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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June 10, 2015

PCSK9 at the FDA

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Posted by Derek

So an FDA advisory committee met yesterday to consider the PCSK9 antibody from Regeneron and Sanofi, and today it's the turn of Amgen's candidate. These, as anyone with even a passing interest in cardiovascular medicine will know, are potential gigantic blockbusters and advances in the field, promising to lower LDL across a huge swath of the patient population. The question, though, is clinical outcomes - the big question is always clinical outcomes. Does lowering LDL via this mechanism lead to lower CV mortality, fewer heart attacks, etc.? By now, we have such data for statin therapy, and it does indeed seem to provide those benefits. Those numbers take years to generate, though, and although these studies are underway, the various PCSK9 developers would much rather not wait another two or three years for them to report, in much the same way that you or I would rather not spend that time dangling by our feet. So everyone is looking for a way to get these drugs onto the market.

Sanofi and Regeneron are looking to target patients who have a genetic predisposition to high LDL levels, and a larger group who are intolerant to statin therapy. The FDA committee was fine with the first plan, but not wildly enthusiastic about the second one. One worry they seemed to have was sending a "ditch your statins" message, which they don't want to do.

A whole generation of well-known statins, now cheap and easily available, has emerged with proven cardiovascular benefits for patients. Other LDL drugs, though, turned out to be controversial failures on CV outcomes. The FDA is fretting that an approval based on the LDL surrogate leaves it with no authority to demand a cardiovascular study. And regulators are alarmed over the impact these new drugs could have on statins, even though there are no proven CV advantages.

That's from this FierceBiotech piece, written before the committee meeting. Here's their take afterwards. Matthew Herper has an analyst who thinks that many statin-intolerant patients will go onto the new therapies, no matter what the label might way. We'll see. No PCSK9 antibody is going to reach its full market potential until the outcomes data arrive - that much has been clear for a long time. But now the companies (and their investors) are wondering about what they'll be able to realize before that happens.

Comments (23) + TrackBacks (0) | Category: Cardiovascular Disease | Regulatory Affairs

Defibrillating Dalcetrapib

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Posted by Derek

In 2012, Roche halted development of their CETP inhibitor dalcetrapib, part of what (so far) has been a grim chapter in cardiovascular drug development. At the time, this was put down to lack of efficacy, rather than the bad effects seen with Pfizer's torcetrapib, news that did nothing to cheer up the CETP research community.

Now DalCor (of Montreal) has licensed the compound, and is planning to go back into the clinic. What makes them think that they'll have any better time of it? The plan is to restrict the clinical trial (and the eventual patient population) to a group that appears to be genetically predisposed to respond. An analysis of the trial data suggests that polymorphisms in the ADCY9 gene (adenylate cyclase 9) could account for large variations in the effects of dalcetrapib. DalCor and the Montreal Heart Institute plan to screen about 30,000 potential patients to find enough of them with the right profile.

What's not clear to me is how many potential patients (and customers) this polymorphism leaves you with. DalCor has apparently run the numbers, and believes that there's potential here but (naturally) this also all depends on that analysis from the previous trials being solid. Dalcetrapib will never be the blockbuster that Roche hoped for some years ago, but just turning it into a drug at all would (by this point) make for quite a story.

Comments (3) + TrackBacks (0) | Category: Cardiovascular Disease

May 13, 2015

How Not to Handle Your Clinical Data

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Posted by Derek

We turn now to Orexigen, one of the small companies trying to make headway in the obesity market. Earlier this year, a patent application from them published, claiming that their drug (Contrave, a sustained release formulation combining the known drugs naltrexone and bupropion) had cardiovascular benefits above and beyond its weight-loss effects. Problem was, they based that claim on the first 25% of the data from an ongoing clinical trial. You're not supposed to go around doing that. The disclosure led to a public fight with researchers at the Cleveland Clinic (including well-known cardiologist Steve Nissen) about whether the trial had been compromised, and whether Orexigen was misleading its shareholders.

Now, as Matthew Herper reports, the trial has been halted, on the grounds that it has indeed been compromised by that premature data release. The FDA had also stated that they would not accept the trial results for that very reason. Orexigen and their partner, Takeda (who must be wondering how they got into this) announced this yesterday morning, followed a half-hour later by the release of the (half-completed) trial data by the Cleveland Clinic team. (Takeda is also talking breach-of-contract). The cardiovascular benefit that had been noted at the quarter-way mark had slipped below statistical significance, and the best bet is that it was on its way to disappearing entirely, had the trial actually completed.

It's been ugly. Orexigen released a statement, trying to make their case. Read it at that link and see what you think. I have trouble believing, myself, that they're really pleased that the study is being terminated, and that it's yielded important information nonetheless.

The company also seems to be trying (obliquely) to blame the USPTO for disclosing the data, but they're glossing over the fact that (1) everyone knows the schedule for publication of patent applications, and (2) the PTO is only publishing what you put into your own patent application that you wrote yourself. So this is not even as plausible as blaming the "Reply All" button in an e-mail application. They also seem to be blaming Matt Herper for merely reporting the ways in which the company seems determined to super-glue a clown wig onto its head.

I'll gladly stand by that opinion, in case Orexigen's people get around to reading this, and I'll throw in another one: they would have had trouble paying someone to mess up that trial as throughly as they managed to mess it up themselves. For all the talk in the Orexigen statement about all the tensions and problems with disclosure of clinical data, it's really not all that hard: you shut up about your interim data, unless you've already (from the beginning) planned to disclose something, and the trial has been designed with that in mind. Otherwise, unless the numbers are enough to halt the trial (in either a good or bad way), you just sit tight and see what happens. Because interim data are, well, interim. You run a full trial to see what the real numbers are - until then, they aren't the real numbers.

Update: more on the data release.

Comments (35) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | How Not to Do It

November 21, 2014

Amgen Claims It All

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Posted by Derek

There's plenty of excitement about PCSK9, the latest LDL-lowering pathway to make it deep into the clinic. You can tell that companies (and investors) have high hopes for it, since it's heading right into a market that's dominated by generic statins. The optimism may well be justified - for example, Sanofi and Regeneron recently presented some impressive data comparing their antibody to Zetia in patients who can't take higher statin doses, and Amgen has shown similar numbers. There are at least five antibodies and one RNAi in development, in a very tight race to the FDA and to the market. To give you an idea, the latest development was Sanofi and Regeneron paying cash to Biomarin for an FDA priority voucher that reduces their review time to six months instead of ten. (No, I didn't know that you could do that, either).

Amgen, though, appears to be trying to own the whole racetrack. They're pushing a patent claim to any antibody to PCSK9, not just their own agent. Update: See below for more on this Here's their press release; they're quite up front about this strategy. But I have doubts about how well that's going to work. Over the years, the judicial trend seems to have been to not go for such broad claims in the biomedical field. There are so many potential antibodies to any given protein, and so many ways of modifying them and dosing them, that I find it hard to imagine a straight patent claim on all that space. It's a lot like claiming "All inhibitors of enzyme X" in small molecules, and we already know that such claims don't stand up. It wouldn't surprise me, in fact, if someone had already tried a broad antibody claim like this and had it shot down (does anyone have an example?)

So I don't think that the PCSK9 struggle is going to be decided by the patent lawyers. It looks to be fought out in the clinic, at the FDA, and especially out there in the real market. And it will be quite something to see.

Update: see the comments section. Amgen doesn't seem to be claiming every single antibody; just those against a particular epitope (although a very useful epitope, obviously). And patent litigation in such situations is complex, with precedents (none of them necessarily exact) going both ways. So this will be quite something to watch. Perhaps Amgen is hoping to paid a cut to go away?

Comments (22) + TrackBacks (0) | Category: Cardiovascular Disease | Patents and IP

November 17, 2014

Vytorin Actually Works

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Posted by Derek

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

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

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

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

November 13, 2014

Remember Vytorin? The Data Are Finally Coming.

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Posted by Derek

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

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

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

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

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

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

September 5, 2014

A VC Firm Touts Its Successes - And Its Failures

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Posted by Derek

Here's what sounds like a good idea from VC firm Index Ventures, from the latest issue of BioCentury (same one I referenced the other day). Like many others in the biopharma venture capital world, they're trying to run the "killer experiment" as soon as possible, to see which ideas for new companies look solid. Unlike the others, though, they're planning a web site where they will detail the successes - and the failures. Here's an example:

Founded in 2013, (Purple Pharmaceuticals) was started to identify small molecule inhibitors of proprotein convertase subtilisin/kexin type 9. Two mAbs against PCSK9 are already in Phase III testing to treat hypercholesterolemia with regulatory submissions expected this year: evolocumab from Amgen Inc. and alirocumab from partners Regeneron Pharmaceuticals Inc. and Sanofi.

Grainger said the antibodies have limitations, as they require high doses to suppress PCSK9 activity and once-weekly or once-monthly infusions. Thus a pill that could match the PCSK9 inhibition of the biologics could be “the holy grail” of lowering LDL cholesterol.

Purple began by trying to identify small molecules that were highly selective for PCSK9 over other proprotein convertases because, as Grainger noted, “PCSK9 is a member of a large family of enzymes that do some pretty critical things.”

The killer experiment, he said, “was to ask could we make a small molecule that was selective over these other proprotein convertases, and could we demonstrate that it would lower LDL cholesterol?”

After a year, Purple had identified some hits selective for PCSK9, but a conversation with researchers at the Genentech Inc. unit of Roche led to the realization that the virtual company would need to run a second experiment.

“We learned from that interaction with Genentech that they had also run a PCSK9 screening program the same way we had,” Grainger said. “They discovered that their hits, while preventing PCSK9 from cleaving an external substrate, did not prevent PCSK9 from cleaving itself.”

Purple learned that in vivo, PCSK9 is auto-activated by cleaving itself — meaning the only important interaction to inhibit is PCSK9 auto- activation, not interactions with external substrates.

Purple’s second experiment showed none of its small molecule hits that inhibited PCSK9 interaction with an external substrate also inhibited auto-activation.

“Therefore we were able to kill a project which had spent at that stage only about £300,000 over a year, only to discover at the critical moment that it didn’t have the profile that we wanted,” Grainger said. “We were able to terminate that without having created any infrastructure, without having spent a painful amount of money prosecuting the project.”

That story illustrates a number of points about drug discovery. First off, congratulations to those involved for being able to definitively test a hypothesis; that's the engine at the heart of all scientific research. And as they say, it was good to be able to do that without having spent too much money and time, because both of those have a way of getting a bit out of control as complication after complication gets uncovered. Investors start getting jumpy when you keep coming back to them saying "Well, you know, it turns out that. . . ", but you know, it often turns out that way.

The next thing this story shows is that when you see an obvious gap in the landscape that there may well be a good reason for it. PCSK9 antibodies are widely thought to be potential blockbusters; a huge battle is shaping up in that area. So why no small molecules, eh? That's the question that launched Purple, it seems, and it's a valid one. But it turns out to have a valid answer, one that others in the field had already discovered. I suspect that the people behind this effort were, at the same time they were characterizing their lead molecules, also beating all the bushes for the sort of information that they obtained from Genentech. Somebody must have tried small-molecule PCSK9 inhibitors, you'd think, so what happened? Were those projects abandoned for good reasons, or was there still some opportunity there that a new company could claim for itself?

There may well be more to this story, though, than the Index Ventures people are saying. Update: there is - see the end of this post. The autocatalytic cleavage of PCSK9 was already well-known - pretty much everything in the that protease family works that way. (The difference is that with PCSK9, the prodomain part of the protein stays on longer - details of its cleavage were worked out in 2006). And in this 2008 paper from Journal of Lipid Research, we find this:

Several approaches for inhibiting PCSK9 function are theoretically feasible. Because autocatalytic cleavage is required for the maturation of PCSK9, a small-molecule inhibitor of autocatalysis might be useful, provided that it was specific for PCSK9 processing and did not lead to a toxic accumulation of misfolded PCSK9. Small molecules that block the PCSK9-LDL receptor interactions would likely be efficacious, although designing inhibitors of protein-protein interactions is a tall order. Antisense approaches pioneered by Isis Pharmaceuticals (Carlsbad, CA) are well suited for liver targets, and studies in mice suggest that this approach is efficacious for PCSK9. Finally, there is considerable interest in developing antibody therapeutics to inhibit PCSK9-LDL receptor interactions.

Even more to the point is the paper that that JLR piece is commenting on. That one demonstrates, through studies of mutated PCSK9 proteins, that its catalytic activity does not seem to be necessary at all for its effects on LDL receptors (a result that had already been suggested in cell assays). Taken together, you'd come away with the strong impression that inhibiting PCSK9's catalytic activity, other than stopping it from turning itself into its active form, had a low probability of doing anything to cholesterol levels. And you'd come away with that impression in 2008, at the latest.

So Purple's idea was a longer shot than it appeared on the surface, not that the real information was exactly buried deep in the literature. They shouldn't have needed someone at Genentech to tell them that PCSK9's autocatalysis was the real target - I've never worked in the area at all, and I found this out in fifteen minutes on PubMed while riding in to work. They must have had more reason to think that an assay for PCSK9's exogenous activity would be worth running - either that, or this story has gotten garbled along the way.

But this example aside, I applaud the idea of making these early-stage calls public. And I agree with the Index Ventures folks that this should actually help academics and others unused to drug discovery to see what needs to be done to actually launch an idea out into the world. I look forward to seeing the web site - and perhaps to hearing a bit more about what really happened at Purple.

Update: David Grainger of Index Ventures has more in the comments, and says that there is indeed more to the story. He points out that mutations of PCSK9 were found that inhibited its autocatalytic activity (such as this one), and that work had appeared that suggested that molecules that inhibited only the autocatalytic activity could be useful. This is what Purple was seeking - the BioCentury piece makes things sound a bit different (see above), but the problem seems to have been that molecules that inhibited PCSK9's activity against other substrates turned out not to inhibit its activity against itself. If I'm interpreting this right, then, Genentech's contribution was to point out that the autocatalytic activity couldn't be modeled by looking at another substrate.

Comments (6) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Drug Assays

September 2, 2014

Novartis Impresses Where Others Have Failed

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Posted by Derek

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

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

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

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

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

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

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

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

March 24, 2014

Ezetimibe In the Marketplace

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Posted by Derek

Several years ago, the Schering-Plough cholesterol absorption inhibitor (Zetia, ezetimibe) and its combination pill with simvastatin (Vytorin) were the subject of a lot of puzzled controversy. A clinical trial (ENHANCE) looking at arterial wall thickness in patients with familial hypercholesteremia had unexpectedly shown little or no benefit, although statins themselves had worked in this population. This led to plenty of (still unresolved) speculation about the drug's mechanism of action, whether it really was going to be of benefit to the wider patient population, what this meant for the surrogate endpoint of LDL lowering (which the drug does accomplish), and so on.

Sales of both Zetia and Vytorin took a hit, naturally. But a new editorial in JAMA wonders why they're selling at all, and particularly, why they're doing so well in Canada. A new paper in the American Heart Journal shows that ezetimibe sales in the US went down 47% over the next year after the ENHANCE results came out. But in Canada, it just kept rolling along. (Even after the decline, though, it's still used more in the US).

