuttal

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Posted by Derek

Note: a follow-up post to this one can be found here.

I've had a deluge of emails asking me about this article from Slate on the costs of drug research. It's based on this recent publication from Donald Light and Rebecca Warburton in the London School of Economics journal Biosocieties, and it's well worth discussing.

But let's get a few things out of the way first. The paper is a case for the prosecution, not a dispassionate analysis. The authors have a great deal of contempt for the pharmaceutical industry, and are unwilling (or unable) to keep it from seeping into their prose. I'm tempted to reply in kind, but I'm supposed to be the scientist in this discussion. We'll see how well I manage.

Another thing to mention immediately is that this paper is, in fact, not at all worthless. In between the editorializing, they make some serious points, and most of these are about the 2003 Tufts (diMasi) estimate of drug development costs. This is the widely-cited $802 million figure, and the fact that it's widely cited is what seems to infuriate the authors of this paper the most.

Here are their problems with it: the Tufts study surveyed 24 large drug companies, of which 10 agreed to participate. (In other words, this is neither a random nor a comprehensive sample). The drugs used for the study numbers were supposed to be "self-originated", but since we don't know which drugs they were, it's impossible to check this. And since the companies reported their own numbers, these would be difficult to check, even if they were made available drug-by-drug (which they aren't). Nor can anyone be sure that variations in how companies assign costs to R&D haven't skewed the data as well. We may well be looking at the most expensive drugs of the whole sample; it's impossible to say.

All of these are legitimate objections - the Tufts numbers are just not transparent. Companies are not willing to completely spread their books out for outside observers, in any industry, so any of these estimates are going to be fuzzy. Light and Warburton go on to some accounting issues, specifically the cost-of-capital estimate that took their estimated cost for a new drug from 400 million to 800 million. That topic has been debated around this blog before, and it's important to break that argument into two parts.

The first one is whether it's appropriate to consider opportunity costs at all. I still say that it is, and I don't have much patience for the "argument from unfamiliarity". If you commit to some multi-year use of your money, you really are forgoing what you could have earned with it otherwise. You're giving it up - it's a cost, whether you're used to thinking of it that way or not. But the second part of the argument is, just how much could you have earned? The problem here is that the Tufts study assumes 11% returns, which is just not anywhere near realistic. Mind you, it's on the same order of fantasy as the returns that have been assumed in the past inside many pension plans, but we're going to be dealing with that problem for years to come, too. No, the Tufts opportunity cost numbers are just too high.

Then there's the tax situation. I am, I'm very happy to say, no expert on R&D tax accounting. But it's enough to say that there's arguing room about the effects of the various special tax provisions for expenditures in this area. And it's complicated greatly by different treatment in different part of the US and the world. The Tufts study does not reduce the gross costs of R&D by tax savings, while Light and Warburton argue otherwise. Among other points, they argue that the industry is trying to have it both ways - that cost-of-capital arguments make R&D expenditures look like a long-term investment, while for tax purposes, many of these are deductible each year as more of an ordinary business expense.

Fine, then - I'm in agreement, on general principles, with Light and Warburton when they say that the Tufts study estimates are hard to check and likely too high. But here's where we part company. Not content to make this point, the authors turn around and attempt to replace one shaky number with another. The latter part of their paper, to me, is one one attempt after another to push their own estimate of drug R&D costs into a world of fantasy. Their claim is that the median R&D cost for a new drug is about $43 million. This figure is wrong.

For example, they have total clinical trial and regulatory review time dropping (taken from this reference - note that Light and diMasi, lead author of the Tufts study, are already fighting it out in the letter section). But if that's true why isn't the total time from discovery to approval going down? I've been unable to find any evidence that it is, and my own experience certainly doesn't make me think that the process is going any faster.

The authors also claim that corporate R&D risks are much lower than reported. Here they indulge in some rhetoric that makes me wonder if they understand the process at all:

Reports by industry routinely claim that companies must test 5000-10000 compounds to discover one drug that eventually comes to market. Marcia Angell (2004) points out that these figures are mythic: they could say 20,000 and it would not matter much, because the initial high-speed computer screenings consume a small per cent of R&D costs. . .

The truth is, even a screen of 20,000 compounds is tiny. And those are real, physical, compounds, not "computer screenings". It's true, though, that high-throughput screening is a small part of R&D costs. But the authors are mixing up screening and the synthesis of new compounds. We don't find our drug candidates in the screening deck - at least, not in any project I've worked on since 1989. We find leads there, and then people like me make all kinds of new structures - in flasks, dang it, not on computers - and we test those. Here, read this.

The authors go on to say:

Many products that 'fail' would be more accurately described as 'withdrawn', usually because trial results are mixed; or because a company estimates that the drug will not meet their high sales threshold for sufficient profitability. The difference between 'failure' and 'withdrawal' is important, because many observers suspect that companies withdraw or abandon therapeutically important drugs for commercial reasons. . .

Bring out some of those observers, then! And bring on the list of therapeutically important drugs that have been dropped out of the clinic just for commercial reasons. Please, give us some examples to work with here, and tell me how the disappointing data that the companies reported at the time (missed endpoints, tox problems) were fudged. Now, I have seen a compound fall out of actual production because of commercial reasons (Pfizer's Exubera), but that was partly because it didn't turn out to be as therapeutically important as the company convinced itself that it would be.

And here's another part I especially like:

Company financial risk is not only much lower than usually conveyed by the '1 in 5000' rhetoric, but companies spread their risks over a number of projects. The larger companies are, and the more they merge with or buy up other companies, the less risk they bear for any one R&D project. The corporate risk of R&D for companies like Pfizer or GlaxoSmithKinen are thus lower than for companies like Intel that have only a few innovations on which sales rely.

Well, then. That means that Pfizer, as the biggest and most-merged-up drug company in the world, must have minimized its risk more than anyone in the industry. Right? And they should be doing just fine by that? Not laying people off right and left? Not closing any huge research sites? Not wondering frantically how they're going to replace the lost revenue from Lipitor? Not telling people that they're actually ditching several therapeutic areas completely because they don't think than can compete in them, given the risks? Not announcing a stock buyback program, because they apparently (and rather shamefully) think that's a better use of their money than putting it back into more R&D? I mean, how can Intel be doing better than that? It's almost like chip design is a different sort of R&D business entirely.

Well, this post is already too long, and there's more to discuss in another one, at least. But I wanted to add one more argument from economic reality, an extension of those little questions about Pfizer. If the cost of R&D for a new drug really were $43 million, as Light and Warburton would have it, and the financial and tax advantages so great, why isn't everyone pouring money into the drug industry? Why aren't VC firms lining up to get in on this sweet deal? I mean, $43 million for a drug, you should be able to raise that pretty easily, even in this climate - and then you just stand back as the money gushes into the sky. Don't you?

Why are drug approval rates so flat (or worse?) Why all the layoffs? Why all the doom and gloom? We're apparently doing great, and we never even knew.

Comments (48) + TrackBacks (0) | Category: Business and Markets | Clinical Trials | Drug Development | Drug Industry History | Drug Prices | Why Everyone Loves Us

March 1, 2011

Use Avastin! Don't Use Avastin!

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Posted by Derek

The Genentech/Roche drug Avastin has been in the news a lot lately, mostly about cost/benefit analysis for its uses in oncology. It's nobody's idea of a cheap drug even for those indications where it shows results. But there's one therapeutic area where it's actually the bargain alternative.

That's AMD, wet age-related macular degeneration. Stopping the growth of those leaking blood vessels in the eye is the standard therapy for the condition, so a VEGF-targeted therapy is just the thing. Lucentis is the anti-VEGF antibody that's approved for that use; it showed very impressive results in the clinic, and seems to perform just as well in the real world.

But Lucentis is expensive. And while it's different from Avastin, it's really not that different. It is, in fact, an opthalmic-delivery-optimized version of the same general antibody, and was developed by the same folks at Genentech. Avastin itself isn't packaged in units small enough for AMD therapy, but if you have a practice with a number of patients, well. . .by the time you split it out, an Avastin injection is about $50, versus nearly $2000 for Lucentis. In fact, a great many physicians in the US (possibly a majority) use Avastin off-label in just that fashion. A UK study last fall shored up that practice with some data, and a number of other studies are underway.

One of these, conducted by the NIH, should be reporting soon. And that's putting Roche/Genentech in an odd position. They have not supplied drugs for the trial, for one thing. Last fall the New York Times reported that rebates are now being offered to opthamologists if they'll use Lucentis, which many have interpreted as a preemptive maneuver to deal with the likely NIH results.

This is a mess, no doubt about it. While Genentech did indeed spend the time, money, and effort to develop Lucentis as a separate therapy, there seems to have been an active effort to avoid finding out if Avastin wouldn't have been just as good. The market does provide perverse incentives like this sometimes - this is an instance where I think that the NIH is doing exactly what it should be doing by running the head-to-head trial.

But I don't think that Roche is going to like the results. And they could find themselves arguing, simultaneously, that Avastin should not be used for AMD, even though it's cheaper than the alternatives and may well be just as effective, while Avastin should be used for metastatic breast cancer, even though it's more expensive than the alternatives and may well not be effective at all. And while the company will surely argue that the numbers are not what they appear, and that there are other numbers that say differently, and that it's all quite complex, they're going to be unable to escape the downward slice of Occam's razor: that in every case, they're arguing for the exact position that maximizes their revenue.

This is what companies do, of course. We shouldn't expect any less. But that doesn't mean that the revenue-maximizing path is always the right one, either.

Comments (27) + TrackBacks (0) | Category: Clinical Trials | Drug Prices | Why Everyone Loves Us

February 28, 2011

Down In Phase III. Again.

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Posted by Derek

Past performance (Phase II results) are no guarantee of future success (Phase III). That warning has been proven over and over in this business, and an awful lot of time, effort, and money have gone down the waste chute in the process. To give you an idea, though, of how hard it is to break out of that cycle, consider Renovo.

As the InVivoBlog details, Renovo was founded to try out ideas to reduce scar tissue formation. And their whole strategy was to go into humans as quickly as possible, to firm up the clinical relevance of their candidate therapies. That's a bit easier to do with something like scarring, if you can find patients willing to have small cuts made in their skin. That's just how one of the Phase II trials was run for the company's Juvista (recombinant TGF beta 3) - two cuts, one treated with the drug and one without. And the results looked quite good.

But not in Phase III. Earlier this month, the company announced that Juvista has completely, utterly missed its endpoints in the larger trial, and no one seems to know why. According to the InVivoBlog, investors were reduced on the conference call to asking if somehow the data collection had been messed up - surely some of the placebo group and the treatment group had been, uh, switched somehow? But no.

It's worth remembering, though, that not all the Phase II data were so convincing. In retrospect, the earlier trials that looked bad were predictive, while the impressive numbers appear to have been artifacts. But how do you figure that out in advance? And how do you run only the trials that will be predictive, and how do you know to trust them? I'm tempted to ask Francis Collins to get on this for all of us, but that would be unfair. I think.

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

February 22, 2011

Oncology Follow-Up Trials

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Posted by Derek

During the most recent Avastin controversy (with its conditional approval for metastatic breast cancer being pulled by the FDA), the role of follow-up studies in oncology became a big point of discussion.

Now there are reports that some companies aren't exactly following up in the way that they're supposed to. This isn't good. Conditional approvals are granted under the banner of "better to help people now than wait for more data", but eventually the numbers have to show up. After all, not all of these treatments are going to confirm when they're looked at more closely.

Not all of this can be put down to foot-dragging on the part of the companies. In some cases, it's proven hard to round up enough patients for further trials, and in others, the trial protocols themselves have become outdated. But there needs to be some way to review these things more regularly (as seems to be the case in the EU) to keep the process from getting tangled up.

You'll note from the article that opinions are all over the place on how lenient the FDA's approval process really is. You have people who say that the agency is dragging its feet on life-saving treatments, and people (looking at the same data set) who say that they're letting too much stuff through on the flimsiest grounds. We're not going to resolve that argument any time soon. But can we at least agree that we're going to require evidence at some point?

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

January 31, 2011

Sanofi's PARP1 Inhibitor Misses

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Posted by Derek

Past results, they tell you, are no guarantee of future performance. Sanofi-Aventis is ready to tell you all about that after the results of a Phase III trial of their recently acquired oncology drug, iniparib (BSI-201). This had shown very strong results in Phase II against "triple-negative" breast cancer, but it appears to have missed two survival endpoints in a larger trial. Sanofi bought BiPar, the company that had been developing the drug, a little less than two years ago.

Iniparib's a small molecule indeed - small enough that its systematic name can be immediately parsed by any sophomore chemistry student. It's 4-iodo-3-nitrobenzamide; it's the sort of thing you can order out of a catalog. But it's also an inhibitor of poly-(ADP-ribose) polymerase I (PARP1), and it's the first compound of that class to get this far in the clinic. PARP1 is part of a DNA repair pathway, although it's not on the front line. That would be homologous recombination, which is the pathway that needs the well-known BRCA to function. The idea has been that since so many aggressive breast cancers are deficient in BRCA, that they'd be especially sensitive to something that targeted PARP as well - they should accumulate so many DNA breaks that they'd be unable to replicate.

That's a perfectly reasonable theory. But it doesn't seem to have yielded perfectly reasonable results in this case. Problem is, PARP1 has a lot of functions in the cell, and inhibiting the lot of them all at once may not be such a good idea. One possibility is that effects on the Akt pathway might boomerang and reduce the effectiveness of therapy.

More broadly, this is yet another illustration of the perils of Phase II data. And it does make a person think about the idea of tightening up the endpoints of such trials even more. Problem is, you often don't get good survival numbers until Phase III, anyway, by which time you've spent the money. Like Sanofi-Aventis is spending it now. Let's hope that one of the other indications for the drug works out better.

Update: here's a rundown on competition in this field. The next round of clinical data will be quite interesting. . .

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

January 24, 2011

Not Enough Progress Against Cancer?

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Posted by Derek

Here's a topic that's come up here before: for a new cancer drug, how much benefit is worthwhile? As it stands, we approve things when they show a statistically meaningful difference versus standard of care (with consideration of toxicology and side effects). But should our standards be higher?

That's what this paper in the Journal of the National Cancer Institute is proposing. The authors look at a number of recent Phase III trials for metastatic solid tumors. It's a tricky business:

When designing a randomized phase III clinical trial, the investigators must specify in the protocol the difference (δ) in the primary endpoint between experimental and control groups that they aim to detect or exclude (24). The number of patients to be recruited and the duration of the study will depend on the value of δ; increasing the sample size will allow the detection or exclusion of smaller values of δ. Ideally, trials should be designed such that δ represents the minimum clinically important difference, taking into account the tolerability and toxicity of the new treatment, that would persuade oncologists to adopt the new treatment in place of the standard treatment. Of course, the opinions of oncologists as to what constitutes a minimal important value of δ will vary, but a reasonable consensus can be reached by seeking the opinions of oncologists who manage a given type of cancer. For example, an increase in median survival by less than 1 month for patients with advanced-stage cancer would not be regarded by most as clinically important, unless the new agent had less toxicity than standard treatment, whereas an improvement of median survival by greater than 3 months for a drug that was reasonably well tolerated would usually be accepted as clinically important.

And the problem is, given the costs of some of these drugs versus their benefits, you run the risk of, finally, paying too much for too little. I know that people say that you can't put a cost on a human life, but that's probably not true, when you're talking about an entire economy. As the article points out, the rough estimate is that the developed world can support expenditures of up to roughly US $100,000 per year of life gained, but past that, we're into arguable territory. (If someone wants to spend more out of their own pocket, that's another matter, naturally, but at these levels, we're usually talking public and private insurance).

The benefits can indeed be marginal, and you have to look at the statistics carefully so as not to be misled:

. . .several trials showed a statistically significant difference in a major outcome measure between the experimental and control groups, but the difference in outcome was of lower magnitude (eg, hazard ratio was closer to one) than that specified in the protocol. For example, the clinical trial that led to approval of erlotinib for treatment of pancreatic cancer was designed to detect a relative risk reduction of 25% (HR ≤ 0.75), but the best estimate of hazard ratio from the trial showed a relative risk reduction of 18% (HR = 0.82, 95% confidence interval = 0.69 to 0.99). The difference was statistically significant (P = .038), but the median survival differed by only 10 days.

What happens is that the trials are (understandably enough) designed to detect the minimum difference that regulatory authorities are likely to find convincing enough for approval of the drug. And the FDA has generally set the bar at "anything that's statistically significant for overall survival". These authors (and others) would like to see that raised. They're calling for trials not to go for a statistically significant P value, so much as to show some sort of meaningful clinical benefit - because it's become clear that you can have the first without really achieving the second.

I think that might be a good idea, whether or not you buy into that cost-per-year-of-life figure or not. At this point, I think it's fair to say that we can come up with drugs that provide some statistical measure of efficacy, given enough effort in the clinic, for many kinds of cancer (although certainly not all of them). But how many add-a-month-maybe therapies do we need? Not everyone's convinced, though:

Wyndham Wilson, a lymphoma researcher at the National Cancer Institute in Bethesda, Maryland, argues that the proposed clinical endpoints are somewhat arbitrary. “What constitutes a clinically meaningful difference? Six months is obvious, but where do you cut the line?” What's more, he adds, simply focusing on median responses often ignores important outlier effects that could merit approval for an experimental drug. “The difference in overall survival may not be great, but it may be driven by a great benefit to a small group,” he says.

Problem is, it's often quite difficult to figure out who that small group might be, and just treat them, instead of treating everyone and hoping for the best. And there's always the argument that these therapies are stepping stones to more significant improvements, but I wonder about that. My impression of oncology research has always been more like "OK, this looks reasonable. Lots of these tumors have UVW upregulated; let's make an UVW inhibitor. (Years later): Hmm, that's disappointing. Our UVW inhibitor doesn't seem to do as much as you'd think it should. But now it's been found that XYZ looks like it's necessary for tumor growth; let's see if we can inhibit it. (Years later): Hmm, that's not as big an effect as you would have thought, either, is it? Seems to help a few people, but it's hard to say who they'll be up front. How's the JKL antagonist coming along? No one's tried that yet; looks like a good cell-division target. . ."

