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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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 (6) + 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 (46) + 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 (27) + 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 (31) + 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 (29) + 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 (20) + 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 (20) + 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 (30) + 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 (42) + 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 (20) + 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 sor