What's causing this? Quite likely, an over-focus on cholesterol levels themselves:

Krumholz, one of the coauthors on the study with Jackevicius, remains perplexed as to the continuing popularity of ezetimibe. “The drug continues to defy gravity, and that’s probably a result of really strong marketing and the singular focus on cholesterol numbers,” he said.

Krumholz said heart health campaigns urging patients to “know your numbers” and treatment goals based on cholesterol measurements, such as getting asymptomatic individuals’ LDL-C levels below 130 mg/dL, have worked in ezetimibe’s favor at the expense of evidence-based medicine. “Is this the drug that lowers your LDL-C and helps you? We don’t know that,” he said. “The comfort of hitting a target offers little benefit if you don’t know that it is really protecting you.”

The funny thing is, all that emphasis on LDL assay numbers was supposed to be "evidence-based medicine". But that's the funny thing about science - the evidence keeps leading you in new directions.

Comments (4) + TrackBacks (0) | Category: Cardiovascular Disease

January 27, 2014

The Nasty Side of HDL

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Posted by Derek

A recurring theme here when I talk about cardiovascular drug discovery is how poorly we understand human lipidology. Surprise after surprise has followed on efforts to lower LDL and/or raise HDL, to the point that a person really has to wonder if the success of the statin drugs was a fluke. (And they could be a fluke in more than one way - perhaps the LDL-lowering effects are, for some reason, more beneficial through that mechanism than they might otherwise be, or as many have speculated, there might be off-target effects that are also helpful).

Everyone seems to agree, though, that raising HDL is (or would be) a good thing. Attempts to do that pharmacologically, though, have come to grief, so the evidence we have is through longitudinal studies and the occasional mutant line with unusually high HDL. Both of those have their pitfalls when it comes to drug targeting - there are, for example, people with HDL-raising mutations that don't see to show any good effect for it.

Now comes this paper in Nature Medicine that identifies an oxidized form of HDL (specifically, ApoA1 protein) in arterial plaques. This modified protein is useless for cholesterol scavenging, exacerbates inflammation, and impairs biogenesis of normal HDL. This makes it a good candidate as a diagnostic marker (which is where the paper is aimed, rightly), and also a good candidate for anyone working on HDL-raising ideas to keep an eye on.

Merck, for example, is pushing ahead with their CETP inhibitor compound anacetrapib Last report I saw on that one was on some rather alarming pharmacokinetics - the drug appears to take a long time to wash out. Long, as in "still detectable several years after the last dose". Given that it looks like something that could be used to line a nonstick frying pan (like most of the other CETP compounds), that's quite believable. As late as Merck is in the clinic, they're not going to be able to jump in and start looking for this new oxidized HDL form so easily. But it would be something to think about

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

January 16, 2014

Merck Pulls One Out

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Posted by Derek

Merck's vorapaxar, a thrombin antagonist that many had thought might never make it, has received a positive FDA advisory committee vote. I'm glad to see it - peripherally, I go way back with this compound (well, its ancestors), and I really had doubts that Merck could get things to fly. Anticoagulants are a very tricky business - we'll see (if and when it does get approved) what sort of market it can carve out. They're up for treating patient who have already had one cardiac event, which is still a good-sized market.

Comments (18) + TrackBacks (0) | Category: Cardiovascular Disease | Regulatory Affairs

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

October 24, 2013

Dietary Fat and Heart Disease

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Posted by Derek

Here's a provocative article at the British Medical Journal on cardiovascular outcomes and diet. Now, I free admit that the BMJ has a tendency towards controversialism, but I'm hardly in a position to throw stones. The author, Aseem Malhotra, says "Saturated fat is not the issue".

Human lipidology is a very complex field, and anyone who tells you that they have the definite answers needs to be treated with caution. As has been well documented, the consensus advice about dietary fats of all kinds has varied quite a bit, and I don't think it's anywhere near settling down. The role of pharmaceutical intervention isn't settled, either, despite the huge success of the statin drugs. There's room to argue about their broad effects on cardiovascular morbidity and mortality, and how much of it is mechanism-based:

A meta-analysis of predominantly industry sponsored data reported that in a low risk group of people aged 60-70 years taking statins the number needed to treat (NNT) to prevent one cardiovascular event in one year was 345. The strongest evidence base for statins is in secondary prevention, where all patients after a myocardial infarction are prescribed maximum dose treatment irrespective of total cholesterol, because of statins’ anti-inflammatory or pleiotropic (coronary plaque stabilising) effects. In this group the NNT is 83 for mortality over five years. This doesn’t mean that each patient benefits a little but rather that 82 will receive no prognostic benefit. The fact that no other cholesterol lowering drug has shown a benefit in terms of mortality supports the hypothesis that the benefits of statins are independent of their effects on cholesterol.

You can go on from this to wonder how things are going to work out if any of the HDL-raising therapies ever make it into the general population. Do we know what we're doing there, or are we only going to find out after twenty years in the real world? On saturated fat, Malhotra says that he's not convinced by the standard recommendations, either:

Saturated fat has been demonised ever since Ancel Keys’s landmark “seven countries” study in 1970. This concluded that a correlation existed between the incidence of coronary heart disease and total cholesterol concentrations, which then correlated with the proportion of energy provided by saturated fat. But correlation is not causation. Nevertheless, we were advised to cut fat intake to 30% of total energy and saturated fat to 10%.” The aspect of dietary saturated fat that is believed to have the greatest influence on cardiovascular risk is elevated concentrations of low density lipoprotein (LDL) cholesterol. Yet the reduction in LDL cholesterol from reducing saturated fat intake seems to be specific to large, buoyant (type A) LDL particles, when in fact it is the small, dense (type B) particles (responsive to carbohydrate intake) that are implicated in cardiovascular disease.

I find this sort of thing very interesting, both as an issue in itself, and for what it says about our knowledge of medicine and human biology. You'd think that there would be nothing more well worked-out than the role of different kinds of diets in heart disease, but the closer you look, the messier the situation is. There are big public health issues here, both the obvious primary ones, and the secondary issue of causing people to become frustrated and cynical about big dietary recommendations in general.

Comments (54) + TrackBacks (0) | Category: Cardiovascular Disease

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

July 12, 2013

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

May 9, 2013

An Anticoagulant Antidote

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Posted by Derek

Here's a drug-discovery problem that you don't often have to think about. The anticoagulant field is a huge one, with Plavix, warfarin, and plenty of others jostling for a share of a huge market (both for patients to take themselves, and for hospital use). The Factor Xa inhibitors are a recent entry into this area, with Bayer's Xarelto (rivaroxaban) as the key example so far.

But there's a problem with any Xa inhibitor: there's no antidote for them. Blood clotting therapies have a narrow window to work in - anything effective enough to be beneficial will be effective enough to be trouble under other circumstances. Anticoagulants need a corresponding way to cancel out their effects, in case of overdose or other trouble. (Vitamin K is the answer for warfarin). We don't often have to consider this issue, but it's a big one in this case.

Portola Therapeutics has developed a Factor Xa mimic that binds the inhibitors, and thus titrates their effects. They have their own Xa inhibitor coming along (bextrixaban), but if this protein makes it through, they'll have done the whole field a favor as well as themselves.

Comments (8) + TrackBacks (0) | Category: Cardiovascular Disease

Merck's Liptruzet: A Cause For Shame?

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Posted by Derek

Vytorin's been discussed several times around here. The combination of Zetia (ezetimibe), the cholesterol absorption inhibitor discovered at Schering-Plough, with Merck's simvastatin looked as if it should be a very effective cholesterol-lowering medication, but the real-world data have been consistentlypuzzling. There's a big trial going on that people are hoping will clarify things, but so far it's had the opposite effect. It's no exaggeration to say that the entire absorption inhibitor/statin combination idea is in doubt, and we may well learn a lot about human lipidology as we figure out what's happened. It will have been an expensive lesson.

So in the midst of all this, what does Merck do but trot out anotherezetimibe/statin combination? Liptruzet has atorvastatin (generic Lipitor) in it, instead of simavastatin (generic Zocor), and what that is supposed to accomplish is a mystery to me. It's a mystery to Josh Bloom over at the American Council for Science and Health, too, and he's out with an op-ed saying that Merck should be ashamed of itself.

I can't see how he's wrong. What I'm seeing is an attempt by Merck to position itself should the ongoing Vytorin trial actually exonerate the combination idea. Vytorin, you see, doesn't have all that much patent lifetime left; its problems since 2008 have eaten the most profitable years right out of its cycle. So if Vytorin turns out to actually work out, after all the exciting plot twists, Merck will be there to tell people that they shouldn't take it. No, they should take exciting new Liptruzet instead. It's newer.

If anyone can think of a reason why this doesn't make Merck look like shady marketeers, I'd like to hear it. And (as Bloom points out) it doesn't make the FDA look all that great, either, since I'm sure that Liptruzet will count towards the end-of-the-year press release about all the innovative new drugs that the agency has approved. Not this time.

Update: John LaMattina's concerned about that last part, too.

Comments (38) + TrackBacks (0) | Category: Cardiovascular Disease | Why Everyone Loves Us

April 4, 2013

Regeneron Expands

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Posted by Derek

I feel as if there should be some good news around here on the hiring front, so when any becomes available I want to try to mention it. So here's some: Regeneron has announced today that they're expanding their site in Westchester (NY), adding another 300,000 square feet of lab and office space, and adding over 400 new jobs in a number of areas.

The fusion protein Eylea (aflibercept) has been doing very well for them since its approval in 2011. And they're very much in the hunt for PCSK9 therapies, which could provide a completely new LDL-lowering mechanism. (Here's some good background from John LaMattina on that - Sanofi and Regeneron are running one of those humungous cardiovascular Phase III trials as we speak, and the results of it (compared to the statin standard of care) are going to be extremely interesting). If those numbers come out well, Regeneron could be looking for even more room.

Comments (3) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease

March 19, 2013

Affymax In Trouble

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Posted by Derek

Affymax has had a long history, and it's rarely been dull. The company was founded in 1988, back in the very earliest flush of the Combichem era, and in its early years it (along with Pharmacopeia) was what people thought of when they thought of that whole approach. Huge compound libraries produced (as much as possible) by robotics, equally huge screening efforts to deal with all those compounds - this stuff is familiar to us now (all too familiar, in many cases), but it was new then. If you weren't around for it, you'll have to take the word of those who were that it could all be rather exciting and scary at first: what if the answer really was to crank out huge piles of amides, sulfonamides, substituted piperazines, aminotriazines, oligopeptides, and all the other "build-that-compound-count-now!" classes? No one could say for sure that it wasn't. Not yet.

Glaxo bought Affymax back in 1995, about the time they were buying Wellcome, which makes it seem like a long time ago, and perhaps it was. At any rate, they kept the combichem/screening technology and spun a new version of Affymax back out in 2001 to a syndicate of investors. For the past twelve years, that Affymax has been in the drug discovery and development business on its own.

And as this page shows, the story through most of those years has been peginesatide (brand name Omontys, although it was known as Hematide for a while as well). This is synthetic peptide (with some unnatural amino acids in it, and a polyethylene glycol tail) that mimics erythropoetin. What with its cyclic nature (a couple of disulfide bonds), the unnatural residues, and the PEGylation, it's a perfect example of what you often have to do to make an oligopeptide into a drug.

But for quite a while there, no one was sure whether this one was going to be a drug or not. Affymax had partnered with Takeda along the way, and in 2010 the companies announced some disturbing clinical data in kidney patients. While Omontys did seem to help with anemia, it also seemed to have a worse safety profile than Amgen's EPO, the existing competition. The big worry was cardiovascular trouble (which had also been a problem with EPO itself and all the other attempted competition in that field). A period of wranging ensued, with a lot of work on the clinical data and a lot of back-and-forthing with the FDA. In the end, the drug was actually approved one year ago, albeit with a black-box warning about cardiovascular safety.

But over the last year, about 25,000 patients got the drug, and unfortunately, 19 of them had serious anaphylactic reactions to it within the first half hour of exposure. Three patients died as a result, and some others nearly did. That is also exactly what one worries about with a synthetic peptide derivative: it's close enough to the real protein to do its job, but it's different enough to set off the occasional immune response, and the immune system can be very serious business indeed. Allergic responses had been noted in the clinical trials, but I think that if you'd taken bets last March, people would have picked the cardiovascular effects as the likely nemesis, not anaphylaxis. But that's not how it's worked out.

Takeda and Affymax voluntarily recalled the drug last month. And that looked like it might be all for the company, because this has been their main chance for some years now. Sure enough, the announcement has come that most of the employees are being let go. And it includes this language, which is the financial correlate of Cheyne-Stokes breathing:

The company also announced that it will retain a bank to evaluate strategic alternatives for the organization, including the sale of the company or its assets, or a corporate merger. The company is considering all possible alternatives, including further restructuring activities, wind-down of operations or even bankruptcy proceedings.

I'm sorry to hear it. Drug development is very hard indeed.

Comments (11) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Drug Development | Drug Industry History | Toxicology

February 15, 2013

Merck Finally Settles Over Vytorin

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Posted by Derek

You may remember that Merck and Schering-Plough took a lot of fire for the way that they released the clinical data for one of the key Vytorin trials (ENHANCE). The numbers were delayed for months, and when they were finally released, they were. . .problematic for the drug. And for the companies' stocks.

The institutional shareholders did not take that one well; and a number of them filed suit. This week it was announced that Merck has settled for $688 million, while admitting no wrongdoing. This settles the suit, but it isn't going to settle anyone's nerves, as Matthew Herper rightly observes:

Merck admitted no liability or wrongdoing in the decision, and continues to believe its handling of the study was proper. But the settlement could make investors nervous anyway. One of the reasons Vytorin has never recovered (sales of the pill are $1.5 billion, $1 billion less than before the results were released, but that partly reflects a price increase) is that Merck’s other clinical trials, so far, have never again compared Vytorin to Zocor to look for differences in real cardiovascular problems like heart attack and stroke. Instead, the other big trial of Vytorin compared it to placebo in patients who had a heart valve that did not close fully.

But Merck is doing that big Vytorin versus Zocor study, a giant clinical trial called IMPROVE-IT. Results have been delayed several times, and probably won’t come until next year. But the company has said that the independent board that is monitoring the results of the trial will meet in March. They could decide to stop the trial if it has already proved more effective, if Vytorin appears more dangerous than Zocor, or if there is no hope that Vytorin will prove more effective.

I doubt that the trial will be stopped, but at this point I'll be surprised if it yield enough strong data to vindicate Vytorin, either. The delays seen in the trial so far make that look like a very outside chance. My guess is "beneficial effect, but not as much as you'd want", which won't satisfy anyone.

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

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

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 14, 2012

Mipomersen In Trouble

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Posted by Derek

I wrote here in 2009 about Kynamro (mipomersen), an antisense oligonucleotide from Isis targeted LDL cholesterol levels. At the time, Isis and Genzyme were starting to look at its use in people with familial hypercholesterolaemia, and its prospects looked promising to become at least a profitable niche drug.