It's just sort of one thing after another - that one didn't work so well, neither did that one, this other one and these three together seem to be a bit better, but not always, and so on. Would we learn as much, or nearly so, just from the earlier clinical work on such compounds as opposed to taking them to market? And although you can't deny that there's been incremental progress, I'm not sure what form it's taking. It's very likely that the answer isn't to keep turning over mechanistic ideas until we find The One That Really Truly Works - cancer is a tough enough (and varied enough) disease that there probably isn't going to be one of those.

My guess is that meaningful cancer success will come from combinations of therapies that we mostly don't even have yet. I think that we'll need to hit several different mechanisms at the same time, but that some of what we'll need to hit hasn't even been discovered. And on top of that, each patient presents a slightly different problem, and ideally would receive a more customized blend of therapies (not that we know how to do that, either, in most cases).

What I'm saying is that we'll probably need combinations of things that already work better than most of what we have already, and that these will stand out enough in clinical trials that we'll know that they're worth developing. As it stands, though, companies see hints here and there in the clinic, enough to run a Phase III trial, and if it's large enough and tightly controlled enough, they see enough efficacy to get things through the FDA and onto the market. Would we be better off to not proceed with the marginal stuff, and put the significant amounts of money into things that stand out more? Or would that choke off the market too much, since we mostly end up making marginal things anyway (damn it all), leaving no one able to keep going long enough to find the good stuff? It's a hard business.

Comments (32) + TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs

January 20, 2011

Merck's Vorapaxar: Bleeding, Indeed

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Posted by Derek

So, as had been suspected, the reason that Merck's thrombin antagonist vorapaxar ran into clinical trouble was excessive bleeding. This is always the first thing to suspect when an anticoagulant has difficulty in human trials.

It's really a delicate balance, the human clotting cascade, and it's all too easy to end up on the wrong side of it. When you think about it, the whole pathway has to be under very tight regulation - I mean, here's the fluid that transports oxygen and nutrients and removes waste. Absolutely crucial to the life of every cell in the body. And here's an option to have that fluid thicken up and turn to jelly, very quickly, and once it happens it can't be reversed. No, you're going to want a lot of safeguards around that switch. But if you lean over too far the other way, well. . .there's a lot of vascular plumbing in the body, and it gets a lot of stress. Leaks and rips are inevitable. You have to have a method for patching holes, and it has to be ready to go everywhere, at all times. Dial it down just a bit too much, and hemorrhages are inevitable. Thus all the different clotting mechanism steps, and the different drugs targeting them.

As Matthew Herper explains at that link above, the prospect for this drug are completely dependent on which side of the line it ends up on. In this patient population, it's already stepped over - another result like this one, and vorapaxar could be completely sunk.

Comments (8) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development

January 17, 2011

Reboxetine Doesn't Work. But That's Not the Real Problem.

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Posted by Derek

Some time ago, I took nominations for Least Useful Animal Models. There were a number of good candidates, many of them from the CNS field. A recent report makes me think that these are even stronger contenders than I thought.

The antidepressant reboxetine (not approved in the US, but sold in a number of other countries by Pfizer) was recently characterized by a German meta-analysis of the clinical data as "ineffective and potentially harmful". Its benefits versus placebo (and SSRI drugs) have been overestimated, and its potential for harm underestimated. It was approved in Europe in 1997, and provisionally by the FDA in 1999, although that was later rolled back when more studies came in that showed lack of efficacy.

Much has been made of the fact that Pfizer had not published many of the studies they conducted on the drug. These do seem, however, to have been available to regulatory authorities, and were the basis for the FDA's decision not to grant full approval. As that BMJ link discusses, though, there's often not a clear pathway, especially in the EU, for a regulatory agency to go back and re-examine a previous decision based on efficacy (as opposed to safety).

So the European regulatory agencies can be faulted for not revisiting their decision on this drug in a better (and quicker) fashion, and Pfizer can certainly be faulted for letting things stand (in the face of evidence that the drug was not effective). All this is worrisome, but these are problems that are being dealt with. Since 2007, for example, trials for the FDA have been required to be posted at, although the nontranparency of older data can make it hard to compare newer and older treatments in the same area.

What's not being dealt with as well is an underlying scientific problem. As this piece over at Scientific American makes plain, reboxetine, although clinically ineffective, works just fine in all the animal models:

And this is a rough moment for scientists studying depression. Why? Because reboxetine works beautifully in our animal models. It’s practically a poster-child antidepressant. It produces acute effects in tests such as forced-swim tests and tail-suspension tests (which use changes in struggle as a measure of antidepressant efficacy). It produces neurogenesis in the hippocampus, which is thought to be correlated with antidepressant effects. When behavioral pharmacologists are doing comparisons between older antidepressants and newer ones, reboxetine is often used as a positive control, a drug known to have an effect in the behavioral test of choice.

But it doesn’t work in patients. And patients are what matters. Now, scientists are stuck with a difficult question: What went wrong?

A very good question, and one without any very good answers. And this certainly isn't the first CNS drug to show animal model efficacy but do little good in people. So, how much is the state of the art advancing? Are we getting anywhere, or just doing the same old thing?

Comments (50) + TrackBacks (0) | Category: Animal Testing | Clinical Trials | Regulatory Affairs | The Central Nervous System | The Dark Side

January 13, 2011

Merck's Thrombin Antagonist In Trouble

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Posted by Derek

Very bad news today for Merck (and the Schering-Plough people therein). Their thrombin receptor antagonist vorapaxar (formerly SCH 530348) has run into trouble.

A review board monitoring the compound's clinical trials has suddenly halted two of them. All we know at the moment is that the drug is "not appropriate for stroke patients", and it's also being pulled from a study in people who have had mild heart attacks. The best guess, as with any drug in the clotting field, is that it may be causing bleeding instead, but we'll have to see. Problem is, those are two of the more important patient populations that a company would be targeting, and if there's trouble in those groups, then it could be waiting to show up in others as well.

Vorapaxar has an unusual history at Schering-Plough (I wrote about it here, with some personal experiences from my own time at the company thrown in). I'm very sorry to see this news - sorry for the patients involved (and those who won't be helped later on), for the researchers involved (several of whom I've worked with in the past), and for Merck's investors, who are taking about a 6% trim today on the NYSE.

This compound wasn't the whole reason for Merck to buy Schering-Plough, but it wasn't a small part of the deal, either. That other stuff had better work out. . .

Comments (12) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Clinical Trials | Drug Development

January 4, 2011

Detecting Single Cancer Cells

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Posted by Derek

This story on a new diagnostic method in oncology is getting a lot of attention in the press. It's a collaboration between J&J, a small company they've bought called Veridex, and several oncology centers to see if very sensitive monitoring of circulating tumor cells could be a more useful biomarker.

The press coverage has some hype in it - for one thing, all the stuff about detecting one single cancer cell in the whole body isn't too helpful. The cells have to be circulating in the blood, and they have to display the markers you're looking for, to start with. But I can't deny that this is an interesting and potentially exciting field. There's some evidence to suggest that circulating tumor cells could be a strongly predictive marker can in several kinds of cancer.

These studies are looking at the sorts of endpoints that clinicians (and patients, and the FDA) all respect: overall survival, and progression-free survival. As discussed around here before, it's widely felt in oncology that these are where the field should really be spending its time, rather than on tumor size and so on. (You'd think that tumor size or number of detectable tumors would correlate with survival, but in many cases it's a strikingly poor predictor - which is a shame, since those are easier and faster numbers to get). A blood test, on the other hand, that strongly correlates with survival would be a real advance.

The value would not just be in telling (some) patients that they're showing better chances for survival, although I'm sure that'll be greatly appreciated. It's the patients whose numbers come back worse that may well be helped out the most, because that indicates that the current therapy isn't doing the job, and that it's time to switch to something else (assuming that there is something else, of course). The more quickly and confidently you can make that call, the better.

And from a drug development perspective, the uses of such assays in clinical trials are immediately obvious. Additionally, I'd think that these would be a real help to rolling-enrollment Bayesian trial designs, since you could assign patients to (and move them between) the different study groups with more confidence.

The Veridex/J&J assay (called CellSearch) uses an ingenious magnetic immunochemical approach. Blood samples are treated with antibody-coated iron nanoparticles that recognize a common adhesion protein. The cells that get bound are separated magnetically on a diagnostic chip for further immunostaining and imaging. There are other techniques out there as well - here's an article from Technology Review on a competing one that's said to be more sensitive, and here's a San Diego company trying to enter the market with an assay that's supposed to be broader-based). The key for all of these things will be bringing the costs down (and the speed of production up, in some cases). These are tests that ideally would be run early and often, so the cheaper and faster the assay can be made, the better.

Now, of course, we just need some more therapies that work, so that when people find out that their current regimen isn't working, then they have something else to try. If these circulating-cell assays help us sort things out faster in the clinic, maybe we'll be able to make better use of our time and money to that end.

Comments (14) + TrackBacks (0) | Category: Analytical Chemistry | Cancer | Clinical Trials

December 1, 2010

Resveratrol (SRT501): Development Halted

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Posted by Derek

Back in May, GlaxoSmithKline halted a trial of SRT501, which is a formulation of resveratrol, in myeloma. Now the folks at the Myeloma Beacon site are the first with the news that the company has halted all further development:

According to a GlaxoSmithKline spokesperson, an internal analysis of the kidney failure cases has concluded that they “most likely were due to the underlying disease … However, the formulation of SRT501 was not well tolerated, and side effects of nausea / vomiting / diarrhea may have indirectly led to dehydration, which exacerbated the development of the acute [kidney] failure.”

For this reason, the company decided to halt further development of SRT501 in multiple myeloma. The SRT501 formulation of resveratrol “may only offer minimal efficacy,” explained the Glaxo spokesperson, while increasing the chances of kidney failure. . .

. . .In a separate statement to The Myeloma Beacon, a Glaxo spokesperson explained the rationale for the company’s decision to halt all development of SRT501. Ending all work on SRT501, the spokesperson said, will allow Glaxo to focus its resources on the development of drugs that act similarly to SRT501, but have more favorable properties. The spokesperson mentioned, in particular, SRT2104 and SRT2379 as drugs similar to SRT501 that the company is developing.

These compounds are still a bit of a mystery - they've been in the clinical trial registry for a while, and are certainly the subject of active investigation, but we don't know how they fit into the whole activation-of-SIRT1 brouhaha. They haven't been challenged by the critics of the work, nor specifically defended by GSK, so we're just going to have to see how they perform out there in the real world (which was always going to be the final word, anyway).

But this would appear to be it for resveratrol itself in the real world, as far as GSK's concerned. Hey, does this mean that they'll let their two former Sirtris execs start selling it again on the side, now that they have no interest in the parent compound? One doubts it. But why not?

Comments (27) + TrackBacks (0) | Category: Aging and Lifespan | Cancer | Clinical Trials

November 23, 2010

Of Deck Chairs, Six Sigma, And What Really Ails Us

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Posted by Derek

We talked a little while back here about "Lean Six Sigma" as applied to drug discovery organizations, and I notice that the AstraZeneca team is back with another paper on the subject. This one, also from Drug Discovery Today, at least doesn't have eleventeen co-authors. It also addresses the possibility that not everyone in the research labs might welcome the prospect of a business-theory-led revolution in the way that they work, and discusses potential pitfalls.

But I'm not going to discuss them here, at least not today. Because this reminds me of the post last week about the Novartis "Lab of the Future" project, and of plenty of other initiatives, proposals, alliances, projects, and ideas that are floating around this industry. Here's what they have in common: they're all distractions.

Look, no one can deny that this industry has some real problems. We're still making money, to be sure, but the future of our business model is very much in doubt. And those doubts come from both ends of the business - we're not sure that we're going to be able to get the prices that we've been counting on once we have something to sell, and we're not sure that we're going to have enough things to sell in the first place. (There, that summarized about two hundred op-ed pieces, some of them mine, in one sentence. Good thing that I'm not paid by the word for this blog.) These problems are quite real - we're not hallucinating here - and we're going to have to deal with them one way or another. Or they're going to deal with us, but good.

I just don't think that tweaking the way that we do things will be enough. We're not going to do it by laying out the labs differently, or putting different slogans up on the walls, or trying schemes that promise to make the chemists 7.03% more productive or reduce downtime in the screening group by 0.65 assays/month. This is usually where people trot out that line about rearranging deck chairs on the Titanic, but the difference is, we don't have to sink. The longer things go on, though, the more I worry that incremental improvements aren't going to bail us out.

This is a bit of a reversal for me. I've said for several years that the low success rates in the industry mean that we don't necessarily have to make some huge advance. After all, if we made it up to just 80% failure in the clinic, that would double the number of drugs reaching the market. That's still true - but the problem is, I don't see any signs of that happening. If success rates are improving anywhere, up and down the whole process from target selection to Phase III, it's sure not obvious from the data we have.

What worries me is that the time spent on less disruptive (but more bearable) solutions may be taking away from the time that needs to be spent on the bigger changes. I mean, honestly, raise your hands: who out there thinks that "Lean Six Sigma" is the answer to the drug industry's woes? Right. Not even all the consultants selling this stuff could get that one out with a straight face. "But it'll help!" comes the cry, "and it's better than doing nothing!". Well, in the short term, that may be true, although I'm not sure if there is a "short term" with some of these things. If it gives managers and investors the illusion that things are really being fixed, though, and if it takes mental and physical resources away from fixing them, then it's actually harmful.

What would it take to really fix things? Everyone knows - really, everyone does. Some combination of progress on the following questions would do just fine:

1. A clear-eyed look at target-based drug design, by which I mean, whether we should be doing it at all. More and more, I worry that it's been a terrible detour for the whole project of pharmaceutical research. There have been successes, of course, but man, look at the failures. And the number of tractable targets (never high) is lower than ever, as far as I can tell. If we're going to do it, though, we need. . .

2. The ability to work on harder target classes. The good ol' GPCRs and the easy-to-inhibit enzyme classes are still out there, and still have life in them, but the good ideas are getting thinner. But there are plenty of tougher mechanisms (chief among them protein-protein interactions) that have a lot of ideas running around looking for believable chemical matter. Making some across-the-board progress in those areas would be a huge help, but it would avail us not without. . .

3. Better selection of targets. Too many compounds fail in the clinic because of efficacy, which means that we didn't know enough about the biology going in. Most of our models of disease have severe limitations, and in many cases, we don't even know what some of those limitations are until we step into them. Maybe we can't know enough in many cases, so we need. . .

4. More meaningful clinical trials. And by that I mean, "for a given cost", because these multi-thousand-people multi-year things, which you need for areas like cardiovascular, Alzheimer's, osteoporosis, and so on, are killing us. We've got a terrible combination of huge potential markets in areas where we hardly know what we're doing. And that leads to gigantic, expensive failures. Could they somehow be less expensive? One way would be. . .

5. A better - and that means earlier - handle on human tox. I don't know how to do this one, either, but there are billions of dollars waiting for you if you can. Efficacy is the big killer in the late clinic these days, but that and toxicity put together account for a solid majority of the failures all the way through. (The rest are things like "Oops, maybe we should sell this program off" kinds of decisions).

There are plenty of others, but I think that improvements in those would fix things up just fine. Don't you? And maybe I'm just slow-witted, but I can't see how changing the way the desks face, or swapping out all the business cards for new titles, or realigning the therapeutic area teams - again - are going to accomplish any of it. At best, these things will make the current process run a bit better, which might buy us some more time before we have to confront the big stuff anyway. At worst, they'll accomplish nothing at all, but just give the illusion that something's being done.

To be fair, there are some initiatives around the industry that address these (and the other) huge problems. As I said, it's not like no one knows what they are. And to be fair, these really are difficult things to fix. Saying that you want to get a better early read on human tox in the clinic, the way I just did so blithely, is easy - actually doing something about it, or even finding a good place to start doing something about it, is brutally hard. But it's not going to be as brutal as what's been happening to us the last few years, or what's we're headed for if we don't get cracking.

Comments (53) + TrackBacks (0) | Category: Business and Markets | Clinical Trials | Drug Development | Drug Industry History

November 19, 2010

Merck's CETP Compound: Still Alive, But The Big Fun Awaits

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Posted by Derek

Four years after the torcetrapib disaster, Merck has released some new clinical trial data on their own CETP inhibitor, anacetrapib. It's doing what it's supposed to, when added to a statin regimen: decrease LDL even more, and strongly raise HDL.

So that's good news. . .but it would actually be quite surprising if these numbers hadn't come out that way. Pfizer's compound had already proven the CETP mechanism; their compound did the same thing at this stage of the game. The problems came later, and how. And that's where the worrying kicks in.

As far as I know, no one is still quite sure why torcetrapib actually raised the death rate slightly in its phase III treatment group. One possible mechanism was elevated blood pressure (part of a general off-target effect on the adrenals) and Merck saw no sign of that. But no matter what, we're going to have to wait for a big Phase III trial, measuring real-world cardiovascular outcomes, to know if this drug is going to fly, and we're not going to see that until 2015 at the earliest. Well, unless there's unexpected bad news at the interim - that, we'll see.

I hope it doesn't happen. If the whole LDL-bad HDL-good hypothesis is correct, you'd think that a CETP inhibitor would show a strong beneficial effect. This compound is either going to help a lot of people, or it's going to tell us something really significant that we didn't know about human lipid handling (and/or CETP). Problem is, telling us something new is almost certainly going to be the same as telling us something bad. It's still going to be a long road in this area, and good luck to everyone involved. . .

Comments (17) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology

October 19, 2010

Trusting the Medical Literature?

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Posted by Derek

How reliable is the medical literature, anyway? This profile of John Ioannidis at The Atlantic is food for thought. Ioannidis is the man behind the famous "Why Most Published Medical Findings Are False" paper a few years ago, and many others in the same vein.

The problems are many: publication bias (negative findings don't get written up and reported as often), confirmation bias, and desire to stand out/justify the time and money/get a grant renewal. And then there's good old lack of statistical power. Ioannidis and his colleagues have noted that far too many studies that appear in the medical journals are underpowered, statistically, relative to the claims made for them. The replication rates of such findings are not good.

Interestingly, drug research probably comes out of his analysis looking as good as anything can. A large confirmatory Phase III study is, as you'd hope, the sort of thing most likely to be correct, even given the financial considerations involved. Even then, though, you can't be completely sure - but contrast that with a lot of the headline-grabbing studies in nutrition or genomics, whose results are actually more likely to be false than true.

Ioannidis's rules from that PLoS Medicine paper are worth keeping in mind:

The smaller the studies conducted in a scientific field, the less likely the research findings are to be true.

The smaller the effect sizes in a scientific field, the less likely the research findings are to be true.

The greater the number and the lesser the selection of tested relationships in a scientific field, the less likely the research findings are to be true.

The greater the flexibility in designs, definitions, outcomes, and analytical modes in a scientific field, the less likely the research findings are to be true.

The greater the financial and other interests and prejudices in a scientific field, the less likely the research findings are to be true.

The hotter a scientific field (with more scientific teams involved), the less likely the research findings are to be true.

And although he's talking about the published literature, these things are well worth keeping in mind when you're looking at your own internal data in a drug discovery project. Some fraction of what you're seeing is wrong.

Comments (17) + TrackBacks (0) | Category: Clinical Trials | Drug Development | The Scientific Literature

August 17, 2010

Avastin: Taking It Back

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Posted by Derek

As if one were needed, here's an example of how rough the state of current oncology therapy is today. Avastin, the antibody-based therapy from Genentech/Roche, had been approved (conditionally) for advanced breast cancer, based on a study showing about a five-month benefit in tumor growth. (Everyone should already know that such numbers, for many types of cancer, are indeed enough to get an indication approved, and everyone has, I'm sure, already decided what they think about that.)

But the approval came with a requirement to follow up on those results. For one thing, the study that led to conditional approval didn't show much of a survival benefit, making the approval itself controversial at the time.. The follow-up work has shown that those initial results were right on target. For metastatic breast cancer, Avastin has something like a month-and-a-half survival benefit. That probably doesn't outweigh the risks, and the FDA is seriously thinking about revoking that earlier approval.

Based on these numbers, I think that they should go ahead and do that. The whole point of conditional or accelerated approval is that it can go either way when the harder numbers come in, and in this case, it seems pretty clear that the benefit isn't there. No one cares about tumor growth if it doesn't affect survival or (at the very least) quality of life. And in this case, the later studies have suggested that even the earlier tumor growth numbers were too optimistic. You have to be willing to abide by the evidence.

Because of Avastin's high cost, this is probably going to turn into a rationing-health-care argument - in fact, it probably has already. But I'm not even talking cost here. Avastin, by the evidence we have, does not seem to help advanced breast cancer patients. It wouldn't help them even if it were free.

Comments (30) + TrackBacks (0) | Category: Cancer | Clinical Trials

August 16, 2010

Cancer Cells: Too Unstable For Fine Targeting?

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Posted by Derek

The topic of new drugs for cancer has come up repeatedly around here - and naturally enough, considering how big a focus it is for the industry. Most forms of cancer are the very definition of "unmet medical need", and the field has plenty of possible drug targets to address.

But we've been addressing many of them in recent years, with incremental (but only rarely dramatic) progress. It's quite possible that this is what we're going to see - small improvements that gradually add up, with no big leaps. If the alternative is no improvement at all, I'll gladly take that. But some other therapeutic areas have perhaps made us expect more. Infectious disease, for example: the early antibiotics looked like magic, as patients that everyone fully expected to die started asking when dinner was and when they could go home. That's what everyone wants to see, in every disease, and having seen it (even fleetingly), we all want to have it happen again.

And it has happened for a few tumor types, most notably childhood leukemia. But we definitely need to add more to the list, and it's been a frustrating business. Believe me, it's not like we in the business aiming for incremental improvements, a few weeks or months here and there. Every time we go after a new target in oncology, we hope that this one is going to be - for some sort of cancer - the thing that completely knocks it down.

We may be thinking about this the wrong way, though. For many years now, there have been people looking at genetic instability in tumor cells. (See this post from 2002 - yes, this blog has been around that long!) If this is a major component of the cancerous phenotype, it means that we could well have trouble with a target-by-target approach. (See this post by Robert Langreth at Forbes for a more recent take). And here's a PubMed search - as you can see, there's a lot of literature in this field, and a fair amount of controversy, too.

That would, in fact, mean that cancer shares something with infectious disease, and not, unfortunately, the era of the 1940s when the bacteria hadn't figured out what we could do to them yet. No, what it might mean is that many tumors might be made of such heterogeneous, constantly mutating cells that no one targeted approach will have a good chance of knocking them down sufficiently. Since that's exactly what we see, this is a hypothesis worth taking seriously.

There are other implications for drug discovery. Anyone who's worked in oncology knows that the animal tumor models we tend to use - xenografts of human cell lines - are not particularly predictive of success. "Necessary but nowhere near sufficient" is about as far as I'd be willing to go. Could that be because these cells, however vigorously they grow, have lost (or never had) that rogue instability that makes the wild-type tumors so hard to fight? I haven't seen a study of genetic instability in these tumor lines, but it would be worth checking.

What we might need, then, are better animal models to start with - here's a review on some efforts to find them. From a drug discovery perspective, we might want to spend more time on oncology targets that work outside the cancer cells themselves. And clinically, we might want to spend more time studying combinations of agents right from the start, and less on single-drug-versus-standard-of-care studies. The disadvantage there is that it can be hard to know where to start - but we need to weigh that against the chances of a single agent actually working

Comments (49) + TrackBacks (0) | Category: Animal Testing | Cancer | Clinical Trials | Drug Development

August 13, 2010

Alzheimer's Markers and Collaboration

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Posted by Derek

I'm of two minds on this New York Times article on Alzheimer's research. It details some recent progress on biomarkers for the disease, and that work does look to be useful. A lot of people have proposed diagnostics and markers for Alzheimer's and its progression over the years, but none of them have really panned out. If these do, that's something we haven't had before.

But my first problem is something we were talking about here the other day. Biomarkers are not necessarily going to help you in drug development, not unless they're very well validated indeed. We really do need them in Alzheimer's research, because the disease progression is so slow. And this effort is really the only way to find such things - a good-sized patient sample, followed over many years. But unfortunately, 800 people (divided out into different patient populations) may or may not be enough, statistically. We're now going to have to take the potential assays and markers that this work has brought up and see how well they work on larger populations - that's the only way that they'll be solid enough to commit a clinical trial to them. Both the companies developing drugs and the regulatory agencies will have to see convincing numbers.

That general biomarker problem is something we really can't do anything about; the only cures are time, effort, money, and statistical power. So it's not a problem peculiar to Alzheimer's (although that's a tough proving ground), or to this collaborative effort. But now we come to the collaborative effort part. . .overall, I think that these sorts of things are good. (This gets back to the discussions about open-source drug discovery we've been having here). Bigger problems need sheer manpower, and smaller ones can always benefit from other sets of eyes on them.

The way that this Alzheimer's work puts all the data out into the open actually helps with that latter effect. All sorts of people can dig through the data set, try out their hypotheses, and see what they get. But I think it's important to realize that this is where the benefit comes from. What I don't want is for people to come away thinking that the answer is that we need One Big Centralized Effort to solve these things.

My problem with the OBCE model, if I can give it an acronym, is that it tends to cut back on the number of ideas and hypotheses advanced. Big teams under one management structure don't tend to work out well when they're split up all over the place. There's managerial (and psychological) pressure, from all directions, to get everyone on the same idea, to really get in and push that one forward with all the resources. This is why I worry about all the consolidation in the drug industry: fewer different approaches get an airing when it's all under the roof of one big company.

So this Alzheimer's work is just the sort of collaboration I can admire: working on a big problem, sharing the data, and leaving things open so that everyone with an idea can have a crack at it. I just hope that people don't get the wrong idea.

Comments (3) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Press Coverage | Who Discovers and Why

August 12, 2010

Resveratrol (SRT501): Buy Now - Why Wait?

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Posted by Derek

Update - see below for more on this story. GSK has reacted quickly. . .

Now this seems rather odd. According to Xconomy, two former Sirtris higher-ups have formed a nonprofit foundation which is selling resveratrol online.

Michelle Dipp, a Sirtris-turned-Glaxo executive, confirmed that the nonprofit that she and former Sirtris CEO Christoph Westphal co-founded last year has started online sales of resveratrol. Dipp leads the effort on the off hours when she isn’t doing her main job as senior vice president of Glaxo’s Center of Excellence for External Drug Discovery.

While the group is charging $540 for a one-year supply of resveratrol, Dipp says that the nonprofit is selling the supplements for cost and is not profiting from the sales.

And thanks to Hatch-Waxman, since this is being offered as a "dietary supplement", hey, it can go straight into people - people with $540, anyway:

To be clear, this resveratrol operation is a volunteer effort that Dipp and Westphal do on the side. Both are still employees of Glaxo, and they have also started a Boston venture firm called Longwood Founders Fund with fellow Sirtris co-founder Rich Aldrich.

“Our main business is brining new drugs to patients through our work at Longwood and (Glaxo),” says Dipp, who is president of the Healthy Lifespan Institute. “But there was so much demand for (resveratrol).”

I really don't know what to make of this. This formulation of resveratrol would appear to be basically SRT501, which has been involved in a number of clinical trials (and unexpectedly dropped out of one not too long ago). I can't recall another case where an investigational drug has also been sold as a dietary supplement, by some of the same people, who are working both for the company funding the trials and for a nonprofit foundation. I mean, what if GSK/Sirtris find a clinically relevant use for resveratrol? Why buy it from them if you can get it at cost? Or would all that change if SRT501 gets FDA approval? Makes a person's head hurt, it does. . .

Update - GSK has now asked Dipp and Westphal to resign from their institute, saying that they didn't realize that they were selling resveratrol. That didn't take long!

Comments (69) + TrackBacks (0) | Category: Aging and Lifespan | Clinical Trials

July 27, 2010

Alzheimer's and Amyloid, Again

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Posted by Derek

I wanted to mention this good article in the New York Times on the amyloid hypothesis and Alzheimer's. That's a topic I've covered often here, but this is a good overview of the field. And it's a good overview of the field's big questions, too: is amyloid really the cause of Alzheimer's? Do we have any therapies that can slow amyloid deposition, or not? If so, do any of them actually show any real-world benefit to patients?

This gets into the broader question of biomarkers as well. The FDA is insisting, as they should, that any potential Alzheimer's therapy should show improvements in memory or cognition, not just improvements in number of plaques or the like. Getting that sort of data is very difficult, but it's really the only way to avoid yet another "You'd Have Thought That. . ." moment. We've been having too many of those over the last few years. As the FDA's director of neurology puts it:

“You only care if down the road the patient gets better,” Dr. Katz said. “What we are concerned about is approving a drug based on a lab test and being wrong about what happens to the patient clinically.”

With Alzheimer’s, Dr. Katz said, “the great fear is that maybe amyloid has nothing to do with the disease.” If that were the case, and the agency approved a drug that blocked amyloid formation, millions of healthy people could end up taking something useless or even dangerous. And because it takes so long for Alzheimer’s to develop, it could be decades, if ever, before anyone knew the drug did not work.

“It is a conundrum,” Dr. Katz said. “We all hope to get to the point in our understanding of the disease process where everyone in the field says: ‘Look. We know it now. Amyloid causes Alzheimer’s, and we have drugs that decrease amyloid.’ But we are not there yet.”

Biomarkers, ideally, are supposed to speed up drug development. But validating a good one might just as slow a process as if you didn't have a biomarker at all. What I worry about is a situation where the first people to discover these things end up with no chance to benefit from their work, but actually end up helping out other groups much more. And while there's a place for altruism in medical research, I doubt if making it the driving force will lead to success. . .

Comments (17) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

July 23, 2010

Vivus, Qnexa, Arena, Lorcaserin and the FDA

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Posted by Derek

One big story from the last week was the FDA advisory panel's "No" decision on Qnexa, the drug-combo obesity therapy developed by Vivus. This is the one that's a combination of phentermine and topiramate, both of which have been around for a long time. And clinical trials showed that patients could indeed lose weight on the drug (with the required diet and exercise) - but also raised a lot of questions about safety.

And it's safety that's going to always be a worry with any obesity drug, even once you get past the (rather large) hurdle of showing efficacy. That's what took the Fen-Phen combination off the market, and what torpedoed Acomplia (rimonabant) and the other CB-1 compounds before they'd even been property launched. The FDA panel basically agreed that Qnexa helps with weight loss, but couldn't decide how bad the side effects might be in a wider patient population, and whether they'd be worth it:

But the drug has side effects, both known and theoretical. It may cause birth defects, it may increase suicide risk, it can cause a condition called metabolic acidosis that speeds bone loss, it increases risk of kidney stones, and may have other serious effects.

"It is difficult if not impossible to weigh these issues as the clinical trials went on only for a year, and patients will use this drug for lifetime," (panel chair Kenneth) Burman said. "It is impossible to extrapolate the trial data to the wider population."

That's a problem, all right, and it's not just Vivus that has to worry about it. When the potential number of patients is so large, well, any nasty side effects that are out there will show up eventually. How do you balance all these factors? Is it possible at all? As that WebMD article correctly points out, a new obesity drug will come on the market with all kinds of labeling about how it's only for people over some nasty BMI number, the morbidly obese, people with other life-threatening complications, and so on. But that's not how it's going to be prescribed. Not after a little while. Not with all the pent-up demand for an obesity drug.

Although that's probably the worst situation, this problem isn't confined to obesity therapies - any other drug that requires long-term dosing has this hanging over it (think diabetes, for one prominent example). That brings up the question that anyone looking over clinical trial data inevitably has to face: how much are the trials telling us about the real world? After all, the only way to be sure about how a drug will perform in millions of people for ten years is to dose millions of people for ten years. No one's going to want to pay for any drugs that have been through that sort of testing, I can tell you, so that puts us right where we are today, making judgment calls based on the best numbers we can get.

The FDA itself still has that call to make on Qnexa, and they could still approve it with all kinds of restrictive labeling and follow-up requirements. What about the other obesity compound coming along, then? A lot of people are watching Arena's lorcaserin (which I wrote about negatively here and followed up on here). Arena's stock seems to have climbed on the bad news for Vivus, but I have to say that I think that's fairly stupid. Lorcaserin may well show a friendlier side-effect profile than Qnexa, but if the FDA is going to play this tight, they could just let no one through at all - or send everyone back to the clinic for bankrupting.

As the first 5-HT2C compound to make it through, lorcaserin still worries me. A lot of people have tried that area out and failed, for one thing. And being first-to-market with a new CNS mechanism, in an area where huge masses of people are waiting to try out your drug. . .well, I don't see how you can not be nervous. I said the same thing about rimonabant, for the same reasons, and I haven't changed my opinion.

Since I got a lot of mail the last time I wrote about Arena, I should mention again that I have no position in the stock - or in any of the other companies in this space. But I could change my mind about that. If Arena runs up in advance of their FDA advisory panel in the absence of any new information, I'd consider going short (with money I could afford to lose). If I do that, I'll say so immediately.

Comments (24) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | Regulatory Affairs | The Central Nervous System | Toxicology

July 13, 2010

Avandia: Was the Evidence Buried?

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Posted by Derek

The New York Times has added to the arguments over Avandia (rosiglitazone) this morning, with an above-the-fold front page item on when its cardiovascular risks were first discovered. According to leaked documents, that may have been as early as the end of 1999 - just a few months after the drug had been approved by the FDA.

According to Gardiner Harris's article, SmithKline (as it was at the time) began a study that fall, and "disastrous" results were in by the end of the year that showed "clear risk" of cardiovascular effects. (They must have been disastrous indeed to show up in that short a time, I have to say). He quotes a memo from an executive at the company:

“This was done for the U.S. business, way under the radar,” Dr. Martin I. Freed, a SmithKline executive, wrote in an e-mail message dated March 29, 2001, about the study results that was obtained by The Times. “Per Sr. Mgmt request, these data should not see the light of day to anyone outside of GSK,” the corporate successor to SmithKline.

The only possible way I can see this being taken out of context would be if the rest of the memo talked about how poorly run the study was and how unreliable its data were - in which case, someone was an idiot for generating such numbers. But that puts the company in the situation of "idiots" being the most benign (and least legally actionable) explanation. Which is not where you want to be.

Without seeing the actual material, it's hard to comment further. But what's out there looks very, very bad.

Comments (29) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | The Dark Side | Toxicology

June 11, 2010

Alzheimer's: Extracting Data From Failed Trials

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Posted by Derek

It's no secret that Alzheimer's disease has been a disastrous area in which to do drug discovery. Every large drug company has had failures in the area, and many smaller ones have gone out of business trying their hands. (I had several years in the field myself earlier in my career, trying three different approaches, none of which panned out in the end).

Now the Coalition Against Major Diseases has announced an open-access database of clinical trial results from failed drug candidates in the area. J&J, GlaxoSmithKline, Abbott, SanofiAventis, and AstraZeneca have contributed data from 11 failed drug candidates, and more look to be on the way from other companies. I hope that Eli Lilly, Merck (their own compounds and those from Schering-Plough), and Pfizer all join in on this - right off the top of my head, I can think of failed drugs from all of them, and I know that there are plenty more out there. (Pfizer seems to have dodged a question about whether or not they're participating, to judge from that Wall Street Journal article linked to above).

It'll be difficult to comb through all this to extract something useful, of course. But without sharing the data on these compounds, it would be utterly impossible for anything to come out of their failures. I think this is an excellent idea, and well worth extended to other therapeutic areas.