But the European Medicines Authority just turned down the drug, saying that its risk/benefit ratio just looks unacceptable. Efficacy was not in doubt, but a substantial number of patients stopped taking mipomersen because of side effects, including liver toxicity. That's bad enough, but the treatment groups also showed a great incidence of cardiovascular events, which is particularly worth thinking about when you're trying to lower LDL to prevent. . .cardiovascular events.

Human lipid handling continues to be a minefield for new therapies. The statins (which lower LDL through inhibiting cholesterol biosynthesis) appear, more and more, to be outliers in their safety and efficacy. That's not to say that statin drugs never have problems (they do - just ask Bayer, among others). But the risk/benefit for them does appear to be robust and positive, and how many other lipid-altering drugs can say that?

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

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 30, 2012

Niacin: How Does It Work, Anyway?

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Posted by Derek

Here's yet another chance to play the human biology game that might as well be called "Now what?" That's when we find that what we thought we knew is actually wrong, more complicated, or a sign of something else entirely.

Today's entry is niacin. As many readers know, it looks like it should be a promising therapy for patients whose lipoproteins are out of whack. It lowers LDL, raises HDL, lowers free fatty acids, and lowers triglycerides, and all those things are supposed to be good. (As came up in the comments yesterday's post, though, the evidence is pretty strong for that first proposition, but not as solid for the others). Still, if you went around to thousands of cardiologists and asked them if they'd be interested in a therapy that did those four things, you'd get a resounding "Yes".

So why hasn't niacin taken over the world? Because of the side effects. It has to be taken in rather stiff doses to show the lipid effects, and those tend to cause a nasty skin flush reaction, which is apparently unpleasant enough that most people won't put up with it. Various attempts have been made to abrogate this, with the most direct assault being Merck's (failed) Cordaptive.

The flushing is thought to be mediated through the receptor GPR109A, via a prostaglandin pathway. Unfortunately, it's also believed that niacin's beneficial effects are mediated through that receptor, too, via some mechanism that starts with the lowering of free fatty acids. If you knock out the receptor in mice, you get no skin flushing, but no FFA lowering, either.

We must now revise that idea. A new paper tests that hypothesis with two non-niacin agonists, MK-1903 (a compound via Arena Pharmaceuticals, I believe) and SCH900271, and their effects in humans. They also report niacin's effects in the receptor knockout mice, claiming that although the FFA lowering does indeed disappear, that the downstream lipid effects remain. (That surprises me; I'd thought that had already been studied).

But the human data are especially revealing. The two new agonists do indeed show FFA effects, as you'd expect from compounds hitting GPR109A. But they do not show chronic free fatty acid lowering, nor do they have the desired downstream effects on blood lipids. So it appears inescapable that niacin's effects are going through some other pathway, one that doesn't depends on GPR109A or its (transient) free fatty acid lowering. Back to the drawing board everyone gets to go.

But niacin has been heading there already. Readers may remember a trial of a niacin-and-statin combination had to be stopped early because the cardiovascular effects were (alarmingly) going in the other direction. Not only was there no benefit, but there seemed to be active harm. Taken together, all this tells us that we have an awful lot to learn about some things that we thought we were starting to understand. . .

Comments (23) + TrackBacks (0) | Category: Cardiovascular Disease

August 29, 2012

Caloric Restriction Flops?

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Posted by Derek

Nature is out today with a paper on the results of a calorie-restriction study that began in 1987. This one took place with rhesus monkeys at the National Institute of Aging, and I'll skip right to the big result: no increase in life span.

That's in contrast to a study from 2009 (also in rhesus) that did see an extension - but as this New York Times article details, there are a number of differences between the two studies that confound interpretation. For one thing, a number of monkeys that died in the Wisconsin study were not included in the results, since it was determined that they did not die of age-related causes. The chow mixtures were slightly different, as were the monkeys' genetic background. And a big difference is that the Wisconsin control animals were fed ad libitum, while the NIA animal were controlled to a "normal" level of calorie intake (and were smaller than the Wisconsin controls in the end).

Taken together with this study in mice, which found great variation in response to caloric restriction depending on the strain of mouse used, it seems clear that this is not one of those simple stories. It also complicates a great deal the attempts to link the effect of various small molecules to putative caloric restriction pathways. I used to think that caloric restriction was the bedrock result of the whole aging-and-lifespan research world - so now what? More complications, is what. Some organisms, under some conditions, do seem to show longevity effects. But unraveling what's going on is just getting trickier and trickier as time goes on.

I wanted to take a moment as well to highlight something that caught my eye in the Times article linked above. Here:

. . .Lab test results showed lower levels of cholesterol and blood sugar in the male monkeys that started eating 30 percent fewer calories in old age, but not in the females. Males and females that started dieting when they were old had lower levels of triglycerides, which are linked to heart disease risk. Monkeys put on the diet when they were young or middle-aged did not get the same benefits, though they had less cancer. But the bottom line was that the monkeys that ate less did not live any longer than those that ate normally. . .

Note that line about "benefits". The problem is, as far as I can see (Nature's site is down as I write), the two groups of monkeys appear to have shown the same broad trends in cardiovascular disease. And cardiovascular outcomes are supposed to be the benefits of better triglyceride numbers, aren't they? You don't just lower them to lower them, you lower them to see better health. More on this as I get a chance to see the whole paper. . .

Comments (13) + TrackBacks (0) | Category: Aging and Lifespan | Cardiovascular Disease | Diabetes and Obesity

June 29, 2012

The CETP Rogues Gallery

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Posted by Derek

Has there ever been a less structurally appealing class of drugs than the cholesteryl ester transfer protein (CETP) inhibitors? Just look at that bunch. From left to right, that's Pfizer's torcetrapib (which famously was the first to crash and burn back in 2006), Roche's dalcetrapib (which was pulled earlier this year from the clinic, a contributing factor to the company's huge recent site closure), Merck's anacetrapib (which is forging on in Phase III), Lilly's evacetrapib (which when last heard from was also on track to go into Phase III), and a compound from Bristol-Myers Squibb, recently published, which must be at least close to their clinical candidate BMS-795311.


Man, is that ever an ugly-looking group of compounds. They look like fire retardants, or something you'd put in marine paint formulations to keep barnacles from sticking to the hull. Every one of them is wildly hydrophobic, most are heavy on aromatic rings, and on what other occasion did you ever see nine or ten fluorines on one drug molecule? But, as you would figure, this is what the binding site of CETP likes, and this is what the combined medicinal chemistry talents of some of the biggest drug companies in the world have been driven to. You can be sure that they didn't like it, but the nice-looking compounds don't inhibit CETP.

Will any of these fancy fluorocarbon nanoparticles make it through to the market, just on properties/idiosyncratic toxicity concerns alone? How do their inhibitory mechanisms differ, and what will that mean? Is inhibiting CETP even a good idea in the first place, or are we finding out yet more fascinating details about human lipoprotein handling? Money is being spent, even as you read this, to find out. And how.

Comments (22) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology

May 30, 2012

500,000 Excess Deaths From Vioxx? Where?

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Posted by Derek

Several people have sent this along, or similar writeups. The claim is that Vioxx actually was responsible for over 500,000 deaths, which would be about ten times the absolute highest (and much disputed) estimate that's been seen to date. Ron Unz, the publisher of the American Conservative who makes these allegations, says that they're obvious in death-rate figures, particularly in the older population:

"We find the largest rise in American mortality rates occurred in 1999, the year Vioxx was introduced, while the largest drop occurred in 2004, the year it was withdrawn," says Unz. "Vioxx was almost entirely marketed to the elderly, and these substantial changes in the national death-rate were completely concentrated within the 65-plus population.">

I found this claim very hard to believe. (For one thing, how could all those patients and lawyers suing Merck have let this get past them?) Looking at the statistics themselves, I can see no evidence for Unz's claim. Here, for example, is the death rate in the US, crude and age-adjusted, over this time span:

And to get more specific, here are the numbers for cardiovascular deaths for people 65 and over. (They're in a chart comparing them to cancer death rates as well):

I do not see the effects that Unz is talking about. Not at all. A single-cause change in the death rate of the magnitude that he's proposing should most certainly show up in these figures (particularly the latter chart), but it isn't there. I see no reason to take this claim seriously.

For those wanting more, there are more arguments against this theory in the comments here).

Comments (24) + TrackBacks (0) | Category: Cardiovascular Disease

May 18, 2012

Strangely Good Results in Diabetes and Cardiovascular Disease

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Posted by Derek

I've read a couple of medical papers recently that show how tricky it is to draw conclusions on what patients would be best helped by a specific therapy. Many of you will have seen the paper in The Lancet on the use of statins in low-risk patients. This isn't something you'd necessarily think would do much good - it all depends on what the benefits are, at the margin, of lowering LDL. But the results appear surprisingly strong:

In individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This benefit greatly exceeds any known hazards of statin therapy. Under present guidelines, such individuals would not typically be regarded as suitable for LDL-lowering statin therapy. The present report suggests, therefore, that these guidelines might need to be reconsidered.

A note to the conspiratorially minded, should any such come across this: it's worth noticing that this "maybe everyone should take statins" result comes after the major ones have gone off patent. Pfizer, Merck et al. would have greatly enjoyed this recommendation had it occurred ten years ago, but it didn't (and probably couldn't have, since we didn't have as much data as we do now).

Now to another (often related) disease, type II diabetes. It's been found that bariatric surgery improves glycemic control in the very obese patients who are candidates for the procedure. And that makes sense - obesity is absolutely a risk factor for type II in the first place. But as more and more of these surgeries are being done, something odd is becoming apparent:

Clinicians note that bariatric operations can dramatically resolve type 2 diabetes, often before and out of proportion to postoperative weight loss. Now two randomized controlled trials formally show superior results from surgical compared with medical diabetes care, including among only mildly obese patients. The concept of 'metabolic surgery' to treat diabetes has taken a big step forward.

Why this happens is a very good question indeed. Patients seem to benefit greatly within the first two weeks after gastric bypass surgery, well before any significant weight loss has occurred. My first guess is that it's something to do with secretion of hormones from the gut itself, and you'd also have to think that nutrient sensing gets profoundly altered. It's not going to be easy to turn this into an approved therapy, though. Running randomized clinical trials for dramatic surgical procedures (versus noninvasive care) is difficult, as you'd imagine:

Despite these compelling clinical observations, RCTs of surgery versus nonsurgery are sorely needed. Ample precedents exist wherein RCTs reversed longstanding paradigms derived from nonrandomized clinical trials. Some of the best evidence in bariatric surgery, from the Swedish Obese Subjects study (a long-term observation of various operations versus conventional care), is prone to allocation bias because participants were not randomized. Subjects who actively chose surgery may be more motivated overall and generally take better care of themselves. The NIH is unlikely to reconsider its guidelines without pertinent RCTs, and insurance companies are unlikely to pay for operations that are not NIH-sanctioned.

Both of these results point out the completely nonlinear nature of living systems. It can work for good, as in these cases, or for bad. Alzheimer's, the subject of yesterday's post, is a perfect example of the latter: one protein, out of perhaps a few million, has one of its hundreds of amino acids changed in one small way on its side chain. And it's a death sentence. Good to know that things can work in the other way once in a while.

Comments (14) + TrackBacks (0) | Category: Alzheimer's Disease | Cardiovascular Disease | Diabetes and Obesity

May 17, 2012

Is HDL Always "Good Cholesterol"?

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Posted by Derek

The failure of Roche's dalcetrapib has a lot of people wondering just what's going on with HDL as a cardiovascular drug target. And this isn't the first time - there have been a number of puzzling findings in the lipoprotein field that point out to us that we don't know nearly as much about this area as we might think. Many promising therapeutic ideas in it have turned out disastrously.

Now there's a new paper in The Lance that underscores this, and how. The authors have done large genome-wide association studies looking for polymorphisms that affect lipoproteins, and they're following those up with clinical data on cardiovascular outcomes. Untangling the effects of HDL, LDL, triglycerides and other factors isn't easy, but they did find one mutation that appears to raise HDL alone. Looking at the people carrying that one, they find that there's no amelioration of risk in them at all. That's as opposed to the mutations that lowered LDL levels, which were consistently associated with lower risks.

This doesn't (necessarily) mean that HDL is useless as a predictor of cardiovascular risk, but it definitely means that it isn't as simple as "HDL = Good Cholesterol!". What this means for things like CETP inhibition is anyone's guess.

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

May 7, 2012

The CETP Saga Continues (And It's Not Getting More Entertaining)

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Posted by Derek

Roche has halted trials of its CETP inhibitor dalcetrapib. Many will remember the Pfizer compound in this class, torcetrapib, which went down catastrophically in Phase III back in 2006. In that case, deaths in the treatment group were higher than the placebo group, which will bring you to a screeching halt every time. The generally accepted story is that the compound's effects on blood pressure (and possibly electrolyte balance) negated its beneficial effects on lipoproteins. But was torcetrapib actually working? It certainly raised HDL levels - but is that enough?

You have to wonder. Dalcetrapib wasn't taken out by toxicity - it was dropped because of "a lack of clinically meaningful efficacy". Analysis of several Phase II trials seems to have shown no beneficial outcome in cardiovascular mortality and mobidity. So what is it that we don't know about CETP, about HDL, and about lipoprotein roles in cardiovascular disease in general? Quite a bit, is my guess.

Two companies that are very, very much pondering that question are Merck and Eli Lilly, both with competing CETP inhibitors in the clinic. Expect statement from each of them that they continue to have confidence in their clinical candidates. But behind the scenes, expect a lot of very intense re-evaluation.

Comments (32) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials

February 29, 2012

Statin Safety

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Posted by Derek

You'll have seen the news about the FDA safety warning on statins. The agency is warning that instances of hyperglycemia have occurred with statin use, as well as memory loss and confusion.

I'm really not sure what to make of this. On the one hand, these drugs have been through many, many large clinical trials under controlled conditions, and they've been taken by a huge numbers of patients out in the real world. So you might think that if these effects were robust, that they might have been noticed before now. But there are side effects that are below the threshold of even the largest clinical trials, and a patient population the size of the one taking these drugs is just where you might be able to see such things.

I lean towards the latter, and if that's true, then the agency's statement is appropriate. If these could be real effects in some patients, then it's worth keeping an eye out for them. One problem, though, is that hyperglycemia is rather more sturdy. You can measure it, and people don't really feel it when they have it. Memory loss and confusion are fuzzier, but they're immediately felt, so they're subject to more post hoc ergo propter hoc judgments. It's possible that more people will stop taking statins because of that part of the warning to cancel out the public health good that it might do otherwise.

Comments (12) + TrackBacks (0) | Category: Cardiovascular Disease | Regulatory Affairs | Toxicology

November 30, 2011

Lipitor Expiration Day

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Posted by Derek

As one of Garrison Keillor's characters says (in WLT), "I always knew the end would come. And here it is, the end". Lipitor (atorvastatin) goes off patent today, and I can recommend this overview by Matthew Herper at Forbes. Will there ever be another drug like it? The people developing the CETP inhibitors hope so. . .

Comments (15) + TrackBacks (0) | Category: Cardiovascular Disease | Drug Industry History

November 22, 2011

Regeneron Finally Makes It to the Market

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Posted by Derek

I've been doing drug research since 1989 myself, which means that I'm fairly experienced. But Regeneron started in this business a year or two before I did, and they're just now getting their first major drug, Eylea (aflibercept) onto the market. To be fair, they did get approval for Araclyst (rilonacept) in 2008, but that one pays the electric bill and not much more - although that might be changing (see below).

As Andrew Pollack at the New York Times points out, the company has run through over two billion dollars over the years. I remember when they were working on nerve growth factors for ALS and other diseases, back in the early 1990s (I worked in the area briefly myself, to no good effect whatsoever). There are not a lot of nerve growth factor drugs on the market, although it seemed like a perfectly plausible mechanism for one back then.

That work shaded into another indication, ciliary neurotrophic factor for obesity. Regeneron spent a lot of time and money developing a modified form of that protein called Axokine, but in 2003 that project ran into the rocks. Some patients did lose weight on the drug (with daily injections), but too many of them developed antibodies to it, which raised the possibility of cross-reactivity with their own CNF, which would surely not have been a good thing. So much for Axokine.

But Eylea, a VEGF-based therapy for macular degeneration (entering the same space as Lucentis and Avastin), has now made it. And the company has another use for Arcalyst in preventative gout therapy coming along, and some interesting cholesterol work targeting PCSK9 in collaboration with Sanofi. So welcome, Regeneron, to the ranks of profitable biotech companies (well, pretty soon) who've developed their own products. It's taken a lot of time, a lot of patience - yours and your investors' - and a lot of cash. But you're still here, and how many other bioctech startups from the late 1980s can say that?

Comments (6) + TrackBacks (0) | Category: Cardiovascular Disease | Diabetes and Obesity | Drug Industry History | Regulatory Affairs | The Central Nervous System

November 18, 2011

Pushing Onwards with CETP: The Big Money and the Big Risks

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Posted by Derek

Remember torcetrapib? Pfizer always will. The late Phase III failure of that CETP inhibitor wiped out their chances for an even bigger HDL-raising follow-up to LDL-lowering Lipitor, the world's biggest drug, and changed the future of the company in ways that are still being played out.

But CETP inhibition still makes sense, biochemically. And the market for increasing HDL levels is just as huge as it ever was, since there's still no good way to do it. Merck is pressing ahead with anacetrapib, Roche with dalcetrapib, and Lilly is out with recent data on evacetrapib. All three companies have tried to learn as much as they could from Pfizer's disaster, and are keeping a close eye on the best guesses for why it happened (a small rise in blood pressure and changes in aldosterone levels). So far, so good - but that only takes you so far. Those toxicological changes are reasonable, but they're only hypotheses for why torcetrapib showed a higher death rate in the drug treatment group than it did in the controls. And even that only takes you up to the big questions.

Which are: will raising HDL really make a difference in cardiovascular morbidity and mortality? And if so, is inhibiting CETP the right way to do it? Human lipidology is not nearly as well worked out as some people might think it is, and these are both still very open questions. But such drugs, and such trials, are the only way that we're going to find out the answers. All three companies are risking hundreds of millions of dollars (in an area that's already had one catastrophe) in an effort to find out, and (to be sure) in the hope of making billions of dollars if they're correct.

Will anyone make it through? Will they fail for tox like Pfizer did, telling us that we don't understand CETP inhibitors? Or will they make it past that problem, but not help patients as much as expected, telling us that we don't understand CETP itself, or HDL? Or will all three work as hoped, and arrive in time to split up the market ferociously, making none of them as profitable as the companies might have wanted? If you want to see what big-time drug development is like, I can't think of a better field to illustrate it.

Comments (17) + TrackBacks (0) | Category: Cardiovascular Disease | Drug Development | Toxicology

November 15, 2011

Geron, Stem-Cell Pioneers, Drop Stem Cells

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Posted by Derek

Are stem cells overhyped? That topic has come up around here several times. But there have been headlines and more headlines, and breathless reports of advances, some of which might be working out, and many of which are never heard from again. (This review, just out today, attempts to separate reality from hype).

Today brings a bit of disturbing news. Geron, a company long associated with stem cell research, the company that started the first US trial of embryonic stem cell therapy, has announced that they're exiting the field. Now, a lot of of this is sheer finances. They have a couple of oncology drugs in the clinic, and they need all the cash they have to try to get them through. But still, you wonder - if their stem cell trial had been going really well, wouldn't the company have gotten a lot more favorable publicity and opportunities for financing by announcing that? As things stand, we don't know anything about the results at all; Geron is looking for someone to take over the whole program.

As it happens, there's another stem-cell report today, from a study in the Lancet of work that was just presented at the AHA. This one involves injecting heart attack patients with cultured doses of their own cardiac stem cells, and it does seem to have helped. It's a good result, done in a well-controlled study, and could lead to something very useful. But we still have to see if the gains continue, what the side effects might be, whether there's any advantage to doing this over other cell-based therapies, and so on. That'll take a while, although this looks to be on the right track. But the headlines, as usual, are way out in front of what's really happening.

No, I continue to think that stem cells are a very worthy subject of research. But years, quite a few years, are going to be needed before treatments using them can become a reality. Oh, and billions of dollars, too - let's not forget that. . .

Comments (12) + TrackBacks (0) | Category: Biological News | Business and Markets | Cancer | Cardiovascular Disease | Press Coverage

November 14, 2011

Anticoagulants, One After Another

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Posted by Derek

Back earlier this year, when some bad results had come out about Merck's thrombin receptor antagonist, I wrote ". . .another result like this one, and vorapaxar could be completely sunk". Well, perhaps it is. Merck has unveiled the results of a large Phase III trial in 13,000 at-risk patients, and the drug failed completely to beat a placebo control. Moreover, there were higher bleeding risks in the treatment group, and theh follow-up phase of the trial was terminated early for safety reasons. There are a lot of potential markets for an anticoagulant, and a lot of trials that can potentially be run, but this compound is in a great deal of trouble at the very least.

Meanwhile, at the same AHA meeting, Pfizer and BMS had the unpleasant job of announcing that their anticoagulant hope, apixaban, did not beat heparin (in the form of enoxaparin, Lovenox) for protection against cardiovascular events. About 5,000 patient participated in that study.

You can see from this sort of news how much fun it is to work in the anticoagulant field. Great big expensive trials await you, and the standard of care is surprisingly hard to beat. That's not to say that the standard is so wonderful - physicians would be glad to ditch things like warfarin and heparin. But they're still out there, and with Plavix going generic, the cost/benefit bar isn't going down any, either.

One big drug that actually did provide some good news was the Bayer Factor Xa inhibitor rivaroxaban (Xarelto). That one did manage to beat placebo in post-heart-attack patients (a mere 15,500 of them), albeit with, again, an increased risk of bleeding. Overall, though, it was a grim weekend for a lot of big clinical programs.

Comments (17) + TrackBacks (0) | Category: Cardiovascular Disease

July 22, 2011

A Few More Victories Like This, And We Will Be Undone

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Posted by Derek

AstraZeneca has a lot of problems these days, so you'd think that approval of their new anticoagulant Brilinta would be reason for the company to celebrate. Not much, though - see this post at InVivoBlog for more.

A lot of companies have piled into this space over the last ten years, seeking some of those huge, huge Plavix-style revenues. But blood thinning is a tricky business. One step over the line and you're causing more problems than you're helping. And given the heterogeneity of the patient population, you never quite know where that line is going to be. By this point, too, any new therapy is going to have to compete with the generic of tried-and tested Plavix pretty soon. No, anticoagulants of all sorts don't seem to making anyone as rich as they were supposed to. King Pyrrhus would understand perfectly.

Comments (7) + TrackBacks (0) | Category: Cardiovascular Disease

June 9, 2011

Cardiac Hope and Cardiac Hype

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Posted by Derek

There have been quite a few headlines over the last few days like this one: "A New Drug Makes Hearts Repair Themselves". Unfortunately, that's not quite true. Not yet.

It's this paper in Nature that's getting the attention, and it is a very interesting one. The authors have identified a population of progenitor cells in the adult heart that can be induced to turn into fully differentiated myocytes after an infarction. In fewer syllables, and reasonably accurately: stem cells, already in the heart, can be made to repair it after a heart attack. And that's getting closer to that headline I was just complaining about - so what's the gap between the two?

Well, there are several rather huge factors. One of them is that the way that these cells were stimulated into action was by treatment with thymosin beta-4, which is a potent regulator of cardiac cells and blood vessel development. Tβ4 is not quite a drug yet, although RegeneRx is giving it a shot. There have been some phamacokinetic studies in animals and other preliminary work, and I wish them every good fortune. But it's got a ways to go.

Second, this study treated the animals with Tβ4 for seven days before inducing the cardiac injury. That's perfectly reasonable for a proof-of-concept study like this one, but it's not the real-world therapeutic option that you'd imagine from the press coverage. As one correspondent put it to me in an e-mail, "if you’re a mouse, and you know that later on this week you’re going to have an MI, then this is the treatment for you". That might be unfair to the original authors, who are working their way up carefully through some very tricky biology, but it's not unfair at all to the people who write headlines like the one I quoted above.

No, this is very interesting stuff, but it's quite a ways from being ready to help any of us out. This is where such therapies start, though, and we can only hope that something makes it through this time. The authors themselves know the score:

". . .The induced differentiation of the progenitor pool described into cardiomyocytes by Tβ4 is at present an inefficient process relative to the activated progenitor population as a whole. Consequently, the search is on via chemical and genetic screens to identify efficacious small molecules and other trophic factors to underpin optimal progenitor activation and replacement of destroyed myocardium.

Comments (5) + TrackBacks (0) | Category: Cardiovascular Disease | Press Coverage

May 27, 2011

Niacin's Unexpected Flop

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Posted by Derek

Let's add to the uncertainty about whether we understand cardiovascular disease, OK? The NIH has been conducting a large statin-plus-niacin trial, which is definitely a combination worth looking at. The statin will lower your LDL, and niacin will raise your HDL and lower your triglycerides (albeit with some irritating side effects). An earlier trial of niacin versus Zetia (ezetimibe) made the former look pretty good (and Zetia look pretty bad) using an endpoint of arterial examination by ultrasound.

But now the NIH trial has been stopped, a full 18 months early. Not only did the addition of niacin show no benefit at all, but that treatment group actually had a slightly higher rate of ischemic stroke. This despite the combination working as planned, from a blood-marker standpoint. No, we really still have a lot to learn, particularly when we're trying to raise HDL and lower triglycerides. These results, together with the fenofibrate data, really make a person wonder.

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

May 18, 2011

Fenofibrate: Good For Much?

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Posted by Derek

Abbott has some difficult times ahead with their fenofibrate franchise. That's TriCor, and its newer formulation, TriLipix. Fenofibrate, as I've mentioned here before, is an oddity among drugs. It was discovered way before anyone had a mechanism of action, and even now, while it's supposed to be a PPAR-alpha ligand, no one's completely happy with that explanation. (For one thing, it's not very potent at that nuclear receptor, while other PPAR-alpha compounds have crashed in clinical trials for various reasons). But it can lower triglycerides and raise HDL, which should both (in theory) be beneficial effects, and it's been a big seller over the years.

But how much good does it do? That's always the big, important, slow question in the cardiovascular field. The data for fenofibrate have always been somewhat messy (although probably positive overall), but a new study has muddied things up. As the FDA puts it, in the documents for an advisory committee meeting tomorrow (PDF):

Over the last 40 years laboratory and clinical data have suggested the potential of fibrates to reduce cardiovascular risk. However, data from large clinical outcomes trials have produced mixed results. The inconsistent outcomes may be a result of differences in pharmacodynamic properties among individual fibrates or study populations or both.

The new data, from a trial called ACCORD-Lipid, is another one looking at fenofibrate plus a statin, which is the usual combination (that way, at least in theory, you go after triglycerides, low HDL, and high LDL simultaneously). But this trial, in a large population of diabetic patients, showed that overall, the rate of major adverse cardiovascular events (MACE) was statistically identical between the statin/fenofibrate and statin/placebo groups. No advantage! It gets trickier with a bit of subgroup analysis: women showed some evidence of worse outcomes with fenofibrate as opposed to statin alone. The group that seemed to benefit, on the other hand, were the patients who started out with the highest triglycerides and the lowest HDL. (See that FDA file above for all the numbers and more).

That's disconcerting. Is fenofibrate only helping the worst-off patients, and doing nothing (or worse) for the others? That a question worth wrestling with for a drug that sold well over a billion dollars last year. And beyond that is the same sort of question that came up when all the ezetimibe data hit: how much do we really know about blood markers versus real cardiovascular outcomes? Can you hit the various numbers by different routes, some of which are beneficial and some of which aren't? What is it that we're not understanding?

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

May 10, 2011

Phase II Failures

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Posted by Derek

We know what clinical trial success rates have been like for the last twenty years or so (hint: not so good). Are things turning around, or not? This Nature Reviews Drug Discovery piece takes a look at the 2008-2010 data. It's not necessarily reassuring:

At present, however, Phase II success rates are lower than at any other phase of development. Analysis by the Centre for Medicines Research (CMR) of projects from a group of 16 companies (representing approximately 60% of global R&D spending) in the CMR International Global R&D database reveals that the Phase II success rates for new development projects have fallen from 28% (2006–2007) to 18% (2008–2009), although these success rates do vary between therapeutic areas and between small molecules and biologics.

There were 108 Phase II failures in 2008-2010, and for 87 of those we have a stated reason. Half of those were good old lack of efficacy, another 19% failed on safety grounds, and the rest failed for "strategic reasons". The best guess there is that the compounds seem to have been targeting areas where there was already competition, and they didn't differentiate themselves enough from the standard of care to be worth continuing. That's worth thinking about in the context of the arguments about "me-too" drugs. To hear some of the industry's critics tell it, there shouldn't be any such failures at all, since they seem to believe that even most marketed drugs really don't differentiate themselves from their competition as it is.

Nearly 70% of those 108 failures, by the way, were in four therapeutic areas: cardiovascular, CNS, metabolics, and oncology. (What we don't have are the failures adjusted for how many drugs were taken into the clinic in the first place in those areas). CNS and oncology are traditional high-risk areas, of course, and I think that a lot of the metabolics failures were in diabetes. That's a tough field - big market, but pretty well-served, making efficacy versus the standard of care a high bar to clear, and this while the FDA's safety requirements have gotten very stiff indeed.

But cardiovascular - that's interesting, since that area has traditionally had one of the better trial success rates. Perhaps that one is also suffering from the standard of care being pretty good (and often generic, or soon to be). So the high-success-rate mechanisms of the old days are well covered, leaving you to try your luck in the riskier ideas, while still trying to beat some pretty good (and pretty cheap) drugs. . .

Update: it's been suggested that some of these "strategic" failures are a sign of what happens during merger/acquisition activity. Could be, but you'd have to run these down company-by-company. I'll see if I can contact the authors of this paper about that idea. . .

Comments (38) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials

January 20, 2011

Merck's Vorapaxar: Bleeding, Indeed

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Posted by Derek

So, as had been suspected, the reason that Merck's thrombin antagonist vorapaxar ran into clinical trouble was excessive bleeding. This is always the first thing to suspect when an anticoagulant has difficulty in human trials.