Comments (12) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Drug Industry History

May 27, 2010

Pfizer Halts a Trial Early - On Good News

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Posted by Derek

Pfizer was able to announce some good news today - their trial of Inspra (eplerenone) for patients with a particular combination of heart failure symptoms. The trial was halted early, but (for once) because the endpoints were reached so early that it would have been unethical to continue the placebo arm. It's always nice to hear about one of those; we don't get them that often.

The drug is an aldosterone antagonist which had already been approved several years ago for heart failure and hypertension, so it's not really a surprise that it worked in this population. But you never know, and Pfizer wanted to be able to get specifically recommended for patients of this type. And that they will.

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

May 14, 2010

DCA And Cancer: More Results

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Posted by Derek

In early 2007 there was quite a stir caused by reports of dichloroacetate (DCA) salts as possible cancer therapies. I didn't cover it as well as I should have here, partly because I was in the final stages of getting laid off from my previous job at the time, but here's a good roundup from Orac while the story was going on. It appeared that dichloroacetate was quite active in a number of cancer cell lines, where it worked by some sort of metabolic disruption pathway, quite possibly involving the Warburg effect through inhibition of mitochondrial PDHK. In short form, what that means is that some of these tumors stop using glucose exclusively as an energy source, and divert more of it into other pathways where it's used as a feedstock for the synthesis of other biomolecules. That allows the cells to get by on less oxygen (since the traditional glucose pathways use up a fair amount), which is particularly important in a solid tumor. This is also tied with with a resistance to apoptosis (programmed cell death), so it makes a pretty good package, if you're a tumor cell. But it does leave them metabolically vulnerable, and there have been attempts over the years to target this. (The latest idea in the area is a kinase called PKM2, a good candidate for the key switch that turns on the whole Warburg effect).

The news sent a lot of people searching for their own sources of dichloroacetic acid, and also was the occasion for a lot of "Unpatentable Cancer Wonder Drug Ignored By Big Pharma" commentary, which is always enjoyable. A new paper is now out in Science Translational Medicine looking at DCA in glioblastoma. That's a good place to look, because aggressive solid tumors of that sort are probably the most vulnerable to a Warburg-effect strategy. The authors found that mitochondia from glioblastoma tissue isolated from a number of patients do indeed show the signs of altered metabolism, which DCA reversed in cell culture. And they present the results of treating 5 patients over a period of months with oral DCA therapy.

How'd it work? They were able to compare pre- and post-therapy tissue samples in only three of the patients, but all three showed signs that more cells were undergoing apoptosis, slowing the growth of the tumors. So this wasn't an amazing cancer-disappears result, but it definitely keeps the story going. Three patients is not enough to draw robust conclusions from, of course, and they did see some (reversible) neuropathy as a side effect, but I'd say that DCA is still worth looking into on a larger scale.

Should cancer patients just up and take it themselves? It's really hard to recommend that, since we still don't know a lot about what's going on with the stuff. But it's also hard to tell someone with a refractory solid tumor not to try whatever they can get their hands on.

Update: more from Orac, including details of all five patients treated in this study.

Comments (43) + TrackBacks (0) | Category: Cancer | Clinical Trials

May 6, 2010

Perverse Incentives In Clinical Trials

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Posted by Derek

I came across an article from 2007 that I'd missed, and I'm willing to bet others have, too. It's on the sometimes perverse incentives in developing oncology drugs (although the points in it apply to many other fields as well. The author (Tony Fiorino) is an investor, not a researcher, and seems to be an exceptionally clear-headed one.

He notes that larger profitable companies have more of an incentive to be careful about what drug candidates they take into the clinic, since they're spending their own profits when they do so. Start-up companies, on the other hand, tend to get valued according to how many clinical candidates they have going, so their incentive is to push things along rather more. . .briskly. This will be a familiar phenomenon to many readers here - the topic has come up whenever we talk about some compound wiping out in Phase III after what looked like promising data:

"This factor often leads development-stage companies to make very poor assessments with their own product candidates and to radically misjudge their likelihood of success. Indeed, if the fortunes of the entire company depend on the fate of a single phase II compound, and the interests of those deciding whether or not to enter phase III are tied entirely to the ongoing viability of the company, it would hardly seem surprising that companies push forward with the development of drugs when to objective outside observers further development seems futile. Indeed the market is likely to punish correct decision making by development-stage biotechnology companies. Given a set of questionable phase II data, the stock price of a company would suffer far more if management concluded it would be improper to expend shareholder capital on a phase III program likely to fail than if management decided to forge ahead into phase III on the basis of some dubious, post hoc subgroup analyses."

Of course, when this article was written, the funding environment was more permissive than it is today - but it will surely go that way again, and anyway, when the money is tight, the pressures to fight for it are even stronger.

"Thus, market forces do not produce efficient drug development; at least for the biotechnology industry, they may actually hinder it. This is particularly true in oncology drug development, where a set of unique circumstances conspire to make drug development more difficult and increase the likelihood that drug candidates are advanced too quickly. Zia et al1 documented a high rate of phase III failures in oncology, even when the phase III protocol uses a regimen identical to what was used in phase II. In particular, the lack of reliable surrogate markers and the common practice of looking for response rates in single arm trials make phase II oncology trials unreliable.

Most troubling, in my view (which is admittedly the view of a battle-scarred skeptic), oncology clinical development programs often appear to be designed specifically not to provide insight into the likelihood of success in phase III. . ."

Remind you of any events of the last few years? Fiorino's only answer to these problems is to call for the oncology clinical community to be more skeptical when it comes to enrolling patients in Phase III trials. And that might help a bit, but in a better world, we'd be running better Phase IIs.

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

May 5, 2010

Steve Nissen vs. GlaxoSmithKline

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Posted by Derek

You don't often get to see so direct an exchange of blows as this: Steve Nissen, of cardiology and drug-safety fame, published an editorial about GlaxoSmithKline and Avandia (rosiglitazone) earlier this year in the European Heart Journal. And GSK took exception to it - enough so that that the company's head of R&D, Moncef Slaoui, wrote to the editors with a request:

". . .(the editorial) is rife with inaccurate representations and speculation that fall well outside the realm of accepted scientific debate. We strongly disagree with several key points within the editorial, most importantly those which imply misconduct on the part of GSK and have identified some of these issues below. On this basis, GSK believes that it is necessary for the journal to withdraw this editorial from the website and refrain from publishing it in hard copy, until the journal has investigated these inaccuracies and unsubstantiated allegations.

Instead of doing that the EHJ invited Nissen to rebut GSK's views, and ended up publishing both Slaoui's letter and Nissen's reply, while leaving the original editorial up as well. (Links are PDFs, and are courtesy of Pharmalot). Looking over the exchange, I think each of the parties score some points - but I have to give the decision to Nissen, because the parts that he wins are, to my mind, more important - both for a discussion of Avandia's safety and of GSK's conduct.

For example, Slaoui disagreed strongly with Nissen's characterization of the company's relations with a coauthor of his, Dr. John Buse. Nissen referred to him as a prominent diabetes expert who had been pressured into signing an agreement barring him from publicly expressing his safety concerns, but Slaoui countered by saying:

The document that Dr Buse signed was not an agreement barring him from speaking but was a factual correction regarding data, which did not bar him from speaking at all. In fact, Dr Buse subsequently communicated his views regarding the safety of rosiglitazone to FDA.

Nissen's reply is considerably more detailed:

The intimidation of Dr John Buse by GSK was fully described in a report issued by US Senate Committee on Finance.3 The Senate Report quotes an e-mail message from Dr Buse to me dated 23 October 2005 following publication of our manuscript describing the risks of the diabetes drug muraglitazar. In that e-mail, Buse stated: ‘Steve: Wow! Great job on the muraglitazar article. I did a similar analysis of the data at rosiglitazone’s initial FDA approval based on the slides that were presented at the FDA hearings and found a similar association of increased severe CVD events. I presented it at the Endocrine Society and ADA meetings that summer. Immediately the company’s leadership contact (sic) my chairman and a short and ugly set of interchanges occurred over a period of about a week ending in my having to sign some legal document in which I agreed not to discuss this issue further in public. I was certainly intimidated by them but frankly did not have the granularity of data that you had and decided that it was not worth it’. In an e-mail to GSK, Dr Buse wrote: ‘Please call off the dogs. I cannot remain civilized much longer under this kind of heat’

This, to me, looks like a contrast between legal language and reality, and in this case, I'd say reality wins. The same sort of thing occurs when the discussion turns to the incident where a copy of Nissen's original meta-analysis of Avandia trials was faxed to GSK while it was under review at the NEJM. Nissen characterizes this as GSK subverting the editorial process by stealing a copy of the manuscript, and Slaoui strongly disagrees, pointing out that the reviewer faxed it to them on his own. And that appears to be true - but how far does that go? GSK knew immediately, of course, that this was a manuscript that they weren't supposed to have, but it was then circulated to at least forty people at the company, where it was used to prepare the public relations strategy for the eventual NEJM publication. I don't think that GSK committed the initial act of removing the manuscript from the journal's editorial process - but once it had been, they took it and ran with it, which doesn't give them much ethical high ground on which to stand.

Many other issues between the two letters are matters of opinion. Did enough attention get paid to the LDL changes seen in Avandia patients? Did the lack of hepatotoxicity (as seen in the withdrawn first drug in this class) keep people from looking closely enough at cardiac effects? Those questions can be argued endlessly. But some of GSK's conduct during this whole affair is (unfortunately for them) probably beyond argument.

Comments (31) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | Toxicology | Why Everyone Loves Us

May 3, 2010

SRT501 - A Trial Suspended

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Posted by Derek

A comment to this post on the Sirtris compound saga just had me checking And indeed the commenter is correct: a trial against myeloma of a combination of Velcade (bortezomib) and SRT501, which I believe is reformulated resveratrol itself, was suspended as of April 22 for "unexpected safety concerns".

There's no way of knowing what those are, and it's worth keeping in mind that a number of other studies have been completed with SRT501. But since there's been (as far as I can tell) no mention of this trial's halt anywhere, I thought it worth noting.

Comments (35) + TrackBacks (0) | Category: Aging and Lifespan | Cancer | Clinical Trials

April 16, 2010

A Landmark In Clinical Trial Data Interpretation

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Posted by Derek

You know, let's just declare this "Sketchy Biotech Day" around here. A reader sends along this intriguing news item from Maryland regarding Rexahn Pharmaceuticals. They recently reported clinical data on their lead compound, Serdaxin,:

On Tuesday, the Rockville company reported the drug performed well in a phase 2a clinical trial for treating patients with one such ailment: major depressive disorder. But the announcement also said "the overall study did not achieve statistical significance," worrying investors and sending Rexahn's stock price tumbling from $3.53 to $1.76 that day.

Wednesday morning, executives felt compelled to issue a follow-up statement, offering "additional commentary, clarifications and insights" to allay investors' concerns. That apparently did the trick — at least somewhat. By the end of trading on Wednesday, the price had rebounded to $2.15. By Thursday morning, shares had climbed to $2.51; they were trading at $2.47 Thursday afternoon.

In its initial statement, Rexahn said that results from the trial, which enrolled 77 patients at several sites in the U.S., "are compelling and warrant further study in a larger phase 2 trial."

Well, to me, "compelling" clinical trial numbers are a hard thing to sell without the statistics to back them up. But that's not slowing these folks down. Here I offer you what is perhaps the most breathtaking rationalization I have yet heard about drug development - and mind you, that is saying a lot. Says Rexahn's CEO:

"Based on the feedback and reaction from our shareholders, stakeholders and other market participants, it is clear that neither the purpose of the Serdaxin trial or its results were well understood.

"The purpose of the Serdaxin Phase IIa trial was to establish, as a proof of concept, that Serdaxin can work as an antidepressant drug for patients suffering from Major Depressive Disorder," Ahn said. "I am happy to say that this is exactly what the study accomplished. The trial results unambiguously reach the conclusion that patients, especially those suffering from severe depression, respond positively to Serdaxin.

"Some market participants have asked us why our overall trial results were not statistically significant," he said. "The answer is simply that the Serdaxin study was never designed to achieve statistical significance as a primary objective, but rather to establish a positive signal among treated patients. This is exactly what the trial succeeded in accomplishing."

So here you have it: a clinical trial that was, apparently, not designed to show statistical significance. And it didn't! Champagne for everyone! Think of how many other drugs have had results just this compelling, but we've all just been too stupid to realize what we had. Throw open the pharma mausoleums and let the dead compounds come forth!

Perhaps some day we'll all look back on this event as the Day the Drug Industry Changed Forever. Or perhaps it's time to ask just what Serdaxin is. . .well, you'll never guess. It's clavulanic acid. (See, I told you that you wouldn't get it). Yep, the beta-lactamase inhibitor that's given as part of Augmentin, to overcome resistant strains of bacteria. Weirdly, it does seem to penetrate the blood-brain barrier, which is not something I would have guessed. And the Rexahn people have done some animal studies that suggest it has anxiolytic effects (as well as effects on sexual arousal, which they're not ignoring: that, friends, is the drug development candidate Zoraxel on their web site. Still clavulanic acid, though, but a rose by any other name. . .).

But none of that means a thing unless you achieve results in humans. And though I hate to contradict such a visionary mind as Dr. Ahn's, I'm afraid I'm going to have to hold out for statistical significance. And wonder, in the meantime, if any of the zillions of people who've taken clavulanate before ever noticed any elevation in their mood. Never happened to me, that's for sure. . .

Comments (53) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Infectious Diseases | The Central Nervous System

April 1, 2010

Ardea's Gout Drug Progresses

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Posted by Derek

Ardea's serendipitous gout drug RDEA594, which I wrote about here last year, is still alive. Phase IIb results had the compound meeting its endpoints (although not at the lowest dose), so on it goes to Phase III. Since we've been talking all week around here about how Phase III is a different world, it's worth noticing that the primary endpoint is still a biomarker (reduction of serum urate levels), not a real clinical outcome. But in the case of gout, that association is probably strong enough to be optimistic. Good luck to 'em.

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

March 30, 2010

Animal Studies: Are Too Many Never Published At All?

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Posted by Derek

A new paper in PLoS Biology looks at animal model studies reported for the treatment of stroke. The authors use statistical techniques to try to estimate how many have gone unreported. From a database with 525 sources, covering 16 different attempted therapies (which together come to 1,359 experiments and 19,956 animals), they find that only a very small fraction of the publications (about 2%) report no significant effects, which strongly suggests that there is a publication bias at work here. The authors estimate that there may well be around 200 experiments that showed no significant effect and were never reported, whose absence would account for around one-third of the efficacy reported across the field. In case you're wondering, the therapy least affected by publication bias was melatonin, and the one most affected seems to be administering estrogens.

I hadn't seen this sort of study before, and the methods they used to arrive at these results are interesting. If you plot the precision of the studies (Y axis) versus the effect size (X axis), you should (in theory) get a triangular cloud of data. As the precision goes down, the spread of measurements across the X-axis increases, and as the precision goes up, the studies should start to converge on the real effect of the treatment, whatever that might be. (In this study, the authors looked only at reported changes in infarct size as a measure of stroke efficacy). But in many of the reported cases, the inverted-funnel shape isn't symmetrical - and every single time that happens, it turns out that the gaps are in the left-hand side of the triangle, the not-as-precise and negative-effect regions of the plots. This doesn't appear to be just due to less-precise studies tending to show positive effects for some reason - it strongly suggests that there are negative studies that just haven't been reported.

The authors point out that applying their statistical techniques to reported human clinical studies is more problematic, since smaller (and thus less precise) trials may well involve unrepresentative groups of patients. But animal studies are much less prone to this problem.

The loss of experiments that showed no effect shouldn't surprise anyone - after all, it's long been known that publishing such papers is just plain harder than publishing ones that show something happening. There's an obvious industry bias toward only showing positive data, but there's an academic one, too, which affects basic research results. As the authors put it:

These quantitative data raise substantial concerns that publication bias may have a wider impact in attempts to synthesise and summarise data from animal studies and more broadly. It seems highly unlikely that the animal stroke literature is uniquely susceptible to the factors that drive publication bias. First, there is likely to be more enthusiasm amongst scientists, journal editors, and the funders of research for positive than for neutral studies. Second, the vast majority of animal studies do not report sample size calculations and are substantially underpowered. Neutral studies therefore seldom have the statistical power confidently to exclude an effect that would be considered of biological significance, so they are less likely to be published than are similarly underpowered “positive” studies. However, in this context, the positive predictive value of apparently significant results is likely to be substantially lower than the 95% suggested by conventional statistical testing. A further consideration relating to the internal validity of studies is that of study quality. It is now clear that certain aspects of experimental design (particularly randomisation, allocation concealment, and the blinded assessment of outcome) can have a substantial impact on the reported outcome of experiments. While the importance of these issues has been recognised for some years, they are rarely reported in contemporary reports of animal experiments.

And there's an animal-testing component to these results, too, of course. But lest activists seize on the part of this paper that suggests that some animal testing results are being wasted, they should consider the consequences (emphasis below mine):

The ethical principles that guide animal studies hold that the number of animals used should be the minimum required to demonstrate the outcome of interest with sufficient precision. For some experiments, this number may be larger than those currently employed. For all experiments involving animals, nonpublication of data means those animals cannot contribute to accumulating knowledge and that research syntheses are likely to overstate biological effects, which may in turn lead to further unnecessary animal experiments testing poorly founded hypotheses.

This paper is absolutely right about the obligation to have animal studies mean something to the rest of the scientific community, and it's clear that this can't happen if the results are just sitting on someone's hard drive. But it's also quite possible that for even some of the reported studies to have meant anything, that they would have had to have used more animals in the first place. Nothing's for free.

Comments (19) + TrackBacks (0) | Category: Animal Testing | Cardiovascular Disease | Clinical Trials | Drug Assays | The Scientific Literature

GeneVec's Pancreatic Cancer Therapy Crashes

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Posted by Derek

Another promising Phase II oncology idea goes into the trench in Phase III: GenVec has been working on a gene-therapy approach ("TNFerade") to induce TNF-alpha expression in tumors. That's not a crazy idea, by any means, although (as with all attempts at gene therapy) getting it to work is extremely tricky.

And so it has proved in this case. It's been a long, hard process finding that out, too. Over the years, the company has looked at TNFerade for metastatic melanoma, soft tissue sarcoma, and other cancers. They announced positive data back in 2001, and had some more encouraging news on pancreatic cancer in 2006 (here's the ASCO abstract on that one). But last night, the company announced that an interim review of the Phase III trial data showed that the therapy was not going to make any endpoint, and the trial was discontinued. Reports are that TNFerade is being abandoned entirely.

This is bad news, of course. I'd very much like gene therapy to turn into a workable mode of treatment, and I'd very much like for people with advanced pancreatic cancer to have something to turn to. (It's truly one of the worst diagnoses in oncology, with a five-year survival rate of around 5%). A lot of new therapeutic ideas have come up short against this disease, and as of yesterday, we can add another one to the list. And we can add another Promising in Phase II / Nothing in Phase III drug to the list, too, the second one this week. . .

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

March 29, 2010

Antisoma's Phase III Disaster

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Posted by Derek

We get reminded again and again that interesting Phase II results are only that: interesting, and no guarantee of anything. Antisoma (and their partner Novartis) are the latest company to illustrate that painful reality - their drug AS404 (vadimezan) looked in Phase II as if it might be a useful addition to oncology treatments, but has completely missed its endpoints in the bigger, more realistic world of Phase III. The trial was halted after an interim analysis showed basically no hope of it showing benefit if things continued.

There are many reasons for why these things happen. Phase II trials are typically smaller, and their patient populations are more carefully selected. And they're quite susceptible to wishful thinking. They're designed to keep things going, to show some reason to proceed, and they often do. If your drug candidate makes it through Phase II, that may say more about how you designed the trial than it says about the compound.

That's not to say that getting past Phase II is meaningless. Compared to having no efficacy data at all, it's a big step. But Phase III, when a compound goes out to a larger and more diverse patient population, is a much bigger one. And plenty of candidates aren't up to it.

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

March 26, 2010

Diminishing Returns

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Posted by Derek

As we slowly attack the major causes of disease, and necessarily pick the low-lying fruit in doing so, it can get harder and harder to see the effects of the latest advances. Nowhere, I'd say, is that more true than for cardiovascular disease, which is now arguably the most well-served therapeutic area of them all. It's not that there aren't things to do (or do better) - it's that showing the benefit of them is no easy task.

Robert Fortner has a good overview of the problem here. The size of the trials needed in this area is daunting, but they have to be that size to show the incremental improvements that we're down to now. He also talks about oncology, but that one's a bit of a different situation, to my mind. There's plenty of room to show a dramatic effect in a lot of oncology trials, it's just that we don't know how to cause one. In cardiovascular, on the other hand, the space in which to show something amazing has flat-out decreased. This is a feature, by the way, not a bug. . .

Comments (40) + TrackBacks (0) | Category: Cancer | Cardiovascular Disease | Clinical Trials | Drug Industry History

March 25, 2010

Nanoparticles and RNA: Now In Humans

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Posted by Derek

In recent years, readers of the top-tier journals have been bombarded with papers on nanotechnology as a possible means of drug delivery. At the same time, there's been a tremendous amount of time and money put into RNA-derived therapies, trying to realize the promise of RNA interference for human therapies. Now we have what I believe is the first human data combining both approaches.

Nature has a paper from CalTech, UCLA, and several other groups with the first data on a human trial of siRNA delivered through targeted nanoparticles. This is only the second time siRNA has been tried systemically on humans at all. Most of the previous clinical work has been involved direct injection of various RNA therapies into the eye (which is a much less hostile environment than the bloodstream), but in 2007, a single Gleevec-resistant leukaemia patient was dosed in a nontargeted fashion.

In this study, metastatic melanoma patients, a population that is understandably often willing to put themselves out at the edge of clinical research, were injected with engineered nanoparticles from Calando Pharmaceuticals, containing siRNA against the ribonucleotide reductase M2 (RRM2) target, which is known to be involved in malignancy. The outside of the particles contained a protein ligand to target the transferrin receptor, an active transport system known to be upregulated in tumor cells. And this was to be the passport to deliver the RNA.

A highly engineered system like this addresses several problems at once: how do you keep the RNA you're dosing from being degraded in vivo? (Wrap it up in a polymer - actually, two different ones in spherical layers). How do you deliver it selectively to the tissue of interest? (Coat the outside with something that tumor cells are more likely to recognize). How do you get the RNA into the cells once it's arrived? (Make that recognition protein is something that gets actively imported across the cell membrane, dragging everything else along with it). This system had been tried out in models all the way up to monkeys, and in each case the nanoparticles could be seen inside the targeted cells.

And that was the case here. The authors report biopsies from three patients, pre- and post-dosing, that show uptake into the tumor cells (and not into the surrounding tissue) in two of the three cases. What's more, they show that a tissue sample has decreased amounts of both the targeted messenger RNA and the subsequent RRM2 protein. Messenger RNA fragments showed that this reduction really does seem to be taking place through the desired siRNA pathway (there's been a lot of argument over this point in the eye therapy clinical trials).

It should be noted, though, that this was only shown for one of the patients, in which the pre- and post-dosing samples were collected ten days apart. In the other responding patient, the two samples were separated by many months (making comparison difficult), and the patient that showed no evidence of nanoparticle uptake also showed, as you'd figure, no differences in their RRM2. Why Patient A didn't take up the nanoparticles is as yet unknown, and since we only have these three patients' biopsies, we don't know how widespread this problem is. In the end, the really solid evidence is again down to a single human.

But that brings up another big question: is this therapy doing the patients any good? Unfortunately, the trial results themselves are not out yet, so we don't know. That two-out-of-three uptake rate, although a pretty small sample, could well be a concern. The only between-the-lines inference I can get is this: the best data in this paper is from patient C, who was the only one to do two cycles of nanoparticle therapy. Patient A (who did not show uptake) and patient B (who did) had only one cycle of treatment, and there's probably a very good reason why. These people are, of course, very sick indeed, so any improvement will be an advance. But I very much look forward to seeing the numbers.

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

March 22, 2010

Benford's Law, Revisited

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Posted by Derek

I mentioned Benford's Law in passing in this post (while speculating on how long people report their reactions to have run when publishing their results). That's the rather odd result that many data sets don't show a random distribution of leading digits - rather, 1 is the first digit around 30% of the time, 2 leads off about 18% of the time, and so on down.

For data that come from some underlying power-law distribution, this actually makes some sense. In that case, the data points spend more time being collected in the "lag phase" when they're more likely to start with a 1, and proportionally less and less time out in the higher-number-leading areas. The law only holds up when looking at distributions that cover several orders of magnitude - but all the same, it also seems to apply to data sets where there's no obvious exponential growth driving the numbers.

Lack of adherence to Benford's Law can be acceptable as corroborative evidence of financial fraud. Now a group from Astellas reports that several data sets used in drug discovery (such as databases of water solubility values) obey the expected distribution. What's more, they're suggesting that modelers and QSAR people check their training data sets to make sure that those follow Benford's Law as well, as a way to make sure that the data have been randomly selected.

Is anyone willing to try this out on a bunch of raw clinical data to see what happens? Could this be a way to check the integrity of reported data from multiple trial centers? You'd have to pick your study set carefully - a lot of the things we look for don't cover a broad range - but it's worth thinking about. . .

Comments (9) + TrackBacks (0) | Category: Clinical Trials | In Silico | The Dark Side

March 15, 2010

Tricor's Troubles

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Posted by Derek

It's easy to lose sight of what a drug is supposed to do. Many conditions come on so slowly that we have to use blood chemistry or other markers to see the progress of therapy in a realistic time. And over time, that blood marker can get confused with the disease itself.

To pick one famous example, try cholesterol. Everyone you stop on the street will know that "high cholesterol is bad for you". But the first thing you have to do is distinguish between LDL and HDL cholesterol - if the latter is a large enough fraction of the total, the aggregate number doesn't matter as much. And fundamentally, there's not a disease called "high cholesterol" - that's a symptom of some other cluster of metabolic processes that have gone subtly off. And the endpoint of any therapy in that field isn't really to lower the number in a blood test: it's to prevent heart attacks and to extend healthy lifetimes, mortality and morbidity. As we're seeing with Vytorin, it may be possible to drop the numbers in a blood test but not see the benefit that's supposed to be there.

Another example of this came up over the weekend. The fibrates are a class of drugs that change lipid levels, although the way they work is still rather obscure. They're supposed to be ligands for the PPAR-alpha nuclear receptor, but they're not very potent against it when you study that closely. At any rate, they do lower triglycerides and have some other effects, which should be beneficial in patients whose lipids are off and are at risk for cardiac problems.

But are they? Type II diabetics tend to be people who fit that last category well, and that's where a lot of fenofibrate is prescribed (as Abbott's Tricor in the US, and under a number of other names around the world). A five-year study in over five thousand diabetic patients, though, has just shown no difference versus placebo. Again, there's no doubt that the drug lowers triglycerides and changes the HDL/LDL/VLDL ratios. It's just that, for reasons unknown, doing so with fenofibrate doesn't seem to actually help diabetic patients avoid cardiac trouble.

Mortality and morbidity: lowering them is a very tough test for any drug, but if you can't, then what's the point of taking something in the first place? This is something to keep in mind as the push for biomarkers delivers more surrogate endpoints. Some of them will, inevitably, turn out not to mean as much as they're supposed to mean.

Comments (15) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | Drug Assays

March 11, 2010

Intermune's Rise

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Posted by Derek

If you want to know why people continue to speculate in biotech stocks, just take a look at the stairsteppy last few days of trading in Intermune (ITMN). Last Thursday it was at $15; now it's at $38. And all you have to do to cash in on these moves is read the FDA's mind!

That's not a money-making proposition, in case anyone thinks I'm advocating it. There are just too many surprises. But Intermune's good fortune started last week, when the FDA briefing documents came out on the application on the company's pirfenidone for idiopathic pulmonary fibrosis and were characterized as "not as bad as they could have been". (The company's history of overzealous PR wasn't helping it at this point). And if you still don't think that the moves in the stock have been surprising, consider that two ITMN executives sold shares on after the first jump, missing out on the second one completely when the FDA advisory panel gave the drug a favorable recommendation.

Pirfenidone, by the way, is another structure entry in the so-simple-I-can't-believe-it drug sweepstakes. If approved, it would be the first specific therapy for IPF, which can be a nasty disease. I certainly hope it helps out the patients involved (a few hundred thousand in the US), but that small patient population means that the drug isn't going to be cheap. Intermune's investors certainly don't think so.

But as has been clear for some time, we're in a rather tricky environment for expensive health care options. If pirfenidone makes it, I'd guess that it will be picked up widely, but cautiously, by health insurance. No one knows how it'll perform in the real world, and if little benefit is seen, it'll be hard to justify reimbursing for it. (It made one Phase III trial's endpoint, but missed another one, so there's room to wonder). The more cost-conscious European regulatory agencies will be a good place to watch this argument play out. One correspondent of mine refers to the drug as the next Iressa. That's not a compliment.

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

March 9, 2010

Hope Darn Well Springs Eternal

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Posted by Derek

Well, it takes all kinds to make a market. And the collapse in Medivation's shares after their disastrous Phase III results the other day seem to have brought out some hopeful buyers. Take this guy:

. . .I'm telling you right now, I believe that sell-off has gone twice as deep as good sense can justify. At least, that's the way I see it.

First off, we should understand that drug trials are Medivation's business. Clinical trials are what the company does. This failed phase 3 study isn't to be considered a crash into a brick wall. It's not a crippling lawsuit. It's not the loss of a major customer account. It's simply a sudden downshift, a temporary change of gears. In many ways, for Medivation, it's just one facet of business as usual.

As I look at Medivation's one-year and three-year performance charts, the opening to invest is just screaming at me. . .

All I can say is "Go for it, chief!" I might just add, very quietly, that early-stage drug discovery is not really the kind of business where one-year and three-year stock performance is much of a guide. And it's also worth remembering that although clinical trials are indeed what drug companies do, we try not to do big honking Phase III face-plants. You don't start clinical trials that you think are going to end that way, so a crash into a brick wall is actually not a bad analogy.

But hey - the dented hubcaps have just about finished wobbling around into the dust, and who knows, the stock might actually bounce back up a little bit, thanks to the brave and the foolhardy. But if Medivation is ever to make it back to where it was, I don't see how it's going to be because of Dimebon.

Via RJAlvarez on Twitter, who says "Tough call, but this is perhaps the worst post recommending a biotch stock I've ever read."

Comments (6) + TrackBacks (0) | Category: Business and Markets | Clinical Trials

March 4, 2010

Dimebon, Grasping at Straws

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Posted by Derek

Robert Langreth, an editor at Forbes, points to a possible way that Dimebon could get approval for Alzheimer's: for its behavioral effects, not anything to do with amyloid or memory.

I'm not buying it, I have to say. Even Langreth's source admits that behavioral numbers didn't reach statistical significance. I don't see how this will be enough to rescue this one, even if one of the ongoing trials does use a behavioral score as an endpoint.

Update: Langreth has an earlier piece on how Dimebon appears to have been overhyped from the beginning, a viewpoint I concur with. The same thing happens with any drug for Alzheimer's, and is a constant problem in cancer and obesity, too.

Comments (16) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | The Central Nervous System

March 3, 2010

Dimebon Comes Crashing to Earth

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Posted by Derek

Earlier this month I wrote about Medivation and their Russian-derived clinical candidate for Alzheimer's disease, Dimebon (latrepirdine). At the time, I wrote that "A lot of eye-catching numbers from small Phase II trials tend to flatten out in the wider world of Phase III, and if forced, that's the way I'd bet here."

Unfortunately, that's just what appears to have happened. The results are out today, and Dimebon has not showed any efficacy at all versus placebo. From the data given in the press release, the comparison is just absolutely flat; you could have been giving the study patients breath mints and seen the same numbers. Since the design of this trial was similar to the smaller Phase II trials that showed such interesting results, there's clearly something going on that we don't understand. But that's the motto for all central nervous system research, isn't it?

I'm really not sure if there's a way forward for this drug. When you go to a larger, more well-controlled trial and revert back to baseline, it's hard to make a case for continued development. Pfizer (Medivation's partner here) still has a lot of money and a lot of desire to find a good Alzheimer's drug. But I don't think they'll be in the mood to spend much more of it here.

Comments (30) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

February 26, 2010

HER2 Confusion

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Posted by Derek

For years now, drug companies and journalists have been touted the new era of personalized medicine. This is one of those things that always seems to be arriving, but is taking its time getting here. The industry has sunk a huge pile of money into biomarker research, and it's safe to say that it hasn't paid off yet - although, at the same time, one still has to think that it should, eventually.

Nature Biotechnology has a good article that shows how tricky the whole business can be. HER2 is one of the more validated cancer biomarkers, and there's a drug (Herceptin) that's targeted specifically for breast cancer patients that express it. So how's that going? Not so well:

A recent study from the University of California, San Francisco, reveals that one in five HER2 tests gives the wrong answer1. Furthermore, the article, which reviews the medical literature, reports that as many as two-thirds of breast cancer patients who should be tested for HER2 are not, and consequently a significant fraction of women treated with Genentech's Herceptin (trastuzumab) have never been tested for HER2 overexpression.

The health benefit provider Wellpoint, of Indianapolis, might dispute that finding. According to Genentech staff scientist Mark Sliwkowski, the insurer has data showing that 98% of its breast cancer patients are tested. However, doctors differ in their views on testing before prescribing Herceptin. “Some doctors don't know how to interpret test results, they prefer just to prescribe it and assess the patient's progress,” says Michael Liebman of the patient stratification company Strategic Medicine of Kennett Square, Pennsylvania.

More than a decade after the drug received US Food and Drug Administration (FDA) approval, the personalized medicine paradigm clearly has holes. . .

That it does. As the article goes on to explain, there are doubts about how good many of the existing HER2 tests are, worries about how they don't always agree, questions about whether some HER2-negative patients might be benefiting from Herceptin anyway, and more questions about those results due to uncertainties about the tests. That's the state of the art right there, folks, and it's clear that we have a long way to go. I don't see any reason why biomarkers (of various kinds, not just genetic) won't help us figure out which patients should be getting which drugs, but don't let anyone tell you that we're there yet.

Comments (15) + TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs

February 24, 2010

Steve Nissen's Meeting with GSK

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Posted by Derek

Well, this is interesting. Back when Steve Nissen was about to publish his meta-analysis on the safety of Avandia (rosigiltazone), he met with several GlaxoSmithKline executives before the paper came out. At the time, GSK was waiting on data from the RECORD study, which was trying to address the same problem (unconvincingly, for most observers, in the end). Nissen had not, of course, shown his manuscript to anyone at GSK, and for their part, the execs had not seen the RECORD data, since it hadn't been worked up yet.

Well, not quite, perhaps on both counts. As it happens, a reviewer had (most inappropriately) faxed a copy of Nissen's paper-in-progress to the company. And GSK's chief medical officer managed to refer to the RECORD study in such a way that it sounds as if he knew how it was coming out. How do we know this? Because Nissen secretly taped the meeting - legal in Ohio, as long as one party knows the taping is going on. At no point does anyone from GSK give any hint that they knew exactly what was in Nissen's paper. Here's some of it:

Dr. Krall asked Dr. Nissen if his opinion of Avandia would change if the Record trial — a large study then under way to assess Avandia’s risks to the heart — showed little risk. Dr. Krall said he did not know the results of Record.

“Let’s suppose Record was done tomorrow and the hazard ratio was 1.12. What does...?” Dr. Krall said.

“I’d pull the drug,” Dr. Nissen answered quickly.

The interim results of Record were hastily published in The New England Journal of Medicine two months later and showed that patients given Avandia experienced 11 percent more heart problems than those given other treatments, for a hazard ratio of 1.11. But the trial was so poorly designed and conducted that investigators could not rule out the possibility that the differences between the groups were a result of chance.