It's really a delicate balance, the human clotting cascade, and it's all too easy to end up on the wrong side of it. When you think about it, the whole pathway has to be under very tight regulation - I mean, here's the fluid that transports oxygen and nutrients and removes waste. Absolutely crucial to the life of every cell in the body. And here's an option to have that fluid thicken up and turn to jelly, very quickly, and once it happens it can't be reversed. No, you're going to want a lot of safeguards around that switch. But if you lean over too far the other way, well. . .there's a lot of vascular plumbing in the body, and it gets a lot of stress. Leaks and rips are inevitable. You have to have a method for patching holes, and it has to be ready to go everywhere, at all times. Dial it down just a bit too much, and hemorrhages are inevitable. Thus all the different clotting mechanism steps, and the different drugs targeting them.

As Matthew Herper explains at that link above, the prospect for this drug are completely dependent on which side of the line it ends up on. In this patient population, it's already stepped over - another result like this one, and vorapaxar could be completely sunk.

Comments (8) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development

January 13, 2011

Merck's Thrombin Antagonist In Trouble

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Posted by Derek

Very bad news today for Merck (and the Schering-Plough people therein). Their thrombin receptor antagonist vorapaxar (formerly SCH 530348) has run into trouble.

A review board monitoring the compound's clinical trials has suddenly halted two of them. All we know at the moment is that the drug is "not appropriate for stroke patients", and it's also being pulled from a study in people who have had mild heart attacks. The best guess, as with any drug in the clotting field, is that it may be causing bleeding instead, but we'll have to see. Problem is, those are two of the more important patient populations that a company would be targeting, and if there's trouble in those groups, then it could be waiting to show up in others as well.

Vorapaxar has an unusual history at Schering-Plough (I wrote about it here, with some personal experiences from my own time at the company thrown in). I'm very sorry to see this news - sorry for the patients involved (and those who won't be helped later on), for the researchers involved (several of whom I've worked with in the past), and for Merck's investors, who are taking about a 6% trim today on the NYSE.

This compound wasn't the whole reason for Merck to buy Schering-Plough, but it wasn't a small part of the deal, either. That other stuff had better work out. . .

Comments (12) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Clinical Trials | Drug Development

November 19, 2010

Merck's CETP Compound: Still Alive, But The Big Fun Awaits

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Posted by Derek

Four years after the torcetrapib disaster, Merck has released some new clinical trial data on their own CETP inhibitor, anacetrapib. It's doing what it's supposed to, when added to a statin regimen: decrease LDL even more, and strongly raise HDL.

So that's good news. . .but it would actually be quite surprising if these numbers hadn't come out that way. Pfizer's compound had already proven the CETP mechanism; their compound did the same thing at this stage of the game. The problems came later, and how. And that's where the worrying kicks in.

As far as I know, no one is still quite sure why torcetrapib actually raised the death rate slightly in its phase III treatment group. One possible mechanism was elevated blood pressure (part of a general off-target effect on the adrenals) and Merck saw no sign of that. But no matter what, we're going to have to wait for a big Phase III trial, measuring real-world cardiovascular outcomes, to know if this drug is going to fly, and we're not going to see that until 2015 at the earliest. Well, unless there's unexpected bad news at the interim - that, we'll see.

I hope it doesn't happen. If the whole LDL-bad HDL-good hypothesis is correct, you'd think that a CETP inhibitor would show a strong beneficial effect. This compound is either going to help a lot of people, or it's going to tell us something really significant that we didn't know about human lipid handling (and/or CETP). Problem is, telling us something new is almost certainly going to be the same as telling us something bad. It's still going to be a long road in this area, and good luck to everyone involved. . .

Comments (17) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology

October 21, 2010

Apotex's Plavix Adventure: Four Years Later

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Posted by Derek

Remember the Plavix Confusion of 2006? That's when Canadian generic company Apotex managed to jump onto the market for a few weeks with its own version of the BMS/Sanofi-Aventis blockbuster. It was always a bit unclear whether they had the right to do that - there was a case that the company had played rough but fair with some tricky language in their agreements with the two pharmas. Still, Apotex racked up over 800 million dollars in sales while everyone was sorting that out.

Well, four years down the road, a judge has ruled that Apotex owes BMS and S-A damages for their adventure: half the sales, plus interest. That's still less than the triple damages that could be obtained in an open-and-shut case of patent infringement, but it's pretty substantial. I wonder how much of the money Apotex still has handy?

Comments (9) + TrackBacks (0) | Category: Cardiovascular Disease | Patents and IP

July 13, 2010

Avandia: Was the Evidence Buried?

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Posted by Derek

The New York Times has added to the arguments over Avandia (rosiglitazone) this morning, with an above-the-fold front page item on when its cardiovascular risks were first discovered. According to leaked documents, that may have been as early as the end of 1999 - just a few months after the drug had been approved by the FDA.

According to Gardiner Harris's article, SmithKline (as it was at the time) began a study that fall, and "disastrous" results were in by the end of the year that showed "clear risk" of cardiovascular effects. (They must have been disastrous indeed to show up in that short a time, I have to say). He quotes a memo from an executive at the company:

“This was done for the U.S. business, way under the radar,” Dr. Martin I. Freed, a SmithKline executive, wrote in an e-mail message dated March 29, 2001, about the study results that was obtained by The Times. “Per Sr. Mgmt request, these data should not see the light of day to anyone outside of GSK,” the corporate successor to SmithKline.

The only possible way I can see this being taken out of context would be if the rest of the memo talked about how poorly run the study was and how unreliable its data were - in which case, someone was an idiot for generating such numbers. But that puts the company in the situation of "idiots" being the most benign (and least legally actionable) explanation. Which is not where you want to be.

Without seeing the actual material, it's hard to comment further. But what's out there looks very, very bad.

Comments (29) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | The Dark Side | Toxicology

June 28, 2010

That Schering-Plough Lawsuit Isn't Going Away

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Posted by Derek

Last summer I mentioned a shareholder lawsuit against Schering-Plough over the way that the ENHANCE clinical data were handled for Vytorin. One of the interesting features here is that the plaintiffs are claiming that the company knew that the clinical trial was showing troublesome data, but elected to sit on the numbers for as long as possible - and they're introducing a series of posts on Cafe Pharma as evidence. These seem to foretell the 2008 announcement of the bad numbers in early 2007, with disturbing accuracy.

Now, as Jim Edwards points out, this case has not gone away. In fact, the most recent attempt to get it thrown out has failed, and former CEO Fred Hassan faces a possible deposition on the matter. This will be quite interesting to watch, since Merck is on the hook for any judgments that might result. Stay tuned. . .

Comments (3) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | The Dark Side

June 23, 2010

Lilly's Statin - Yes, It Is 2010

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Posted by Derek

Aficionados will remember that Warner-Lambert nearly killed Lipitor along the way because they felt that the statin market was too crowded. Well, now Lipitor's patent is going to finally expire next year, which will make it even harder for anyone to turn a buck on anything higher-priced.

So Eli Lilly is, yes, bringing a statin of their own to market. Livalo (pitavastastin) will try to make headway based on a slightly lower price than Crestor (the big dog, after next year, among the patent-protected statins) and a different metabolic profile that might decrease drug-drug interactions.

Lilly brought this one in from Kowa of Japan, and it's hard to see how they'll get too many people excited about it. And while I certainly understand to need to make some money, one way or another, making it this way doesn't add mmuch to the case for Big Pharma innovation, does it? Maybe there are enough people out there who will benefit from another alternative - but no one can say that the world was waiting for another statin, that's for sure.

Comments (9) + TrackBacks (0) | Category: Cardiovascular Disease

June 14, 2010

Angiotensin Receptor Blockers and Cancer: For Real?

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Posted by Derek

Well, this could be nothing, or it could be big trouble: there's a report out that taking the angiotensin antagonists (the various "sartans") might be linked to increase risk of cancer. A meta-analysis of several large trials, reported in Lancet Oncology, patients in the treatment groups showed a 7.2% incidence of new cancer diagnoses, versus 6% for the control groups. These are large sample sizes, so that difference has a p-value of 0.016.

The authors wisely refuse to take the data any further, and call for more investigation, which certainly seems warranted. The whole renin-angiotensin system is certainly involved in angiogenesis, and thus could very plausibly have effects in oncology. But the surprising thing is that there's evidence that blockade of the receptors could actually cut down on tumor formation, too. If you'd taken a survey last week, you'd probably have gotten a lot of people to bet that these drugs would actually have a protective effect.

So what's going on? It's going to be quite a while before we find out. But an awful lot of people take these drugs, and now they're all wondering what to do. . .

Comments (9) + TrackBacks (0) | Category: Cancer | Cardiovascular Disease

June 9, 2010

Raising Your HDL - Through the Brain?

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Posted by Derek

For a long time now, people have been searching for a way to raise HDL levels (the so-called "good cholesterol"). Statins will lower your LDL, while raising HDL just a pinch, but no one has a good, robust way to do it. (Niacin is probably the closest thing, but not everyone can take it). Many have tried, and failed, with Pfizer's CETP inhibitor torcetrapib being the most notably horrendous.

Now there's a completely new way to regulate HDL, and it comes from a direction you might not expect: the brain. A new paper in Nature Neuroscience demonstrates that melanocortin signaling, ghrelin and GLP-1 change HDL levels, through both altered cholesterol synthesis and uptake. Since these are involved in a number of ways in food intake and metabolism, it makes sense (in retrospect) that there would be a lipoprotein connection, but this does seem to be a dramatically direct one. (More and more, it appears that many metabolic processes that were thought to be more peripheral are under some sort of central control, actually). As the authors put it:

An integrated neuroendocrine control of food intake, body weight and glucose homeostasis, as well as cholesterol metabolism and cardiovascular lipid exposure, would connect all of the hallmarks of the metabolic syndrome. Therapies promoting the increase of HDL levels have been proposed for the prevention of atherosclerosis in humans. . . We speculate that modulation of neuroendocrine circuits may offer therapeutic opportunities to prevent cardiovascular disease.

Yes, indeed. It's not going to be easy, though. Ghrelin and GLP-1 have already been looked at for diabetes and obesity therapy, and they're tricky to deal with. Small-molecule ghrelin antagonists are known - as I should know - and there have been many reports of melanocortin receptor ligands as well. Of course, the question will be how many other things you might mess with at the same time, but it's going to be very interesting and worthwhile to unravel these.

Comments (12) + TrackBacks (0) | Category: Cardiovascular Disease | The Central Nervous System

May 27, 2010

Pfizer Halts a Trial Early - On Good News

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Posted by Derek

Pfizer was able to announce some good news today - their trial of Inspra (eplerenone) for patients with a particular combination of heart failure symptoms. The trial was halted early, but (for once) because the endpoints were reached so early that it would have been unethical to continue the placebo arm. It's always nice to hear about one of those; we don't get them that often.

The drug is an aldosterone antagonist which had already been approved several years ago for heart failure and hypertension, so it's not really a surprise that it worked in this population. But you never know, and Pfizer wanted to be able to get specifically recommended for patients of this type. And that they will.

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

May 5, 2010

Steve Nissen vs. GlaxoSmithKline

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Posted by Derek

You don't often get to see so direct an exchange of blows as this: Steve Nissen, of cardiology and drug-safety fame, published an editorial about GlaxoSmithKline and Avandia (rosiglitazone) earlier this year in the European Heart Journal. And GSK took exception to it - enough so that that the company's head of R&D, Moncef Slaoui, wrote to the editors with a request:

". . .(the editorial) is rife with inaccurate representations and speculation that fall well outside the realm of accepted scientific debate. We strongly disagree with several key points within the editorial, most importantly those which imply misconduct on the part of GSK and have identified some of these issues below. On this basis, GSK believes that it is necessary for the journal to withdraw this editorial from the website and refrain from publishing it in hard copy, until the journal has investigated these inaccuracies and unsubstantiated allegations.

Instead of doing that the EHJ invited Nissen to rebut GSK's views, and ended up publishing both Slaoui's letter and Nissen's reply, while leaving the original editorial up as well. (Links are PDFs, and are courtesy of Pharmalot). Looking over the exchange, I think each of the parties score some points - but I have to give the decision to Nissen, because the parts that he wins are, to my mind, more important - both for a discussion of Avandia's safety and of GSK's conduct.

For example, Slaoui disagreed strongly with Nissen's characterization of the company's relations with a coauthor of his, Dr. John Buse. Nissen referred to him as a prominent diabetes expert who had been pressured into signing an agreement barring him from publicly expressing his safety concerns, but Slaoui countered by saying:

The document that Dr Buse signed was not an agreement barring him from speaking but was a factual correction regarding data, which did not bar him from speaking at all. In fact, Dr Buse subsequently communicated his views regarding the safety of rosiglitazone to FDA.

Nissen's reply is considerably more detailed:

The intimidation of Dr John Buse by GSK was fully described in a report issued by US Senate Committee on Finance.3 The Senate Report quotes an e-mail message from Dr Buse to me dated 23 October 2005 following publication of our manuscript describing the risks of the diabetes drug muraglitazar. In that e-mail, Buse stated: ‘Steve: Wow! Great job on the muraglitazar article. I did a similar analysis of the data at rosiglitazone’s initial FDA approval based on the slides that were presented at the FDA hearings and found a similar association of increased severe CVD events. I presented it at the Endocrine Society and ADA meetings that summer. Immediately the company’s leadership contact (sic) my chairman and a short and ugly set of interchanges occurred over a period of about a week ending in my having to sign some legal document in which I agreed not to discuss this issue further in public. I was certainly intimidated by them but frankly did not have the granularity of data that you had and decided that it was not worth it’. In an e-mail to GSK, Dr Buse wrote: ‘Please call off the dogs. I cannot remain civilized much longer under this kind of heat’

This, to me, looks like a contrast between legal language and reality, and in this case, I'd say reality wins. The same sort of thing occurs when the discussion turns to the incident where a copy of Nissen's original meta-analysis of Avandia trials was faxed to GSK while it was under review at the NEJM. Nissen characterizes this as GSK subverting the editorial process by stealing a copy of the manuscript, and Slaoui strongly disagrees, pointing out that the reviewer faxed it to them on his own. And that appears to be true - but how far does that go? GSK knew immediately, of course, that this was a manuscript that they weren't supposed to have, but it was then circulated to at least forty people at the company, where it was used to prepare the public relations strategy for the eventual NEJM publication. I don't think that GSK committed the initial act of removing the manuscript from the journal's editorial process - but once it had been, they took it and ran with it, which doesn't give them much ethical high ground on which to stand.

Many other issues between the two letters are matters of opinion. Did enough attention get paid to the LDL changes seen in Avandia patients? Did the lack of hepatotoxicity (as seen in the withdrawn first drug in this class) keep people from looking closely enough at cardiac effects? Those questions can be argued endlessly. But some of GSK's conduct during this whole affair is (unfortunately for them) probably beyond argument.

Comments (31) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | Toxicology | Why Everyone Loves Us

March 30, 2010

Animal Studies: Are Too Many Never Published At All?