Somehow, I don't think that many pharma executives are going to agree to meetings with Nissen in his office in Cleveland after this. But I certainly don't blame him for making the tape, either.

Comments (24) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | The Dark Side | Toxicology

February 22, 2010

The Front Lines of Cancer Treatment

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Posted by Derek

The New York Times is starting a series of articles on the clinical trials of a recent B-Raf inhibitor (from Plexxikon and Roche, PLX4032). The first installment is an excellent look at what early-stage clinical research is like in this field. For example:

Typically, Phase 1 trials are limited to a few dozen patients and end when the dose reaches the point where side effects like rashes and diarrhea make patients too uncomfortable.

Dr. Flaherty and Dr. Chapman started the first three patients on 200 milligrams per day. After two months with no side effects — and no response — they doubled it.

Two more months passed, still nothing. They gave three more patients 800 milligrams, the equivalent of the dose that made tumors stop growing in mice. Even shrinking tumors, the doctors knew, would not mean the cancer had been cured but might at least offer a reprieve.

Dr. Flaherty pounced on the scans when they arrived. In some patients, tumors had remained the same size. “Maybe we’re starting to see something,” he could not help thinking. But at the next set of scans, the disease had progressed. On conference calls, Dr. Nolop sometimes referred to those patients as “responders.”

“They’re not responders,” Dr. Flaherty gently corrected him: under the accepted definition, tumors had to shrink to qualify patients as responders.

By the time they had doubled the dose four times, Dr. Flaherty could not help wondering if the targeted therapy skeptics were right. Dr. Chapman, crisp and businesslike on the weekly calls, supplied no comfort. He pointed out new research that B-RAF was mutated even in benign moles, and therefore could not be the key driver in melanoma. . .

What everyone involved in this work has to deal with is living between two very different mental states: you have to see people who are dying, and who you will probably not be able to help, even with your best efforts. But it's also possible that the next new thing you try might be the thing that keeps some of them alive. It's a hard place to work.

Back here in early research we don't see the patients, of course (which is good, since I'm pretty sure I couldn't take it). But we also have the same narrow path to walk: most of the compounds we make aren't drug candidates. Most of the drug candidates we send on for development fail. But the answer to that is not to stop making drug candidates, because every so often, something works.

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

February 3, 2010

Dimebon for Alzheimer's: A Black Box Indeed

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Posted by Derek

Dimebon (dimebolin) is a perfect example of the black-box nature of drug research for the central nervous system. Any medicinal chemist who looks at its structure would immediately say "CNS", but shrug when asked what specific receptors it might hit. I'd have guessed histamine (correctly), since loratidine used to pay my salary, and I also would have guessed a clutch of 5-HT stuff as well. But it also has activity at AMPA and NMDA glutamate receptors, L-type calcium channels, and more. If you can tell me what it's really doing up there, you shouldn't bother: hang up on me and start calling people with money, because you're ready to take over the CNS therapeutic area for sure.

This blunderbuss is getting a lot of attention these days, since the data for a Phase III trial against Alzheimer's should be available sometime in the spring. The road to that was a strange one. Dimebolin was used for years as an antihistamine in Russia, although I'm not aware if it had any particular reputation for cognitive enhancement in its time as a Soviet allergy pill. It was picked up in screening done during the 1990s at a research institute in the (once secret) military/industrial research city of Chemogolovka Chernogolovka, about two hours from Moscow. It showed effects on learning in rodent models, and gradually advanced to human trials for Alzheimer's. Impressive data came out in 2008, and Medivation, who own the rights to it here, partnered with Pfizer for development.

Update: the city mentioned above is surely Chernogolovka, but it's interesting that it's appeared many times as Chemogolovka in the English press and literature. I chalk that up to the "rn" looking very much like an "m", and to the mistaken name being semi-plausible in a Stalinist-industrial way, as witness Magnitogorsk. Chernogolovka's much older, though.)

That Bloomberg report I linked to above has a lot of people excited, since there hasn't been a new therapy for Alzheimer's in quite a while (or, arguably, a decent one ever). I don't know what to think, myself. It's absolutely possible that the drug could turn out to have beneficial effects, but it's just as possible that it could miss meeting the high expectations that many investors seem to have for it. (Medivation's stock is up 80% over the last year, for example). A lot of eye-catching numbers from small Phase II trials tend to flatten out in the wider world of Phase III, and if forced, that's the way I'd bet here. (I am most definitely not giving investment advice, though - Alzheimer's drug development is a total crap shoot, and should only be approached with money you can afford to see incinerated).

I hope that Dimebon actually works, though - the world could use something that does. Just don't let anyone convince you that they know how it works, if it makes it through. Unraveling that will take quite a while. . .

Comments (10) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | The Central Nervous System

January 20, 2010

A Database of Side Effects

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Posted by Derek

There's probably a lot of undiscovered information sitting out there in clinical trial data sets. And while I was just worrying the other day about people with no statistical background digging through such things, I have to give equal time to the flip side: having many different competent observers taking a crack at these numbers would, in fact, be a good thing.

Here's one effort of that sort, as detailed in Molecular Systems Biology. The authors have set up a database of all the side-effect information released through package inserts of approved drugs, which was much more of a pain than it sounds like, since the format of this information isn't standardized.

Looking over their data, the drugs with the highest number of side effects are the central nervous system agents, which makes sense. Many of these are polypharmacological; I'm almost surprised they aren't even worse by a wider margin. Antiparasitics have the fewest side effects (possibly because some of these don't even have to be absorbed?), followed by "systemic hormonal preparations". To be fair, the CNS category has the largest number of drugs in it, and those other two have the least, so this may be just a sampling problem. At a glance, one category that seems to have a disproportionate number of side effects, compared its number of approved drugs, is the "genitourinary/sex hormone" class, with muskoskeletal agents also making a stronger showing than their numbers might indicate.

Comments (15) + TrackBacks (0) | Category: Clinical Trials | Toxicology

January 18, 2010

Correlations, Lovely Correlations

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Posted by Derek

Anyone looking over large data sets from human studies needs to be constantly on guard. Sinkholes are everywhere, many of them looking (at first glance) like perfectly solid ground on which to build some conclusions. This, to be honest, is one of the real problems with full release of clinical trial data sets: if you're not really up on your statistics, you can convince yourself of some pretty strange stuff.

Even people who are supposed to know what they're doing can bungle things. For instance, you may well have noticed a lot of papers coming out in the last few years correlating neuroimaging studies (such as fMRI) with human behaviors and personality traits. Neuroimaging is a wonderfully wide-open, complex, and important field, and I don't blame people for a minute for pushing it as far as it can go. But just how far is that?

A recent paper (PDF) suggests that the conclusions have run well ahead of the numbers. Recent papers have been reporting impressive correlations between the activation of particular brain regions and associated behaviors and traits. But when you look at the reproducibility of the behavioral measurements themselves, the correlation is 0.8 at best. And the reproducibility of the blood-oxygen fMRI measurements is about 0.7. The highest possible correlation you could expect from those two is the square root of their product, or 0.74. Problem is. . .a number of papers, including ones that get the big press, show correlations much higher than that. Which is impossible.

The Neurocritic blog has more details on this. What seems to have happened is that many researchers found signals in their patients that correlated with the behavior that they were studying, and then used that same set of data to compute the correlations between the subjects. I find, by watching people go by the in the street, that I can pick out a set of people who wear bright red jackets and have ugly haircuts. Herding them together and rating them on the redness of their attire and the heinousness of their hair, I find a notably strong correlation! Clearly, there is an underlying fashion deficiency that leads to both behaviors. Or people had their hair in their eyes when they bought their clothes. Further studies are indicated.

No, you can't do it like that. A selection error of that sort could let you relate anything to anything. The authors of the paper (Edward Vul and Nancy Kanwisher of MIT) have done the field a great favor by pointing this out. You can read how the field is taking the advice here.

Comments (13) + TrackBacks (0) | Category: Biological News | Clinical Trials | The Central Nervous System

January 15, 2010

Sirtuin Scenarios

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Posted by Derek

So, after reading what Pfizer has to say about Sirtris (and by extension, about GlaxoSmithKline's heavy investment in them), let's go over the possibilities. What happened, and what's going on?

We'll start out with the first branch point: either Pfizer (and Amgen) are right that there's trouble with the Sirtris assays and compounds (Reality A, I'll call it), or they're wrong (Reality B). For the rest of this piece, I'm going to assume that they're right, because I think that this is almost certainly the case. At least two separate groups of competent investigators have reported trouble, and that's good enough for me. (We'll discuss the implications of that in a bit).

Now we come to the second branch point: either Glaxo did enough due diligence to be aware of the problems (scenario A1) or they didn't realize them at the time of the deal (scenario A2). If A1 is the case, then we'd have to assume that the most likely consequence (A1a) is that Sirtris had other non-public assets that did check out, and that GSK's management felt that these justified the purchase. (A1b would be the scenario where GSK was well aware of the Sirtris problems, knew also that they didn't have anything else to offer, and bought them anyway, which doesn't make sense). These assets could have been other compounds, and/or a leg up on the complicated biology of this field. The difficulty with that line of thinking is that having found the fundamental assay problems with the Sirtris work, the GSK people would surely have been much more cautious about drawing sweeping conclusions about the rest of the company's intellectual property.

If A2 is the case, then we're looking at sheer fecklessness on the part of GSK's upper management. I'd like to be able to rule this out, but there have been other deals in the history of this industry that make that hard to do. I have witnessed at least one such personally. One problem is that these deals tend to be initiated near the highest levels of a company, and these people are not always the most technically savvy (or up-to-date) members of an organization. Even with a science background, the CEO of a large company does not have the time to be a scientist. (I'm reminded of Peter O'Toole's character in My Favorite Year: "I'm not an actor - I'm a movie star!"

Overall, though, I find it hard to believe that no one would have noticed the reported problems at all, which leads me to favor what I'll call scenario A3: the problems with the Sirtris assays may well have been known/realized at the lower scientific levels of GSK's organization, but these concerns may not have made it to the top in a sufficiently timely or vigorous manner. The deal would have gone through under its own momentum, then, in a flurry of last-minute misgivings which would have been hard to distinguish from the usual butterflies that accompany any large transaction or the preliminary stirrings of buyer's remorse. The sorts of reasons advanced in the A1 paragraph above would have been used to justify pushing ahead. With that in mind, this scenario could be broken down further into A3a, where Sirtris also had some other assets that the rest of us haven't seen, and A3b, where they didn't. I think that A3a is more likely, since that would have provided some of the momentum to get the deal done regardless. A3b is basically A2 with different timing and slightly less cluelessness.

So where do things go from here? That obviously depends on which of those three realities obtains. If A1 (specifically A1a) is the case, then GSK plows ahead with their secret Sirtris assets and compounds, and good luck to all concerned. It's worth keeping in mind that sirtuins are quite interesting and important, and that it's an area worth investigating on its own merits. (Pfizer and Amgen, among others, must think so too; that's the only reason that they would have been trying to replicate the Sirtris work).

If A2 is the real story, well, I'm very sorry to hear it. A lot of people seem ready to believe this one, partly because of anger over the layoffs the company has been going through. The most likely consequence of A2 is that $720 million dollars disappears, never to yield anything that's of use to anyone, so I hope that this isn't what happened.

And if, as I think, A3 is what actually happened, then that sort of depends on whether we're looking at A3a or A3b. If the former, then Glaxo overpaid, but has a fighting chance to redeem itself. If the latter, then Glaxo not only overpaid, but (as with A2) is in danger of losing its whole investment as well. We'll all find out.

But we may not find out very quickly. GSK has (like many other companies) a tendency to be rather close-mouthed about the progress of some of its research. When I worked in the nuclear receptor field, we all were very interested in the fate of a particular Glaxo compound, the first selective PPAR-delta ligand to go into the clinic. The company had talked about some animal and preclinical data, but we knew that they were taking it into humans (after all, it was listed that way in their pipeline updates). But it stayed listed like that. . .and stayed. . .and stayed. . .until, as the months and years passed, it became obvious to even the most optimistic observer that the compound's development was (at the very least) extremely complicated, and (more likely) had actually quietly ceased a good while before, albeit with no change in its public status.

In this case, now that these doubts have come up, GSK has a real interest in pointing out any success it may have. If its sirtuin compounds go into the clinic and just sort of hang there, that will probably be an even worse sign than usual. And if no sirtuin compounds even go into the clinic at all, well, the question has answered itself. I hope that's not what happens.

Comments (61) + TrackBacks (0) | Category: Aging and Lifespan | Clinical Trials | Diabetes and Obesity | Drug Development

January 6, 2010

Lilly's R&D Outsourcing

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Posted by Derek

Yesterday's Wall Street Journal ran a story on Eli Lilly, all about how the company is outsourcing a lot of their drug development work. Since Lilly signed a big deal with Covance in 2008 to do just that sort of thing, the first thing you have to wonder is "Is this news?"

But some of the spin in this piece is interesting. Here, see what you think:

Not long ago, a big pharmaceutical company wouldn't have considered farming out the development of a compound found in-house. But expiring patents on top-selling drugs and high-profile failures in finding their replacements have pushed the biggest drug makers to "externalize" much of their R&D, said Peter Tollman, who advises drug makers at Boston Consulting Group. . .

. . .Lilly is relying on outside firms called contract research organizations to do the work. Company researchers, Mr. Tollman said, can get too attached to their own compounds to know when to let them go.

I'm not buying that last part at all. To me, the main reason that Lilly has been using CROs so much (through an R&D unit named Chorus) is that they feel that they can do the job more cheaply. The next most important reasons after that one are (1) that they can do the job for less money, (2) that they can do the job without Lilly spending so much cash, and (3) that they can do the job at lower cost. Have I left anything out?

As a correspondent put it, once you get into the clinic, "the data are the data", whether you're attached to the compound or not. The bigger danger is in how you set up the trials in the first place, whether you've done them in a realistic fashion, and a CRO can fall victim to that just as much as anyone else can. The same incentives are there to fool yourself. So I don't see any special magic in outsourcing clinical work, other than the fact that CROs tend to work their people harder and pay them less money.

To be fair, the rest of the article does show the flip side:

Skeptics say such results may cut R&D costs, but don't address big pharma's main problem of finding new therapies that pan out.

"You get more negative results faster and cheaper," said James Niedel, a former GlaxoSmithKline executive who is now a partner at New Leaf Venture Partners fund. "But the problem with the industry is they're not getting enough positive results and that depends on knowledge and insight about biology and disease" that might be lacking among CROs. . ."Neither the cost cuts nor the structural changes help R&D productivity," said Keyur Parekh, a UBS analyst who thinks Lilly might need to make acquisitions to replenish its pipeline.

Indeed. It's important not to spend money where you don't have to, but it's also important to have things to spend the money on in the first place.

Comments (31) + TrackBacks (0) | Category: Clinical Trials | Press Coverage

December 23, 2009

An Alzheimer's Compound Runs Into Big Trouble

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Posted by Derek

Another interesting approach to Alzheimer's therapy has just taken a severe jolt in the clinic. Elan and Transition Therapeutics were investigating ELEND005, also known as AZD-103, which was targeted at breaking down amyloid fibrils and allowing the protein to be cleared from the brain.

Unfortunately, the two highest-dose patient groups experienced a much greater number of severe events - including nine deaths, which is about as severe as things get - and those doses have been dropped from the study. I'm actually rather surprised that the trial is going on at all, but the safety data for the lowest dose (250mg twice daily) appear to justify continuing. The higher doses were 1g and 2g b.i.d., and the fact that they were going up that high makes me think that the chances of success at the lowest dose may not be very good.

So what is this drug? Oddly enough, it's one of the inositols, the scyllo isomer. Several animal studies had shown improvements with this compound, and there were promising results for Parkinson's as well. At the same time, scyllo-inositol has been implicated as a marker of CNS pathology when it's found naturally, so it's clearly hard to say just what's going on. As it always is with the brain. . .

Comments (18) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | The Central Nervous System | Toxicology

December 3, 2009

All Of You Industrial Scientists: Out Of the Room

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Posted by Derek

Continuing Education (CE) is a big issue in many medical fields and those associated with them. Licensing boards and professional societies often require proof that people are keeping up with current developments and best practices, which is a worthy goal even if arguments develop over how well these systems work.

And it's also been a battleground for fights over commercial conflicts of interest. On the one hand, no one needs a situation where a room full of practitioners sits down to a blatant sales pitch that nonetheless counts as continuing education. But one the other hand, you have the problem that's now developing thanks to new policies by the Accreditation Council for Continuing Medical Education (ACCME) and the Accreditation Council for Pharmacy Education (ACPE). Thanks to a reader, I'm reproducing below some key parts of a letter that one professional organization, the American Society for Clinical Pharmacology and Therapeutics, has recently sent out to its members:

In 2006, ACCME and ACPE adopted new accreditation policies that went into effect in January 2009. Most concerning of these new policies is the requirement that CE providers develop activities/education interventions independent of any commercial interest, including presentation by industry scientists. This requirement greatly impacts the Society as industry scientists constitute nearly 50% of our membership and contribute significantly to the scientific programming of the ASCPT Annual Meeting. . .

ASCPT has been left with two options: 1) stop providing CE credit and continue to involve scientists from industry in the scientific program of the Annual Meeting; or 2) continue providing CE credit and remove all industry scientists from the program and planning process. . .

They go on to say that this year's meeting, having already been planned in the presence of Evil Industry Contaminators (well, they don't quite say it like that), will have no CE component, and that they don't see how they'll be able to have any such in the future, since they can't very well keep half the membership from presenting their work. This is definitely a problem for a number of professional organization, particularly the ones that deal with clinical research. They intersect with the professions that tend to have continuing education requirements, but a significant part of the expertise in their fields is found in industry. The ASCPT is not the only society facing this same dilemma.

It looks as if the accreditation groups decided that they were faced with a choice: commit themselves to judging what sorts of presentations should count for CE credit (which you might think was their job), or just toss out anything that has any connection with industry. That way you can look virtuous and save time, too. My apologies if I'm descending into ridicule here, but as an industrial scientist I find myself resenting the implication that my hands (and those of every single one of my colleagues) are automatically considered too dirty to educate any practicing professionals.

To be fair, this could well be one of those situations that the industry has helped bring on itself. I've no doubt that the CME process has probably been abused in the past. (Update: see the comments section. Am I being too delicate in this phrasing? Probably comes from never having dealt much with the marketing side of the business. . .) But there has to be some way to distinguish the old-fashioned "golf-resort meeting" from a clinical pharmacologist delivering a paper on new protocols for trial designs. The last thing we need is to split the scientific community even more than it's split already.

Comments (14) + TrackBacks (0) | Category: Academia (vs. Industry) | Clinical Trials | Drug Development

November 19, 2009

Plavix vs. Effient

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Posted by Derek

The InVivo Blog has a good article on a controversy in the blood-thinning market. Plavix (clopidogrel) has a very strong share of that, of course, but since Effient (prasugrel) was finally approved, Lilly and Dai-Ichii are looking to take as much of that market as they can. And one opening might be that not everyone responds similarly to Plavix.

In some cases, that's because there are some drug-drug interactions, a problem the FDA has recently addressed. The proton pump inhibitors, especially, are metabolized through the CYP2C19 pathway. That's a problem, since that enzyme is needed to convert clopidogrel into its active form (Plavix, as it comes out of the pill, is a prodrug - its thiophene ring needs to get torn open). This sort of thing has been seen many times before - it's one of the many headaches that you can endure in drug development as you profile the metabolizing pathways for your drug candidate and compare them to the other compounds your patient population might be taking. There are some combinations that just will not work (several involving CYP3A4, which is often the first one you test for), and it looks like we can add Plavix/2C19 to the list.

But the population genetics of the 2C19 enzyme are rather heterogeneous. About a third of the patients taking Plavix have a less-active form of the enzyme to start with, and they might not respond as robustly to the drug. The FDA has emphasized this effect in its latest public health warning. That's an opportunity for Effient, since it doesn't go through that metabolic route.

The In Vivo people point out, though, that this story isn't being driven by the usual players. It's not the FDA that's pushed to find this out, and it's not even Eli Lilly. It's Medco and Aetna. They studied their insurance claims data to see if the numbers supported the proton pump inhibitor/Plavix interaction, found that they did, and publicized their findings - and that led to an actual observational trial from BMS and Sanofi, which confirmed the problem. Now Medco is going further, and is actually running its own observational study comparing Plavix and Effient. Their theory is that the efficacy that Lilly showed compared to Plavix was driven by the (deliberate, one assumes) inclusion of a high number of poor metabolizers.

Medco is getting ready for generic Plavix, and trying to keep its costs down by making the case that the drug will do the job just fine for most patients. They could, on the other hand, end up making the case for Effient in that poor-metabolizing third of the patients, which would also be interesting. Lilly would presumably settle for that, although they'd like even more of the market if they can get it, naturally.

And I have to say: I like this sort of thing. I like it a lot. This, to me, is how the system should work. Companies are pursuing their own competing interests, but in the end, we get a higher standard of care by finding out which drug really works for which patients. The motivation to do all this? Money, of course, earning it and saving it. This may sound crass, but I think that's a reliable, proven method to motivate people and companies, one that works even better than depending on their best impulses. You could even build an economic system around such effects, with some attention to channeling these impulses in ways that benefit the greatest number of people. Worth a try.

Comments (22) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Regulatory Affairs

November 16, 2009

Zetia Takes Another Torpedo

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Posted by Derek

Over the weekend, the results in a small cardiovascular trial came out that compared Merck's Zetia (ezetimibe/simvastatin) (correction - ezetimibe alone) against Abbott's Niaspan (time-release niacin). Niacin's an underappreciated therapy in the field - it has tolerability problems, mainly irritating and uncomfortable hot flushing, but it really does seem to help normalize lipid numbers. (And that's why Merck itself, among others, have taken cracks at the market).

This latest trial was a small one, but people have been starved for data on Zetia ever since it took a surprising hit (in the ENHANCE trial) suggesting that it might not be very efficacious. There's an ongoing larger trial that should answer this question once and for all, but those numbers won't be showing up for another two years. For now, anything that can help clarify what's going on is of great interest to Merck, its investors, and to cardiologists and their patients.

And Matthew Herper at Forbes is right: these latest numbers are disastrous. The study (funded by Abbott) isn't the greatest piece of clinical research in the world - it didn't study nearly as many patients as it was designed to, since it was halted early. (Here it is in the NEJM). But it still shows Niaspan as clearly superior to Zetia, and it makes a person wonder if taking Zetia is basically an expensive way to take a possibly-inadequate dose of simvastatin. In a way, the relatively small size of the study actually helps it a bit - getting numbers that definitive without having to go to much larger sample sizes isn't so easy in cardiovascular trials, so the feeling is that there much be something here.

As Herper's article details, Merck is trying to spin this as a big win for their competition, not a big loss for their own drug. But that comes close to being logically impossible: cholesterol lowering, like many other therapeutic areas, is nearly a zero-sum game. If patients take Niaspan (or any other competing drug), they're not going to be taking Zetia. This one was certainly a victory for Abbott (and generic niacin, for those who can take it), but it was a loss for Merck as well.

The FDA's not coming out of all this looking very good, either:

"How is it possible for a drug to have $4 billion in sales without any evidence of benefit?" says Harlan Krumholz, a cardiologist at Yale University. He said that the small size of the two imaging studies mean they couldn't render a clear verdict on Zetia. "But they don't instill any confidence in it either. " Douglas Weaver, head of cardiology at the Henry Ford Hospital in Detroit says: "We've used Zetia without sufficient amounts of clinical data to support it. Using it may be right, it may be wrong, but we don't know right now."

But it's worth remembering that Zetia's mode of action made perfect sense, and that it really does lower cholesterol to what you'd think would be a very beneficial degree. But it probably has several other effects beyond simple LDL lowering, and just looking at that number is clearly (in hindsight) not enough of a clinical surrogate marker. As the study authors put it:

If viewed properly, this hypothesis-generating finding is not an indictment of the overall importance of reducing LDL cholesterol for the purpose of preventing cardiovascular events, as illustrated by therapies based on statins or nonstatins (e.g., bile acid sequestrants). Rather, this adverse relationship may be attributable to the net effect of ezetimibe, a drug with diverse actions, not all of which are measured through its effects on intestinal cholesterol absorption and LDL cholesterol level. Taken together with a preexisting concern regarding the clinical effectiveness of ezetimibe, our findings challenge the usefulness of LDL cholesterol reduction as a guaranteed surrogate of clinical efficacy, particularly reduction achieved through the use of novel clinical compounds.

But as I recall, statins themselves were first approved based largely on lowered LDL, with better outcome data only showing up later. In that case, the surrogate marker paid off, but not this time. What all this is telling us, then, is that we don't know nearly as much about cholesterol and cardiology as we thought we did. And if we don't understand that area well enough, after all these years and all this effort, what parts of medicine do we really understand?

Comments (31) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials

November 12, 2009

Massaging the Data for Neurontin?

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Posted by Derek

There's a disturbing article out at the New England Journal of Medicine on studies conducted on Neurontin (gabapentin) for various unapproved indications. Parke-Davis (and later Pfizer) looked at a wide range of possible indications for the drug - migraine, neuropathic pain, bipolar disorder, and more. That in itself isn't unusual, since CNS drugs often have rather broad and poorly defined mechanisms, and it's not like we understand any of them all that well.

What is unusual is the pattern found when comparing the internal reports with the published versions that showed up in the literature. The authors found that:

"More than half the clinical trials that we included in our analysis (11 of 20) were not published as full-length research articles. For 7 of the 9 trials that were published as full-length research articles, a statistically significant primary outcome was reported, and for more than half these trials, the outcome specified in the published report differed from the outcome originally described in the protocol. Three of the four trials with an unchanged primary outcome had statistically significant results for the protocol-specified primary outcome. Secondary outcomes also frequently differed between the protocol and the published report. Thus, trials with findings that were not statistically significant (P≥0.05) for the protocol-defined primary outcome, according to the internal documents, either were not published in full or were published with a changed primary outcome. . .all the changes that took place between what was specified in the protocol, what was known before publication (as presented in the internal company research reports), and what was reported to the public led to a more favorable presentation in the medical literature. . ."

The authors go on to point out that changing a primary outcome after you see the data is, in fact, a statistical sin (although that's not quite the phrase they use!) You really can't go around doing that, because you can end up chasing after random chance (and avoiding that is the whole point of running well-controlled trials). This does not cover Pfizer and Parke-Davis with glory, but it's worth noting that there's plenty of blame to go around when it comes to this practice:

"Our study is based on a relatively small number of trials undertaken to test a single drug manufactured by a single company and its successors. Furthermore, if a major purpose of the studies we examined was to promote off-label uses of gabapentin, the selective reporting we observed could be more extreme than that observed for studies conducted for other reasons. Previous studies in different settings have shown evidence of these same biases, however. Indeed, selective outcome reporting does not appear to be limited to studies funded by drug companies. Chan and colleagues examined published trials funded by the Canadian Institutes of Health Research and found that 40% of stated primary outcomes differed between the protocol and the published report. In addition, we cannot be certain that selective reporting was a decision made by employees of Pfizer and Parke-Davis, since the authors of the published reports included nonemployees. We did not systematically assess the methodologic quality of the included trials as described in the publications we examined. Previous research has indicated that quality scores are higher for trials conducted by the pharmaceutical industry than for trials conducted by not-for-profit entities, although reports from industry-sponsored trials have potentially distorted the scientific record because of other, less easily measured study factors."

That doesn't get the folks who conducted these gabapentin studies off the hook, although I should note that Pfizer disputes the conclusions of this article (as you'd certainly think that they would). And it's also worth noting that some of its authors have done work for the plaintiffs in suits against Pfizer over gabapentin (thus all the familiarity with the internal company documents, which came to light during discovery proceedings). But again, I don't see how that negates the paper's conclusions, and if Pfizer has any hard data that would do so, I think they should produce it with all speed.

And no, it's just a coincidence that this post involve Pfizer, after I've been going on about their merger business all week. Unfortunately, I think that they're probably not the only company that could be pointed at. But we in the industry shouldn't have things like this for others to uncover in the first place. Should we?

Comments (12) + TrackBacks (0) | Category: Clinical Trials | The Central Nervous System | The Dark Side | The Scientific Literature

October 2, 2009

Placebos Can Work the Other Way, Too

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Posted by Derek

There's been a lot of valuable research into the placebo effect in recent years. That has interest in and of itself, and it also has a practical side. Understanding how people feel better on their own could tell us more about how to make our actual drugs work better, and it could also help us design clinical trials more efficiently. It would be a great help to know accurately how much of a positive effect is due to an investigational drug, without having to run thousands of people to separate that out statistically from a robust (but highly variable) placebo effect.

A new paper in the journal Pain (which has always gotten my vote for "Most To-the-Point Journal Title Possible") sheds some light on this issue, and on the mirror image "nocebo effect". The authors have looked over trials of several migraine drugs. In each case, there was a study arm and a placebo arm, and (since no one knew which group they were in), every patient got the lecture about possible side effects if you were in the treatment group.

The key point is that the migraine trials were investigating three different classes of drugs (anti-inflammatories, triptans, and anticonvulsants), and these three, not surprisingly, have different sets of possible side effects. The patients taking the drugs certainly manifested some of these, but what about the placebo groups?

Well, the placebo groups in the anti-inflammatory trials reported more dry mouth, nausea and vomiting than the placebo arms of the triptan studies. The placebo patients in the anticonvulsant trials, though, had a higher incidence of fatigue, sleepiness, and dizziness than the anti-inflammatory placebo groups reported. In short:

We found specific side effects in the placebo arms of anti-migraine trials when analyzing the three groups of drugs. We observed that the side effects that are expected for the active drug against which the placebo is compared, are also more frequent in the placebo group. In particular, anticonvulsant-placebos appear to have a higher rate of AEs (adverse events) than the other two classes of anti-migraine drugs. . .

. . .Moreover, it is also important to note that a larger number of patients in the anticonvulsant-placebo group discontinued the study (withdrawals due to AEs) than those in the triptan-placebo and NSAID-placebo groups. Both patients’ and experimenters’ expectations may have affected the AEs occurrence in the placebo groups. . .

This sort of thing has been observed before, but this is a particularly neat example. As a researcher (or a patient), it's important to remember that we tend to get what we think we're going to get. And we need to be aware of that, and be ready to correct for it if we have to.

Comments (28) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | The Central Nervous System

August 24, 2009

Arzoxifene: Not the Road to Big Profits?

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Posted by Derek

Eli Lilly announced some bad news last week when they dropped arzoxifene, a once-promising osteoporosis treatment (and successor to Evista (raloxifene), which has been one of the company's big successes).

If this drug had been found ten or fifteen years ago, it might have made it though. But the trial data showed that while it made its primary endpoints (reducing vertebral fractures, for example), it missed several secondary ones (such as, well, non-vertebral fractures). And the side effect profile wasn't good, either. That combination meant that the drug was going to face at hard time at the FDA for starters, and even if it somehow got through, it would face a hard time competing with generic Fosamax (and Lilly's own Evista).

So down it went, and it sound like the right decision to make. Unfortunately, given the complexities of estrogen receptor signaling, the clinic is the only place that you can find out about such things. And there are no short, inexpensive clinical trials in osteoporosis, so the company had to run one of the big, expensive ones only to find out that arzoxifene didn't quite measure up. That's why this is a territory for the deep-pocketed, or (at the very least) for those who hope to do a deal with them at the first opportunity.

One more point is worth emphasizing. Take a look at the structures of the two compounds (from those Wikipedia links in the first paragraph). Pretty darn similar, aren't they? Arzoxifene is clearly a follow-up drug in every way - modified a bit here and there, but absolutely in the same family. A "me-too" drug, in other words, an attempt to come up with something that works similarly but sands off some of the rough edges of the previous compound. But anyone who thinks that development of a follow-up compound is easy - and a lot of people outside the industry do - should consider what happened to this one.

Comments (14) + TrackBacks (0) | Category: "Me Too" Drugs | Clinical Trials | Drug Development | Toxicology

August 4, 2009

Wasted Money, Wasted Time?

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Posted by Derek

Now, while we've been talking about how much basic research is done in industry, or how much clinical research gets done in academia, here's something that might bear on the discussion. Too much of what looks like useful clinical research on the academic side is actually wasted effort. The New York Times has been running a series called "The Forty Year War", looking at the history of the "War on Cancer", and the latest installment is on clinical trials.

It's been a problem for some time now that there aren't enough patients to go around for many cancer trials. Breast cancer is an especially problematic area, last I heard. It's high-profile, fairly high-incidence, and a lot of investigational anticancer agents are lined up to take a whack at it. So many, in fact, that there aren't enough breast cancer patients available in the US, nowhere near, and the same situation obtains in a number of other areas.

Much of this problem comes from low recruitment rates. As the Times article makes clear, only three per cent of adult cancer patients are enrolled in any kind of trial at all. Many cancer patients want to stick with the best therapy that's currently known, and don't want to add any uncertainty to what they're already dealing with. It's hard to blame them, but that does make the state of the art advance more slowly.

Another factor that may come as a surprise is that many oncology practices find that they lose money by participating in trials. The reimbursement-to-paperwork ratio doesn't always come out very well, especially for centers that don't do a lot of clinical research and haven't been able to streamline the process as much as possible. When they look at the number of patients that they can serve, given the time that's taken up, the trials start to make less sense.

Finally, and this is the least excusable factor on the list, there are many trials that really shouldn't be run at all. The Times does work in a line about how some studies by drug companies are just "designed to persuade doctors to use their drugs." My take on that is that these studies usually are designed to do that by showing that their drug actually works better, which is not such a bad thing. But note this other problem:

There are more than 6,500 cancer clinical trials seeking adult patients, according to, a trials registry. But many will be abandoned along the way. More than one trial in five sponsored by the National Cancer Institute failed to enroll a single subject, and only half reached the minimum needed for a meaningful result, Dr. Ramsey and his colleague John Scoggins reported in a recent review in The Oncologist.

Even worse, many that do get under way are pretty much useless, even as they suck up the few patients willing to participate. These trials tend to be small ones, at single medical centers. They may be aimed at polishing a doctor’s résumé or making a center seem at the vanguard of cancer care. But they are designed only to be “exploratory,” meaning that there are too few patients to draw conclusions or that their design is less than rigorous.

“Unfortunately, many patients who are well intentioned are in trials that really don’t advance the field very much,” said Dr. Richard Schilsky, an oncologist at the University of Chicago and immediate past president of the American Society of Clinical Oncology.

I don't want to dump a bucket of tar on all academic and publicly funded clinical research, because there's a lot of good stuff that goes on as well. (And remember, the publicly basic research is very valuable indeed). But the next time someone tells you about the number of clinical trials run outside of the drug industry, you might want to keep those above figures in mind.

Not all trials are created equal, not by a long shot. But the ones that we run in industry, from what I can see, tend to have a better chance of relevance. That's partly because we're spending our own money on them, and with a goal of finding drugs that people will spend money on in turn. It focuses one's efforts. It's not like we never waste money in this business, but I'm very much willing to bet that we waste it less often than happens with public funds. Companies trying to get an agent through the clinic tend not to set up meaningless trials just to make everyone's resume look better. That I can tell you.

Comments (24) + TrackBacks (0) | Category: Academia (vs. Industry) | Cancer | Clinical Trials

July 20, 2009

Amyloid in Trouble

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Posted by Derek

Here's an interesting look at the current state of the Alzheimer's field from Bloomberg. The current big hope is Wyeth (and Elan)'s bapineuzumab, which I last wrote about here. That was after the companies reported what had to be considered less-than-hoped-for efficacy in the clinic. The current trial is the one sorted out by APOE4 status of the patients. After the earlier trial data, it seems unlikely that there's going to be a robust effect across the board - the people with the APOE4 mutation are probably the best hope for seeing real efficacy.