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Posted by Derek

A new paper in PLoS Biology looks at animal model studies reported for the treatment of stroke. The authors use statistical techniques to try to estimate how many have gone unreported. From a database with 525 sources, covering 16 different attempted therapies (which together come to 1,359 experiments and 19,956 animals), they find that only a very small fraction of the publications (about 2%) report no significant effects, which strongly suggests that there is a publication bias at work here. The authors estimate that there may well be around 200 experiments that showed no significant effect and were never reported, whose absence would account for around one-third of the efficacy reported across the field. In case you're wondering, the therapy least affected by publication bias was melatonin, and the one most affected seems to be administering estrogens.

I hadn't seen this sort of study before, and the methods they used to arrive at these results are interesting. If you plot the precision of the studies (Y axis) versus the effect size (X axis), you should (in theory) get a triangular cloud of data. As the precision goes down, the spread of measurements across the X-axis increases, and as the precision goes up, the studies should start to converge on the real effect of the treatment, whatever that might be. (In this study, the authors looked only at reported changes in infarct size as a measure of stroke efficacy). But in many of the reported cases, the inverted-funnel shape isn't symmetrical - and every single time that happens, it turns out that the gaps are in the left-hand side of the triangle, the not-as-precise and negative-effect regions of the plots. This doesn't appear to be just due to less-precise studies tending to show positive effects for some reason - it strongly suggests that there are negative studies that just haven't been reported.

The authors point out that applying their statistical techniques to reported human clinical studies is more problematic, since smaller (and thus less precise) trials may well involve unrepresentative groups of patients. But animal studies are much less prone to this problem.

The loss of experiments that showed no effect shouldn't surprise anyone - after all, it's long been known that publishing such papers is just plain harder than publishing ones that show something happening. There's an obvious industry bias toward only showing positive data, but there's an academic one, too, which affects basic research results. As the authors put it:

These quantitative data raise substantial concerns that publication bias may have a wider impact in attempts to synthesise and summarise data from animal studies and more broadly. It seems highly unlikely that the animal stroke literature is uniquely susceptible to the factors that drive publication bias. First, there is likely to be more enthusiasm amongst scientists, journal editors, and the funders of research for positive than for neutral studies. Second, the vast majority of animal studies do not report sample size calculations and are substantially underpowered. Neutral studies therefore seldom have the statistical power confidently to exclude an effect that would be considered of biological significance, so they are less likely to be published than are similarly underpowered “positive” studies. However, in this context, the positive predictive value of apparently significant results is likely to be substantially lower than the 95% suggested by conventional statistical testing. A further consideration relating to the internal validity of studies is that of study quality. It is now clear that certain aspects of experimental design (particularly randomisation, allocation concealment, and the blinded assessment of outcome) can have a substantial impact on the reported outcome of experiments. While the importance of these issues has been recognised for some years, they are rarely reported in contemporary reports of animal experiments.

And there's an animal-testing component to these results, too, of course. But lest activists seize on the part of this paper that suggests that some animal testing results are being wasted, they should consider the consequences (emphasis below mine):

The ethical principles that guide animal studies hold that the number of animals used should be the minimum required to demonstrate the outcome of interest with sufficient precision. For some experiments, this number may be larger than those currently employed. For all experiments involving animals, nonpublication of data means those animals cannot contribute to accumulating knowledge and that research syntheses are likely to overstate biological effects, which may in turn lead to further unnecessary animal experiments testing poorly founded hypotheses.

This paper is absolutely right about the obligation to have animal studies mean something to the rest of the scientific community, and it's clear that this can't happen if the results are just sitting on someone's hard drive. But it's also quite possible that for even some of the reported studies to have meant anything, that they would have had to have used more animals in the first place. Nothing's for free.

Comments (19) + TrackBacks (0) | Category: Animal Testing | Cardiovascular Disease | Clinical Trials | Drug Assays | The Scientific Literature

March 26, 2010

Diminishing Returns

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Posted by Derek

As we slowly attack the major causes of disease, and necessarily pick the low-lying fruit in doing so, it can get harder and harder to see the effects of the latest advances. Nowhere, I'd say, is that more true than for cardiovascular disease, which is now arguably the most well-served therapeutic area of them all. It's not that there aren't things to do (or do better) - it's that showing the benefit of them is no easy task.

Robert Fortner has a good overview of the problem here. The size of the trials needed in this area is daunting, but they have to be that size to show the incremental improvements that we're down to now. He also talks about oncology, but that one's a bit of a different situation, to my mind. There's plenty of room to show a dramatic effect in a lot of oncology trials, it's just that we don't know how to cause one. In cardiovascular, on the other hand, the space in which to show something amazing has flat-out decreased. This is a feature, by the way, not a bug. . .

Comments (40) + TrackBacks (0) | Category: Cancer | Cardiovascular Disease | Clinical Trials | Drug Industry History

March 15, 2010

Tricor's Troubles

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Posted by Derek

It's easy to lose sight of what a drug is supposed to do. Many conditions come on so slowly that we have to use blood chemistry or other markers to see the progress of therapy in a realistic time. And over time, that blood marker can get confused with the disease itself.

To pick one famous example, try cholesterol. Everyone you stop on the street will know that "high cholesterol is bad for you". But the first thing you have to do is distinguish between LDL and HDL cholesterol - if the latter is a large enough fraction of the total, the aggregate number doesn't matter as much. And fundamentally, there's not a disease called "high cholesterol" - that's a symptom of some other cluster of metabolic processes that have gone subtly off. And the endpoint of any therapy in that field isn't really to lower the number in a blood test: it's to prevent heart attacks and to extend healthy lifetimes, mortality and morbidity. As we're seeing with Vytorin, it may be possible to drop the numbers in a blood test but not see the benefit that's supposed to be there.

Another example of this came up over the weekend. The fibrates are a class of drugs that change lipid levels, although the way they work is still rather obscure. They're supposed to be ligands for the PPAR-alpha nuclear receptor, but they're not very potent against it when you study that closely. At any rate, they do lower triglycerides and have some other effects, which should be beneficial in patients whose lipids are off and are at risk for cardiac problems.

But are they? Type II diabetics tend to be people who fit that last category well, and that's where a lot of fenofibrate is prescribed (as Abbott's Tricor in the US, and under a number of other names around the world). A five-year study in over five thousand diabetic patients, though, has just shown no difference versus placebo. Again, there's no doubt that the drug lowers triglycerides and changes the HDL/LDL/VLDL ratios. It's just that, for reasons unknown, doing so with fenofibrate doesn't seem to actually help diabetic patients avoid cardiac trouble.

Mortality and morbidity: lowering them is a very tough test for any drug, but if you can't, then what's the point of taking something in the first place? This is something to keep in mind as the push for biomarkers delivers more surrogate endpoints. Some of them will, inevitably, turn out not to mean as much as they're supposed to mean.

Comments (15) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | Drug Assays

February 24, 2010

Steve Nissen's Meeting with GSK

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Posted by Derek

Well, this is interesting. Back when Steve Nissen was about to publish his meta-analysis on the safety of Avandia (rosigiltazone), he met with several GlaxoSmithKline executives before the paper came out. At the time, GSK was waiting on data from the RECORD study, which was trying to address the same problem (unconvincingly, for most observers, in the end). Nissen had not, of course, shown his manuscript to anyone at GSK, and for their part, the execs had not seen the RECORD data, since it hadn't been worked up yet.

Well, not quite, perhaps on both counts. As it happens, a reviewer had (most inappropriately) faxed a copy of Nissen's paper-in-progress to the company. And GSK's chief medical officer managed to refer to the RECORD study in such a way that it sounds as if he knew how it was coming out. How do we know this? Because Nissen secretly taped the meeting - legal in Ohio, as long as one party knows the taping is going on. At no point does anyone from GSK give any hint that they knew exactly what was in Nissen's paper. Here's some of it:

Dr. Krall asked Dr. Nissen if his opinion of Avandia would change if the Record trial — a large study then under way to assess Avandia’s risks to the heart — showed little risk. Dr. Krall said he did not know the results of Record.

“Let’s suppose Record was done tomorrow and the hazard ratio was 1.12. What does...?” Dr. Krall said.

“I’d pull the drug,” Dr. Nissen answered quickly.

The interim results of Record were hastily published in The New England Journal of Medicine two months later and showed that patients given Avandia experienced 11 percent more heart problems than those given other treatments, for a hazard ratio of 1.11. But the trial was so poorly designed and conducted that investigators could not rule out the possibility that the differences between the groups were a result of chance.

Somehow, I don't think that many pharma executives are going to agree to meetings with Nissen in his office in Cleveland after this. But I certainly don't blame him for making the tape, either.

Comments (24) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | The Dark Side | Toxicology

January 4, 2010

Remember Apo-A1 Milano? Pfizer Does.

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Posted by Derek

The folks over at the In Vivo Blog will soon be announcing their "Deal of the Year" in the biotech/pharma sector (you can scroll back over there to see the various nominees). But they could just as well run the competition in reverse, and award some retroactive Bad Deal statues based on what's been happening recently.

One of those might well go to the 2003 deal in which Pfizer paid over a billion dollars in to acquire Esperion and their Apo-A1 Milano lipoprotein. If you've been following the cardiovascular field for a few years, you'll remember the big press that this got. The Milan variant of the protein seemed to be quite effective at reverse cholesterol transport - just typing that phrase takes me back a few years, to be honest. The hope was that periodic treatments might flush the arteries out and avert atherosclerosis.

And there things seemed to stay, hung up in that "promising therapy" zone. At the time, Pfizer was going to be the biggest thing ever in cardiovascular, what with Lipitor, with their CETP inhibitor torcetrapib, and with Apo-A1 Milano coming along at the same time. That dream is a pile of wreckage now, of course - Pfizer has de-emphasized the whole area. Esperion itself was spun back out in 2008 as a much smaller operation, minus the lipoprotein it came in with, and now Apo-A1 Milano itself has been sold off to The Medicines Company. For $10 million up front.

Yep, Pfizer gets $0.01 billion back from its $1.25 billion investment - well, more if things work out, but you'd have to think that most of that money is just gone. But I can't really say that this is just Pfizer's own problem, or just their own folly. This sort of thing can happen to any organization, and the larger it is, the more likely it is to make some sort of Big Move which then sends it falling down the stairs. After all, if you're trying to affect the future of a huge company, you have to do huge things, right? And these huge things take on a momentum of their own - witness another Pfizer disaster, Exubera. That inhaled insulin was going to be a billion-dollar drug, no question about it, and no one could tell the company any different. Well, except their customers.

But again, I don't see these things as coming from some particularly Pfizery mindset. Any other drug company of that size would probably have done things equally catastrophic, and as they get larger, the others surely will find their own open manholes to step confidently into. Since this is the first post of the new year, here's a resolution I wish the industry would consider: no big mergers in 2010. No gigantic sense-of-urgency do-this-deal-now productions, please. Let's try to do what we do better, rather than just do more of it.

Comments (26) + TrackBacks (0) | Category: Cardiovascular Disease | Drug Industry History

November 19, 2009

Plavix vs. Effient

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Posted by Derek

The InVivo Blog has a good article on a controversy in the blood-thinning market. Plavix (clopidogrel) has a very strong share of that, of course, but since Effient (prasugrel) was finally approved, Lilly and Dai-Ichii are looking to take as much of that market as they can. And one opening might be that not everyone responds similarly to Plavix.

In some cases, that's because there are some drug-drug interactions, a problem the FDA has recently addressed. The proton pump inhibitors, especially, are metabolized through the CYP2C19 pathway. That's a problem, since that enzyme is needed to convert clopidogrel into its active form (Plavix, as it comes out of the pill, is a prodrug - its thiophene ring needs to get torn open). This sort of thing has been seen many times before - it's one of the many headaches that you can endure in drug development as you profile the metabolizing pathways for your drug candidate and compare them to the other compounds your patient population might be taking. There are some combinations that just will not work (several involving CYP3A4, which is often the first one you test for), and it looks like we can add Plavix/2C19 to the list.

But the population genetics of the 2C19 enzyme are rather heterogeneous. About a third of the patients taking Plavix have a less-active form of the enzyme to start with, and they might not respond as robustly to the drug. The FDA has emphasized this effect in its latest public health warning. That's an opportunity for Effient, since it doesn't go through that metabolic route.

The In Vivo people point out, though, that this story isn't being driven by the usual players. It's not the FDA that's pushed to find this out, and it's not even Eli Lilly. It's Medco and Aetna. They studied their insurance claims data to see if the numbers supported the proton pump inhibitor/Plavix interaction, found that they did, and publicized their findings - and that led to an actual observational trial from BMS and Sanofi, which confirmed the problem. Now Medco is going further, and is actually running its own observational study comparing Plavix and Effient. Their theory is that the efficacy that Lilly showed compared to Plavix was driven by the (deliberate, one assumes) inclusion of a high number of poor metabolizers.

Medco is getting ready for generic Plavix, and trying to keep its costs down by making the case that the drug will do the job just fine for most patients. They could, on the other hand, end up making the case for Effient in that poor-metabolizing third of the patients, which would also be interesting. Lilly would presumably settle for that, although they'd like even more of the market if they can get it, naturally.

And I have to say: I like this sort of thing. I like it a lot. This, to me, is how the system should work. Companies are pursuing their own competing interests, but in the end, we get a higher standard of care by finding out which drug really works for which patients. The motivation to do all this? Money, of course, earning it and saving it. This may sound crass, but I think that's a reliable, proven method to motivate people and companies, one that works even better than depending on their best impulses. You could even build an economic system around such effects, with some attention to channeling these impulses in ways that benefit the greatest number of people. Worth a try.

Comments (22) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Regulatory Affairs

November 16, 2009

Zetia Takes Another Torpedo

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Posted by Derek

Over the weekend, the results in a small cardiovascular trial came out that compared Merck's Zetia (ezetimibe/simvastatin) (correction - ezetimibe alone) against Abbott's Niaspan (time-release niacin). Niacin's an underappreciated therapy in the field - it has tolerability problems, mainly irritating and uncomfortable hot flushing, but it really does seem to help normalize lipid numbers. (And that's why Merck itself, among others, have taken cracks at the market).

This latest trial was a small one, but people have been starved for data on Zetia ever since it took a surprising hit (in the ENHANCE trial) suggesting that it might not be very efficacious. There's an ongoing larger trial that should answer this question once and for all, but those numbers won't be showing up for another two years. For now, anything that can help clarify what's going on is of great interest to Merck, its investors, and to cardiologists and their patients.

And Matthew Herper at Forbes is right: these latest numbers are disastrous. The study (funded by Abbott) isn't the greatest piece of clinical research in the world - it didn't study nearly as many patients as it was designed to, since it was halted early. (Here it is in the NEJM). But it still shows Niaspan as clearly superior to Zetia, and it makes a person wonder if taking Zetia is basically an expensive way to take a possibly-inadequate dose of simvastatin. In a way, the relatively small size of the study actually helps it a bit - getting numbers that definitive without having to go to much larger sample sizes isn't so easy in cardiovascular trials, so the feeling is that there much be something here.

As Herper's article details, Merck is trying to spin this as a big win for their competition, not a big loss for their own drug. But that comes close to being logically impossible: cholesterol lowering, like many other therapeutic areas, is nearly a zero-sum game. If patients take Niaspan (or any other competing drug), they're not going to be taking Zetia. This one was certainly a victory for Abbott (and generic niacin, for those who can take it), but it was a loss for Merck as well.