And if bapineuzumab doesn't turn out to work even for them? Well:

“Everyone is waiting with bated breath on bapineuzumab,” said Michael Gold, London-based Glaxo’s vice president of neurosciences, in an interview. “If that one fails, then everyone will say we have to rethink the amyloid hypothesis.”

Now that will be a painful process, but it's one that may well already have begun. beta-Amyloid has been the front-runner for. . .well, for decades now, to be honest. And it's been a target for drug companies since around the late 1980s/early 1990s, as it became clear that it was produced by proteolytic cleavage from a larger precursor protein. A vast amount of time, effort, and money have gone into trying to find something that will interrupt that process, and it's going to be rather hard to take if we find out that we've been chasing a symptom of Alzheimer's rather than a cause.

But there's really no other way to find such things out. Human beings are the only animals that really seem to get Alzheimer's, and that's made it a ferocious therapeutic area to work in. The amyloid hypothesis will die hard if die it does.

Comments (21) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Drug Industry History | The Central Nervous System

June 23, 2009

Medarex, Ipilimumab, Prostate Cancer, And Reality

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Posted by Derek

What's really going on with Medarex and ipilimumab? The company made news over the weekend with a press release from the Mayo Clinic, detailed what appears to be a substantial response in two prostate cancer patients. But the more you look at the story, the harder it is to figure out anything useful.

As this WebMD piece makes clear, this study is not a trial of ipilimumab as a single agent. The patients are undergoing prolonged androgen ablation, the testosterone-suppressing therapy that's been around for many years and is one of the standard options for prostate cancer. The trial is to see if ipilimumab has any benefit when it's added to this protocol - basically, to see if it can advance the standard of care a bit.

WebMD quotes Derek Raghavan at the Cleveland Clinic as saying that androgen ablation can sometimes have dramatic results in patients with locally advanced prostate cancer, so it's impossible to say if ipilimumab is helping or not. That's why we run clinical trials, you know, to see if there's a real effect across a meaningful number of patients. But (as this AP story notes) we don't know how many patients are in this particular study, what its endpoints are, or really anything about its design. All we know is that two patients opted out of it for surgery instead. (Credit goes to the AP's Linda Johnson for laying all this out).

Ipilimumab is an antibody against CTLA-4, which is an inhibitory regulator of lymphocytes. Blocking it should, in theory, turn these cells loose to engage tumor cells more robustly. (It also turns them loose to engage normal tissue more robustly, too - most of the side effects seem to be autoimmune responses like colitis, which can be very severe. The antibody has been studied most thoroughly in melanoma, where it does seem to be of value, although the side effect profile is certainly complicating things.

So overall, I think it's way too early to conclude that Medarex has hit on some miracle prostate cure. This press release, in fact, hasn't been too helpful at all, and the Mayo people really should know better.

Comments (34) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Press Coverage | Toxicology

June 9, 2009

Avastin's Numbers

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Posted by Derek

Here's a fascinating (and alarming) look at the clinical data from the recent trial of Avastin (bevacizumab) in adjuvant colorectal cancer (that is, post-surgical therapy). This was an issue in the recent Roche/Genentech takeover, since it could significantly enlarge the market for the drug. According to the In Vivo Blog, the one-year interim look at the data (adding Avastin to the standard chemotherapy regimen) was nearly good enough to stop the trial early. There were 2,710 patients enrolled, and an additional six events would have pushed things over the top, statistically.

The trial went on, though, with two more years of standard therapy as follow-up. But by the (pre-set) three-year endpoint it turned out that there was no eventual real benefit to adding Avastin back in that first year. So what's the story? Is it that you need to keep giving the combination regime? Would those-one year results have held up? Or is this just a case of real long-term survival numbers wiping out what seems to be a promising short-term result?

It looks like Genentech may be gearing up to put that first theory to a test, and I wish them luck. Long-term tolerability will be an issue, and long-term cost will be a big one, too. They're going to have to show some pretty impressive numbers to overcome those two concerns. . .as impressive as, well, as those first-year interim ones they had. Will that effect dissipate or not?

Time and money will answer that little question. But for now, consider what would have happened if a few more patients had shown disease-free survival in time for that interim analysis. The trial would have been stopped early, all kinds of people would have gone on Avastin for their first year of adjuvant therapy. . .and this year we would have seen that it was apparently doing no good at all, at least in the take-it-for-a-year-and-stop mode. Clinical trial design: a real high-wire act.

Comments (9) + TrackBacks (0) | Category: Cancer | Clinical Trials

June 8, 2009

Rolofylline Hits the Skids

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Posted by Derek

There is no good way to spin a Phase III failure. By then you've made it past the main reasons for a drug to wipe out (PK and total mechanistic failure). A breakdown at this stage is a more subtle affair (well, except for the money involved, which is not subtle at all). For example, a drug might show efficacy in a carefully constructed Phase II trial, but can't perform under the wider (and more realistic) conditions of Phase III.

That's what appears to have happened to Merck's MK-7418 (rolofylline, formerly KW-3902). This adenosine A1 antagonist, which Merck picked up by buying NovaCardia a couple of years ago, was being developed for acute heart failure. That's a tough indication, and this isn't going to improve that reputation. (This Forbes piece has a tour of the pile of discards that this area has become over the years. Rolofylline looked as if it might work in Phase II, but (from what I can tell from the press releases) missed every endpoint in Phase III.

On a chemical note, rolofylline is a rather odd-looking molecule. You don't see many noradamantanes hanging off of drug structures. I'm sure this wasn't the reason for the compound's failure (after all, it made it through Phase I and Phase II), but it's sure not something I have on my list of structural fragments to try.

Comments (14) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials

June 4, 2009

CafePharma Will Now Approach The Bench

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Posted by Derek

Here's an interesting situation for you: according to IguanaBio, a shareholder lawsuit over the failed Vytorin ENHANCE clinical trial (that's caused Schering-Plough and Merck so much grief) is going to use posts on CafePharma as evidence.

That will be worth watching. CafePharma's message boards have been described (accurately, I'd say) as often being the electronic equivalent of a bathroom wall. There's good information in there, but the signal/noise ratio is abysmal due to the number of ticked-off people who go there to vent. There do appear to have been some posts suggesting strongly that the ENHANCE data were grim, and who knows? They could have been speaking from real knowledge. But there's no way to be sure - and for every post that turns out to be prophetic, there are ten that are totally wrong.

So I'm surprised that these are going to be considered admissable. Anyone investing on the basis of CafePharma board chatter deserves to lose their money - which will go out in brokerage commission fees, if nothing else. Let's see how this plays in court. . .

Comments (11) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Clinical Trials | Drug Industry History

June 1, 2009

Akt and Mek, But Not PDQ

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Posted by Derek

Well, the ASCO meeting has been roaring along, with dozens of press releases coming out. (Go to Google News and type that acronym in if you want to get the full experience). They range from the pretty-interesting to the despair-inducing, but one bit of news struck me as particularly worth noting. That's the early-stage deal between Merck and AstraZeneca to combine two of their development candidates in a Phase I trial.

That's Merck's AKT inhibitor MK-2206 and AZ's Mek inhibitor AZD6244, and there's room to think that combining those two mechanisms could be beneficial. But as that In Vivo Blog link details, this deal wasn't initiated through any official contact between the two companies. Rather, someone from Merck and someone from AZ got to talking while they were going through airport security in Dublin, and recognized each other's names. A mere year and a half later, the deal was born.

There's a lot to learn from that story. For one, big drug companies are not, for the most part, looking to do early-stage deals with other big drug companies. Perhaps we'll see more of these in the future, but in general, it's about the least likely form of partnership. Another thing to note is how long it took for this idea to bear fruit. Eighteen months is about right for companies of this size to make up their minds about something like this - and you can decide that (since the oncology field is so complicated) that this is a reasonable period of evaluation, or you can decide, equally objectively, that delays of that magnitude remind you of a sauropod turning around in puzzlement three hours after something bit its tail.

I'm impressed that the deal was made at all. The usual path for new ideas of this sort is to the graveyard, especially in very large organizations, so I have to assume that some people within each company must have really pushed things along to make it happen. It's part of the general bias toward inaction: it's harder to get beaten up for decisions that you didn't make, compared to decisions that you did. Missed opportunities are often invisible.

So, no matter how long it took, or even whether it works out, I still have to congratulate the people involved on getting this agreement to happen. It's worthwhile, I think, just because it's the sort of thing that doesn't happen very often. And I have the feeling that (in the coming years) we're going to have to explore a lot of things in this industry that haven't happened very often. We'll need the practice!

Comments (4) + TrackBacks (0) | Category: Business and Markets | Cancer | Clinical Trials | Drug Development | Drug Industry History

May 22, 2009

Arena, Lorcaserin, and the FDA

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Posted by Derek

I’ve been getting a lot of objections to my opinion on Arena’s obesity candidate lorcaserin. Specifically, the first level of the dispute seems to be whether or not the recent clinical trial results met the FDA’s criteria for efficacy or not. So, let’s look at the details. Here’s how Arena press-released the results of the trial:

The hierarchically ordered endpoints were the proportion of patients achieving 5% or greater weight loss after 12 months, the difference in mean weight loss compared to placebo after 12 months, and the proportion of patients achieving 10% or greater weight loss after 12 months. Compared to placebo, using an intent-to-treat last observation carried forward (ITT-LOCF) analysis, treatment with lorcaserin was associated with highly statistically significant (p<0.0001) categorical and average weight loss from baseline after 12 months:

-- 47.5% of lorcaserin patients lost greater than or equal to 5% of their
body weight from baseline compared to 20.3% in the placebo group. This
result satisfies the efficacy benchmark in the most recent FDA draft
-- Average weight loss of 5.8% of body weight, or 12.7 pounds, was achieved
in the lorcaserin group, compared to 2.2% of body weight, or 4.7 pounds,
in the placebo group. Statistical separation from placebo was observed
by Week 2, the first post-baseline measurement.
-- 22.6% of lorcaserin patients lost greater than or equal to 10% of their
body weight from baseline, compared to 7.7% in the placebo group.

Lorcaserin patients who completed 52 weeks of treatment according to the protocol lost an average of 8.2% of body weight, or 17.9 pounds, compared to 3.4%, or 7.3 pounds, in the placebo group (p<0.0001).

Now let’s go to the FDA’s 2007 draft guidance for weight management therapies. Regarding the primary efficacy endpoint in a Phase III trial of such a new agent, the agency says:

The efficacy of a weight-management product should be assessed by analyses of both mean and categorical changes in body weight.

• Mean: The difference in mean percent loss of baseline body weight in the active-product versus placebo-treated group.

• Categorical: The proportion of subjects who lose at least 5 percent of baseline body weight in the active-product versus placebo-treated group.

And here’s the part that people keep wanting me to highlight:

In general, a product can be considered effective for weight management if after 1 year of treatment either of the following occurs:

• The difference in mean weight loss between the active-product and placebo-treated groups is at least 5 percent and the difference is statistically significant

• The proportion of subjects who lose greater than or equal to 5 percent of baseline body weight in the active-product group is at least 35 percent, is approximately double the proportion in the placebo-treated group, and the difference between groups is statistically significant

So lorcaserin showed 47.5% of patients losing at least 5% of their body weight, versus 20.3 for placebo. And yes, that does appear to meet what the FDA's looking for in terms of categorical efficacy, which is why the company highlighted that result in their press release. And yes (here it comes, Arena fans), the FDA does say ("in general") that an agent can be considered efficacious if a compound meets either the mean or the categorical standards.

But (and you knew that this paragraph was going to start with that word). . .but the FDA does not say "efficacious enough for approval". In general, to use their phrase, the agency does approve things that are efficacious and show safety. But they do that on their own terms, and they are (for better or worse) completely within their rights to turn around and ask for more details - for example, how well a compound like this performs as a combination therapy (which is how many physicians would likely wish to prescribe it).

Then we have the issue of "efficacious to interest a partner". Arena is surely looking to do that, since (as noted the other day) it does not appear that they have the resources to push the product through on their own. Given the potential size of the market for an effective obesity drug, we can be sure that a number of potential partners have been approached, and have taken a meaningful look at the data. So far, no one has taken them up on it. And whatever one thinks about the press coverage that lorcaserin has received (or the reaction from analysts who follow the stock, which has also not been good), it's for sure that these opinions don't count for much when it comes time for two companies to do a deal. Put more directly, if Arena sits down with Merck or Pfizer, what I say on this blog means nothing at all once the door closes. Heck, what they say at JP Morgan means nothing at all, either, because we're all outsiders. Potential partners are getting a chance to look over Arena's prospects, and if the numbers look convincing, someone will bite. If no one bites, we can assume that no one was convinced.

Or perhaps they're waiting for Arena to get even more cash-strapped and desperate. That isn't a very nice way to do business, but isn't unheard of, either, and I can tell you that these aren't very nice times in the drug business. At any rate, for those Arena fans who have been waiting for me to say something about all this, well, here you are. This is as good as you'll get from me - but really, you're wasting your time. You need to be hoping to persuade the people who can initiate nine-figure wire transfers.

Comments (9) + TrackBacks (0) | Category: Business and Markets | Clinical Trials | Diabetes and Obesity | Regulatory Affairs

May 14, 2009

Surrogate Markers Are Awful, But They're Ours

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Posted by Derek

And while we're on the subject of clinical trials, and the headaches associated with them, this is a neat little article over at Slate on the subject. Darshak Sanghavi from UMass does a good job of explaining the surrogate-endpoints problem in clinical results, relating it to reality TV:

. . .In the federal Multimodal Treatment Study, hundreds of kids with ADHD, whose families were desperate enough to enroll them in a randomized study, entered a well-funded and highly supervised National Institute for Mental Health program complete with specialized therapy, regular evaluation by developmental experts, and careful drug prescription—a setup that's about as realistic as a date on The Bachelor. Within that very unusual, closely monitored environment, as reported in 1999, stimulant medications caused modest improvement after about a year. In response, use of these products surged nationwide, and Ritalin and its peers became household brands. But in March, the researchers described what happened after the lights went out. In their subsequent years in the real world, the drug-treated kids ultimately ended up no better off than the others.

Epidemiologists call this the problem of "surrogate endpoints," and it's no surprise to fans of reality television. Garnering the greatest number of text-messaging votes after a brief performance doesn't always mean you'll be a successful pop star; winning the final rose after an on-air courtship doesn't mean you'll have a happy marriage; and getting higher scores on a simple rating scale of attention-deficit symptoms doesn't mean you'll later succeed in school. In medicine, this problem happens all the time.

He doesn't shy away from some of the big surrogates in the clinical world, the biggest of which are cholesterol levels. That one, as he says, is at least considered a validated marker (with some relation to real-world mortality and morbidity), but there's plenty of room to argue about that, too. Ask Gary Taubes, who has a lot of provocative things to say about the whole low-fat idea. And if that one is still worth arguing over, what about the less validated endpoints?

In the end, I agree with Sanghavi that we really don't have any good alternatives yet. The real endpoints, in most cases, just take too long to measure. No one can finance a twenty-year clinical trial, and no one would put up with one even if it were feasible. We're stuck with what we have, and we just have to make it work the best we can.

Comments (3) + TrackBacks (0) | Category: Clinical Trials

Goldman Sachs: Out Of the Drug Funding Business Already?

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Posted by Derek

Late last year, I wrote about a possible new way to fund drug discovery, a private-equity model that seemed to be in the works at Goldman Sachs. The driving force behind the idea seemed to be Jon Symonds, former CFO at AstraZeneca.

Well, as the InVivoBlog noted yesterday, Symonds has suddenly decamped to Novartis. He’s press-released as their new CFO (after the current one retires), which makes you wonder what’s happened to that drug funding plan. Given the current environment for new financing schemes, and for banking in general (not to mention the current environment at Goldman Sachs), has the whole idea just been shelved?

As the In Vivo folks go on to say, financing clinical candidates in this way isn’t necessarily a bad idea – it just might be a bad time to try it out. There are a lot of issues to be worked out, but it’s looking more and more like no one’s going to be working them out any time soon. . .

Comments (2) + TrackBacks (0) | Category: Business and Markets | Clinical Trials | Drug Development

May 6, 2009

Into the Clinic. And Right Back Out.

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Posted by Derek

Here's a good example of why all of us in the industry tiptoe into Phase I trials, the first-in-man studies. A company called SGX, recently acquired by Eli Lilly, has been developing a kinase inhibitor (SGX523) targeting the enzyme cMET. That's a well-known anticancer drug target, with a lot of activity going on in the space.

SGX's specialty is fragment-based design, and they've spoken several times at meetings about the SGX523 story. The starting point for the drug seems to have come out of X-ray crystallographic screening (the company has significant amounts of X-ray synchrotron beamline time, which you're going to need if you choose this approach). They refined the lead, in what (if you believe their presentations) was a pretty short amount of time, to the clinical candidate. It seems to have had reasonable potency and pharmacokinetics, very good oral bioavailability, no obvious liabilities with metabolizing enzymes or the dreaded hERG channel. And it was active in the animal models, however much you can trust that in oncology.

So off to the clinic they went. Phase I trials started enrolling patients in January of last year - but by March, the company had to announce that all dosing had been halted. That was fast, but there was a mighty good reason. The higher doses were associated with acute renal failure, something that most certainly hadn't been noticed in the mouse models, or the rats, or the dogs. It turns out that the compound (or possibly a metabolite, it's not clear to me) was crystallizing out in the kidneys. Good-looking crystals, too, I have to say. I can't usually grow anything like that in the lab; maybe I should try crystallizing things out from urine.

Needless to say, obstructive nephropathy is not what you look for in a clinical candidate. There's no market for instant kidney stones, especially when they appear all over the place at the same time. The patients in the Phase I trial did recover; kidney function was restored after dosing was stopped and the compound had a chance to wash out. But SGX523, which was (other than its unlovely structure) a perfectly reasonable-looking drug candidate, is dead. It didn't take long.

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