The FDA's not coming out of all this looking very good, either:

"How is it possible for a drug to have $4 billion in sales without any evidence of benefit?" says Harlan Krumholz, a cardiologist at Yale University. He said that the small size of the two imaging studies mean they couldn't render a clear verdict on Zetia. "But they don't instill any confidence in it either. " Douglas Weaver, head of cardiology at the Henry Ford Hospital in Detroit says: "We've used Zetia without sufficient amounts of clinical data to support it. Using it may be right, it may be wrong, but we don't know right now."

But it's worth remembering that Zetia's mode of action made perfect sense, and that it really does lower cholesterol to what you'd think would be a very beneficial degree. But it probably has several other effects beyond simple LDL lowering, and just looking at that number is clearly (in hindsight) not enough of a clinical surrogate marker. As the study authors put it:

If viewed properly, this hypothesis-generating finding is not an indictment of the overall importance of reducing LDL cholesterol for the purpose of preventing cardiovascular events, as illustrated by therapies based on statins or nonstatins (e.g., bile acid sequestrants). Rather, this adverse relationship may be attributable to the net effect of ezetimibe, a drug with diverse actions, not all of which are measured through its effects on intestinal cholesterol absorption and LDL cholesterol level. Taken together with a preexisting concern regarding the clinical effectiveness of ezetimibe, our findings challenge the usefulness of LDL cholesterol reduction as a guaranteed surrogate of clinical efficacy, particularly reduction achieved through the use of novel clinical compounds.

But as I recall, statins themselves were first approved based largely on lowered LDL, with better outcome data only showing up later. In that case, the surrogate marker paid off, but not this time. What all this is telling us, then, is that we don't know nearly as much about cholesterol and cardiology as we thought we did. And if we don't understand that area well enough, after all these years and all this effort, what parts of medicine do we really understand?

Comments (31) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials

October 2, 2009

Placebos Can Work the Other Way, Too

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Posted by Derek

There's been a lot of valuable research into the placebo effect in recent years. That has interest in and of itself, and it also has a practical side. Understanding how people feel better on their own could tell us more about how to make our actual drugs work better, and it could also help us design clinical trials more efficiently. It would be a great help to know accurately how much of a positive effect is due to an investigational drug, without having to run thousands of people to separate that out statistically from a robust (but highly variable) placebo effect.

A new paper in the journal Pain (which has always gotten my vote for "Most To-the-Point Journal Title Possible") sheds some light on this issue, and on the mirror image "nocebo effect". The authors have looked over trials of several migraine drugs. In each case, there was a study arm and a placebo arm, and (since no one knew which group they were in), every patient got the lecture about possible side effects if you were in the treatment group.

The key point is that the migraine trials were investigating three different classes of drugs (anti-inflammatories, triptans, and anticonvulsants), and these three, not surprisingly, have different sets of possible side effects. The patients taking the drugs certainly manifested some of these, but what about the placebo groups?

Well, the placebo groups in the anti-inflammatory trials reported more dry mouth, nausea and vomiting than the placebo arms of the triptan studies. The placebo patients in the anticonvulsant trials, though, had a higher incidence of fatigue, sleepiness, and dizziness than the anti-inflammatory placebo groups reported. In short:

We found specific side effects in the placebo arms of anti-migraine trials when analyzing the three groups of drugs. We observed that the side effects that are expected for the active drug against which the placebo is compared, are also more frequent in the placebo group. In particular, anticonvulsant-placebos appear to have a higher rate of AEs (adverse events) than the other two classes of anti-migraine drugs. . .

. . .Moreover, it is also important to note that a larger number of patients in the anticonvulsant-placebo group discontinued the study (withdrawals due to AEs) than those in the triptan-placebo and NSAID-placebo groups. Both patients’ and experimenters’ expectations may have affected the AEs occurrence in the placebo groups. . .

This sort of thing has been observed before, but this is a particularly neat example. As a researcher (or a patient), it's important to remember that we tend to get what we think we're going to get. And we need to be aware of that, and be ready to correct for it if we have to.

Comments (28) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | The Central Nervous System

September 22, 2009

Statin Safety?

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Posted by Derek

Senator Charles Grassley of Iowa has sent the FDA a letter asking if the agency has sufficiently considered adverse events from statin drugs. I've been unable to find the text of the letter, but here's a summary at Business Week. (Grassley's own list of press releases, like most other senators and representatives, is a long, long list of all the swag and booty that he's been able to cart back to his constituents.

His main questions seem to be: has the agency seen any patterns in adverse event reports? Is there reason to believe that such events are being under-reported? Is there information from other countries where the drugs are prescribed that might tell us things that we're missing here?

Business Week's reporter John Carey has been on this are-statins-worse-than-they-appear beat for some time now, and it wouldn't surprise me if someone from Grassley's office sent him a copy of the Senator's letter on that basis. Those considerations aside, are statins really worse than they appear, or not?

The muscle side effects of the drugs (rhabdomyolysis) have been known for some time, and it's clear that some patients are more sensitive to this than others. But there are other possible side effects kicking around, such as cognitive impairment. The evidence for that doesn't seem very strong to me, at first glance, and could (as far as I can see) come out the other way just as easily. In the same way, I haven't seen any compelling evidence for increased risk of cancer, although it's quite possible that they may have effects (good and bad) when combined with existing therapies.

The one thing that you can say is that the epidemiological data we have for statin treatment is probably about as good as we're going to get for anything. These drugs are so widely prescribed, and have now been on the market for so many years, that the amount of data collected on them is huge. If that data set is inadequate, then so are all the others. I'm not sure what Sen. Grassley is up to with his letter, but that's something he should probably keep in mind. . .

Comments (20) + TrackBacks (0) | Category: Cardiovascular Disease | Regulatory Affairs | Toxicology

June 8, 2009

Rolofylline Hits the Skids

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Posted by Derek

There is no good way to spin a Phase III failure. By then you've made it past the main reasons for a drug to wipe out (PK and total mechanistic failure). A breakdown at this stage is a more subtle affair (well, except for the money involved, which is not subtle at all). For example, a drug might show efficacy in a carefully constructed Phase II trial, but can't perform under the wider (and more realistic) conditions of Phase III.

That's what appears to have happened to Merck's MK-7418 (rolofylline, formerly KW-3902). This adenosine A1 antagonist, which Merck picked up by buying NovaCardia a couple of years ago, was being developed for acute heart failure. That's a tough indication, and this isn't going to improve that reputation. (This Forbes piece has a tour of the pile of discards that this area has become over the years. Rolofylline looked as if it might work in Phase II, but (from what I can tell from the press releases) missed every endpoint in Phase III.

On a chemical note, rolofylline is a rather odd-looking molecule. You don't see many noradamantanes hanging off of drug structures. I'm sure this wasn't the reason for the compound's failure (after all, it made it through Phase I and Phase II), but it's sure not something I have on my list of structural fragments to try.

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

June 4, 2009

CafePharma Will Now Approach The Bench

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Posted by Derek

Here's an interesting situation for you: according to IguanaBio, a shareholder lawsuit over the failed Vytorin ENHANCE clinical trial (that's caused Schering-Plough and Merck so much grief) is going to use posts on CafePharma as evidence.

That will be worth watching. CafePharma's message boards have been described (accurately, I'd say) as often being the electronic equivalent of a bathroom wall. There's good information in there, but the signal/noise ratio is abysmal due to the number of ticked-off people who go there to vent. There do appear to have been some posts suggesting strongly that the ENHANCE data were grim, and who knows? They could have been speaking from real knowledge. But there's no way to be sure - and for every post that turns out to be prophetic, there are ten that are totally wrong.

So I'm surprised that these are going to be considered admissable. Anyone investing on the basis of CafePharma board chatter deserves to lose their money - which will go out in brokerage commission fees, if nothing else. Let's see how this plays in court. . .

Comments (11) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Clinical Trials | Drug Industry History

May 20, 2009

Mipomersen - It Still Works

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Posted by Derek

Isis Pharmaceuticals has had a long, tough history developing antisense-based therapeutics. I've lost count of the number of promising candidates they've had (and promising deals they've signed). But the latest one seems to be progressing: mipomersen, designed to block production of the ApoB lipoprotein.

That should lower LDL, and help with several other cardiovascular risk factors at the same time. Isis and their partner Genzyme have just announced that a trial of the drug in patients with homozygous familial hypercholesterolemia showed significant LDL reductions (25 per cent). These people are already maxed out on statin therapy, and still have huge LDL levels, so this does seem to represent an advance.

And Genzyme knows all about getting drugs through for very small patient populations (and charging accordingly) - they're definitely a good partner for this sort of drug. But both they and Isis would like for mipomersen to be used more widely. The next target are patients with the heterozygous form of hypercholesterolemia, and then they'll try to move on to various other statin-intolerant patients with risky LDL levels.

Isis could use a success. They were the first to get an antisense therapy approved (Fomiversen), but it really has never brought in much revenue. Mipomersen, as an injectable, is never going to go out and take over the world like the stating drugs, but it could still be a winner in its own (larger) niche.

Comments (18) + TrackBacks (0) | Category: Cardiovascular Disease

May 13, 2009

Exercise and Vitamins: Now, Wait A Minute. . .

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Posted by Derek

Now, this is an example of an idea being followed through to its logical conclusion. Here’s where we start: the good effects of exercise are well known, and seem to be beyond argument. Among these are marked improvements in insulin resistance (the hallmark of type II diabetes) and glucose uptake. In fact, exercise, combined with losing adipose weight, is absolutely the best therapy for mild cases of adult-onset diabetes, and can truly reverse the condition, an effect no other treatment can match.

So, what actually causes these exercise effects? There has to be a signal (or set of signals) down at the molecular level that tells your cells what’s happening, and initiates changes in their metabolism. One good candidate is the formation of reactive oxygen species (ROS) in the mitochondria. Exercise most certainly increases a person’s use of oxygen, and increases the work load on the mitochondria (since that’s where all the biochemical energy is coming from, anyway). Increased mitochondrial formation of ROS has been well documented, and they have a lot of physiological effects.

Of course, ROS are also implicated in many theories of aging and cellular damage, which is why cells have several systems to try to soak these things up. That’s exactly why people take antioxidants, vitamin C and vitamin E especially. So. . .what if you take those while you’re exercising?

A new paper in PNAS askes that exact question. About forty healthy young male volunteers took part in the study, which involved four weeks of identical exercise programs. Half of the volunteers were already in athletic training, and half weren’t. Both groups were then split again, and half of each cohort took 1000 mg/day of vitamin C and 400 IU/day vitamin E, while the other half took no antioxidants at all. So, we have the effects of exercise, plus and minus previous training, and plus and minus antioxidants.

And as it turns out, antioxidant supplements appear to cancel out many of the beneficial effects of exercise. Soaking up those transient bursts of reactive oxygen species keeps them from signaling. Looked at the other way, oxidative stress could be a key to preventing type II diabetes. Glucose uptake and insulin sensitivity aren't affected by exercise if you're taking supplementary amounts of vitamins C and E, and this effect is seen all the way down to molecular markers such as the PPAR coactivator proteins PGC1 alpha and beta. In fact, this paper seems to constitute strong evidence that ROS are the key mediators for the effects of exercise, and that this process is mediated through PGC1 and PPAR-gamma. (Note that PPAR-gamma is the target of the glitazone class of drugs for type II diabetes, although signaling in this area is notoriously complex).

Interestingly, exercise also increases the body's endogenous antioxidant systems - superoxide dismutase and so on. These are some of the gene targets of PPAR-gamma, suggesting that these are downstream effects. Taking antioxidant supplements kept these from going up, too. All these effects were slightly more pronounced in the group that hadn't been exercising before, but were still very strong across the board.

This confirms the suspicions raised by a paper from a group in Valencia last year, which showed that vitamin C supplementation seemed to decrease the development of endurance capacity during an exercise program. I think that there's enough evidence to go ahead and say it: exercise and antioxidants work against each other. The whole take-antioxidants-for-better-health idea, which has been taking some hits in recent years, has just taken another big one.

Comments (26) + TrackBacks (0) | Category: Aging and Lifespan | Biological News | Cardiovascular Disease | Diabetes and Obesity

May 5, 2009

Farewell to ACAT, and to Lots of Time and Money, Too

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Posted by Derek

Back when I joined the first drug company I ever worked for, the group in the lab next door was working on an enzyme called ACAT, acyl CoA:cholesterol acyltranferase. It’s the main producer of cholesterol esters in cells, and is especially known to be active in the production of foam cells in atherosclerosis. It had already been a drug target for some years before I first heard about it, and has remained one.

It hasn’t been an easy ride. Since 1990, several compounds have failed in the clinic or in preclinical tox testing. The most recent disappointment was in 2006, when pactimibe (Daiichi Sankyo) not only failed to perform against placebo, but actually made things slightly worse.

Lipid handling is a tough field, because every animal does is slightly differently. There are all sorts of rabbit strains and hamster models and transgenic mice, but you're never really sure until you get to humans. Complicating the story has been the discovery that there are two ACATs. ACAT-1 is found in macrophages (and the foam cells that they turn into) and many other tissues, and ACAT-2 is found in the intestine and in the liver. Which one to inhibit is a good question - the first might have a direct effect on altherosclerotic plaque formation, while the second could affect general circulating lipid levels. Pactimibe hits both about equally, as it turns out.

Now a second study of that drug has been published this spring. This one was going on at the same time as the earlier reported one, and was stopped when those results hit, but the data were in good enough shape to be worked up, and the company paid for the continued analysis. The new results look at patients with familial hypercholesterolemia, who got pactimibe along with the standard therapies. Unfortunately, the numbers are of a piece with the earlier ones: the drug did not help, and actually seemed to increase arterial wall thickness. I think it's safe to say, barring some big pharmacological revelation, that ACAT inhibitors are a dead end for atherosclerosis.

I bring this up for two reasons. One is that the group that was working next door to me on ACAT was the same group that discovered (quite by accident) the cholesterol absorption inhibitor ezetimibe, known as Zetia (and as half of Vytorin). Although its future is very much in doubt, it's for sure that that compound has been a lot more successful than any ACAT inhibitor. The arguing goes on about how helpful it's been (and will go on until we see the next trial results for another couple of years), but it's already made it further than ACAT.

And that's actually my second point. I suspect that almost no one in the general public has ever heard of ACAT at all. But it's been the subject of a huge amount of research, of time and work and money. And while we've learned more about lipid handling in humans, which is always valuable, the whole effort has been an utter loss as far as any financial return. I have no good way of estimating the direct costs (and even worse, the opportunity costs) involved with this target, but they surely add up to One Hell Of A Lot Of Money. Which is gone, and gone with hardly a sound outside the world of drug development. And this happens all the time.

Comments (15) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development | Drug Industry History | Toxicology

May 1, 2009

Niacin, No Longer Red-Faced?

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Posted by Derek

One of Merck’s less wonderful recent experiences was the rejection of Cordaptive, which was an attempt to make a niacin combination for the cardiovascular market. Niacin would actually be a pretty good drug to improve lipid profiles if people could stand to take the doses needed. But many people experience a burning, itchy skin flush that’s enough to make them give up on the stuff. And that’s too bad, because it’s the best HDL-raising therapy on the market. It also lowers LDL, VLDL, free fatty acids, and tryglycerides, which is a pretty impressive spectrum. So it’s no wonder that Merck (and others) have tried to find some way to make it more tolerable.

A new paper suggests that everyone has perhaps been looking in the wrong place for that prize. A group at Duke has found that the lipid effects and the cutaneous flushing are mechanistically distinct, way back at the beginning of the process. There might be a new way to separate the two.

Niacin’s target seems to be the G-protein coupled receptor GPR109A – and, unfortunately, that seems to be involved in the flushing response, since both that and the lipid effects disappear if you knock out the receptor in a mouse model. The current model is that activation of the receptor produces the prostaglandin PGD2 (among other things), and that’s what does the skin flush, when it hits its own receptor later on. Merck’s approach to the side effect was the block the PGD2 receptor by adding an antagonist drug for it along with the niacin. But taking out the skin flush at that point means doing it at nearly the last possible step.

The Duke team has looked closely at the signaling of the GPR109A receptor and found that beta-arrestins are involved (they’ve specialized in this area over the last few years). The arrestins are proteins that modify receptor signaling through a variety of mechanisms, not all of which are well understood. Wew’ve known about signaling through the G-proteins for many years (witness the name of the whole class of receptors), but beta-arrestin-driven signaling is a sort of alternate universe. (GPCRs have been developing quite a few alternate universes – the field was never easy to understand, but it’s becoming absolutely baroque).

As it turns out, mice that are deficient in either beta-arrestin 1 or beta-arrestin 2 show the same lipid effects in response to niacin dosing as normal mice. But the mice lacking much of their beta-arrestin 1 protein show a really significant loss of the flushing response, suggesting that it’s mediated through that signaling pathway (as opposed to the “normal” G-protein one). And a known GPR109A ligand that doesn’t seem to cause so much skin flushing (MK-0354) fit the theory perfectly: it caused G-protein signaling, but didn’t bring in beta-arrestin 1.

So the evidence looks pretty good here. This all suggests that screening for compounds that hit the receptor but don’t activate the beta-arrestin pathway would take you right to the pharmacology you want. And I suspect that several labs are going to now put that idea to the test, since beta-arrestin assays are also being looked at in general. . .

Comments (9) + TrackBacks (0) | Category: Biological News | Cardiovascular Disease | Toxicology

April 2, 2009

The Polypill Rides Again

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Posted by Derek

There are a lot of recommended mediations for people at cardiovascular risk. ACE inhibitors and diuretics for blood pressure, a bit of aspirin for anti-thrombotic activity, most likely a stain for cholesterol levels. There are plenty of people who are taking all of these at once, and millions are taking some subset of them. So why not combine them into one good-for-what-ails-you pill?

This idea came up a few years ago, and there’s no point in pretending that I wasn’t a bit skeptical of it:

This is a touchingly linear approach to drug therapy. It's actually kind of sweet. Since the authors clearly mean well, I won't wave my fists around too much. But I would like to point out that these things may well work a bit differently in combination than they do in less crowded company. I realize that many people take subsets of these, which is a good starting point, but taking all six at once will be a new adventure. Drug interactions aren't easy to predict, and that's putting it mildly. Some people are going to feel more effects of one part of the mixture, and some will get hit by another. Some of the people taking this monster will also be taking (for example) diabetes medication, which sets off a whole new set of possible interactions.

As I went on to mention in that post, though, the comments that came in to the British Medical Journal, where the original proposal appeared, were (in many cases) a lot nastier than what I had to say:

Some of the responses are favorable, but there are many that really unload on the authors and their idea. Phrases like "one the most egregious presentations that I have ever come across," "it is very dangerous to take bits and pieces of research and cobble it together," "I would like to add my voice to those who are truly dumbfounded," "total disregard for scientific principles" and "It is almost impossible to know where to start" are flying around over there.

Well, that was in the days before I had comment functions on this blog, so no one told me what they thought about my opinion. But now there are some results from just this sort of formulation, and I have to say, they’re not bad. Most of the beneficial results were about the same as the individual drugs (except for lowered triglycerides, where the effect was only about half as strong). And rather more surprisingly, there weren’t any complicating side effects or interactions. Cardiologists are quoted in the news articles as expressing surprise, and although I Am Not a Cardiologist, you can count me in there, too.

My biggest worry was actually getting all these things to absorb properly from the same pill – this thing must be interesting to manufacture. Medicinal chemists like me tend not to think much about excipients, binders, coatings, and the other issues that go into making solid pill formulations, but that stuff is not easy. There’s a lot of voodoo in it, too, since (after all) you’re trying to affect oral absorption, which is not a really well-understood process.

There's still no guarantee that the polypill, or some variation thereof, will make it. This is a first clinical look, and that's still a long way from the end. But it's already made it a bit further than I thought.

Comments (16) + TrackBacks (0) | Category: Cardiovascular Disease

March 17, 2009

Takeda Gets A Surprise

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Posted by Derek

DPP-IV is short for “dipeptidylpeptidase IV”, understandably, and we need a good abbreviation for it. It’s an important enzyme target for diabetes therapy, since under normal conditions it breaks down glucagon-like-peptide 1. Longer-circulating GLP-1 would actually do a lot of diabetics good, and people have actually made such proteins as separate drugs, so inhibiting an enzyme that clears it out looks like a good bet. Of such reasoning are drug targets made.

A lot of companies have bought into this reasoning, for sure. For quite a while, Novartis looked like the leader in the area, with the most advanced clinical candidate and a lot of publications in the literature from their development work. But Merck turned out to be running a big effort of their own, and actually got to market first with Januvia (sitagliptin). Novartis’s drug (Galvus, vildagliptin) looks as if it will never make it at all here in the US.

They had to slow down development due to some troubling side effects, giving Merck the edge. There are several DPP subtypes, and you need to be pretty selective, as it turns out – at least some of the problems stem from that consideration. This wasn’t fully appreciated in the first wave of development in this area – the pioneers had to figure it out the hard and expensive way. But a number of companies have come up behind, trying to get a piece of the market, and they now have a clearer idea of what they need to accomplish.

Or do they? Takeda recently heard from the FDA that their DPP-IV inhibitor alogliptin has been turned down for now. What’s more, the agency wants more cardiovascular safety data from them and from anyone else who comes in with a drug in that category. Cardiovascular problems have always been the weak point for Type II diabetes drugs, to be sure. The patient population tends to be older and overweight, often with elevated blood pressure, so you really don’t have much room to work in when it comes to side effects. That’s led to a lot of attempts to come up with therapies that address the CV side of things at the same time as glucose levels (such as the ill-fated disaster of the PPAR alpha-gamma compounds, all of when went most expensively down in flames). DPP-IV inhibitors wouldn’t be expected to have any direct CV benefits, but they do have to avoid making things any worse.

So Merck looks to have the market to itself for a while longer, but as the only DPP-IV drug on the market, they’re going to be under a good deal of scrutiny. The company has already had its share of post-launch cardiovascular nightmares; you’d think that they’re going to work hard to avoid any more. And now all we have to do is assure ourselves that the actions of the DPP-IV inhibitors are all through making GLP-1 last longer. Because even if you're selective for that one enzyme, it has a lot of other substrates. So the story may well swing back to the biochemical mechanism again before we're through.

Comments (19) + TrackBacks (0) | Category: Cardiovascular Disease | Diabetes and Obesity | Regulatory Affairs

December 2, 2008

Torcetrapib: What Was the Problem? And Does It Matter?

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Posted by Derek

Ever since the catastrophic failure of Pfizer's HDL-raising CETP inhibitor torcetrapib in late 2006, everyone involved has wondered just what the problem was. There was a definitely higher cardiovascular-linked death rate in the drug-treatment group as opposed to placebo - which led to the screeching halt in Phase III, as well it might - but why? Is there something unexpectedly bad about raising HDL? Or just in raising it by inhibiting the CETP enzyme, which might well provide a different lipoprotein profile than other high-HDL ideas? Was it perhaps an off-target effect of the drug that had nothing to do with its mechanism? And for any of these possibilities, is there the possibility of a biomarker that could warn of approaching trouble?

There are now two analyses of clinical data that may shed some light on these questions (thanks to Heartwire for details and follow-up). The first, a new analysis from Holland of the RADIANCE trial data, shows an electrolyte imbalance (low potassium and higher sodium) in the treatment group. Measuring carotid wall thickness, they found no correlation between the degree of HDL elevation and progress of disease, which is disturbing. The only correlation was with lower LDL levels, and the authors point out that torcetrapib has unappreciated LDL-lowering activity. (Of course, there are easier and more proven ways to do that!)

The second, the ultrasound-monitored trial called ILLUSTRATE led by the Cleveland Clinic, actually did show a correlation between HDL levels and disease progression, as measured by PAV (per cent atheroma volume). This paper concludes that the drug did perform mechanistically, but that needs some qualification. Overall, there was no real significant change in PAV, but looking more closely, the individual changes did seem to correlate with the amount of HDL elevation each group of patients achieved. Only the very highest-responding group showed any regression, though.

Interestingly, this study also showed the same sort of electrolyte imbalance, and both teams seem to agree that torcetrapib is showing off-target mineralcorticoid effects. Steve Nissen of the Cleveland group is more optimistic (a phrase one doesn't get to write every day). He thinks that a CETP inhibitor that doesn't hit the adrenals might still find a place - but I have to say, looking over the data, that it sure won't be the place that the companies involved were hoping for. Instead of being world-conquering cardiovascular wonder drugs, perhaps the best this class of compounds can hope for is a niche, perhaps alongside statin therapy. I just don't see how this level of efficacy translates into something all that useful.

But we'll see. Merck's anacetrapib is still going along. The data we have so far suggest that the compound raises HDL without effects on blood pressure, as opposed to torcetrapib. So maybe (for whatever reason - blind luck, I'd say) this compound doesn't do anything to the aldosterone pathway. But does it do anything to atherosclerosis? That's the question, and that's what the big money will have to be spent on in Phase III to find out. A comment at the Wall Street Journal's Helath Blog has it right:

Welcome to the challenges of pharmaceutical research. Pharmacogenomic evidence originally led Pfizer to hope that elevating HDL through inhibiting CETP would be beneficial. A biomarker assessment in patients suggests that plaque reduction is associated with the highest HDL elevations. Yet, with torcetrapib, there appears to be a safety biomarker popping up. Are either the efficacy or safety signals really biomarkers of long term clinical outcome? You only need to ante up $800M to run mortality and morbidity trials for 5 or more years. Any investors?

Comments (3) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology

November 12, 2008

Crestor: Would It Save Any Lives?

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Posted by Derek

Should millions more people be taking Crestor? That’s a real balancing act. You have a decrease in heart attacks, but from a fairly small incidence rate. So at a minimum, you’ll need to balance the costs of those coronary events versus the cost of paying for all that Crestor. And statins are not without side effects themselves, so you’ll need to adjust your figures for the incidence of rhabdomyolosis, among other things. (For example, is the increased evidence of high blood sugar in the Crestor treatment group a real effect, or not? If so, you’ll need to add a bit of diabetes cost to the spreadsheet). In any case, the cost of getting all these people screened for C-reactive protein levels in the first place needs to be added in as well.

Naturally, as in any of these calculations, you’re going to have to figure how much should be spent to prevent each excess death, once you’ve decided that these deaths can indeed be considered excess. (Unfortunately, the answer cannot always be “as much as it takes”, since there is not enough money in the world to treat everyone for everything, forever). And that brings up another key question: would putting high-CRP patients on Crestor save lives at all?

Well, you’d think so, what with lowering the incidence of those coronary events. But mortality figures are tricky. In all the graphs presented in the NEJM paper, the “deaths from all causes” one is the least compelling. That shouldn’t be a real surprise, since cutting something down in the 1% range isn’t going to bend the curve very much on its own. But if you look closer at the data, things are even fuzzier.

As pointed out to me by a correspondent, the Crestor-treated group for some reason showed a lower death rate from cancer (35 deaths versus 58). It doesn’t seem particularly likely that this is a real effect – I’ve never heard of statins showing a protective effect like this, although if someone knows differently, I’d be glad to hear about it. The paper makes nothing of this comparison, at any rate. Minus this effect, though, the death rate between the two groups might well be within the error bars. The argument for Crestor would then have to be made purely on treatment costs, as in the first paragraph, because you’d be saving few, if any, lives at all.

And maybe there’s a case to be made. I’m not a public health expert, so I don’t know what numbers to put into those calculations. But it’s important to realize, contrary to some of the headlines out there, that it’s actually a hard call to make. I note that AstraZeneca is being cautious about what all this means for sales of Crestor. They’re wise to be.

Comments (20) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials

November 10, 2008

Crestor: Risks Up, Risks Down

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Posted by Derek

AstraZeneca took a pretty big risk in running a trial as big as the JUPITER one, but it seems to have paid off for them. As everyone has been reading, it appears that their Crestor (rosuvastatin), lowers the risk of cardiovascular events in patients with elevated C-reactive protein, even those with reasonable cholesterol numbers. (NEJM paper here).

These patients don’t have an awful lot of heart attacks, but they did have less while on the drug. That’s going to be enough, all by itself, to expand the market for Crestor (and probably the other statins as well). The question is whether the others will have the same effect. You’d think so, especially a similar strong one like Lipitor, but AstraZeneca is the only company with numbers for its own product.

The question will be whether it’s worth treating such a wider patient population at these intent-to-treat numbers, a point made in an accompanying editorial in the New England Journal of Medicine:

The relative risk reductions achieved with the use of statin therapy in JUPITER were clearly significant. However, absolute differences in risk are more clinically important than relative reductions in risk in deciding whether to recommend drug therapy, since the absolute benefits of treatment must be large enough to justify the associated risks and costs. The proportion of participants with hard cardiac events in JUPITER was reduced from 1.8% (157 of 8901 subjects) in the placebo group to 0.9% (83 of the 8901 subjects) in the rosuvastatin group; thus, 120 participants were treated for 1.9 years to prevent one event.

It’s interesting to imagine these numbers flipped over, though – if a drug caused heart attacks at these same statistical levels in these same patients, it would be taken off the market immediately. Look, for example, at the risks of cardiovascular problems with Vioxx. The VIGOR trial showed 17 heart attacks in a group of over 4,000 patients, a rate (at the highest dose) of about four times the naproxen-treated control group. In relative risk terms, that’s a serious alarm bell – but in absolute risk, not so much.

This isn’t a completely fair comparison, of course – in the case of statins, cardiovascular events are what you’re trying to treat for in the first place, as opposed to having them as a totally unrelated side effect in a pain medication. And there were other options than a Cox-2 inhibitor for many (although not for all) of the people taking Vioxx. And there’s the general primum non nocere principle: when we find that a drug is causing actual harm (as opposed to doing nothing), it’s likely to be withdrawn, even if the harm is at very low statistical levels.

But at the same time, not giving people something that could prevent these heart attacks is still rather equivalent to causing said heart attacks – isn’t it? We have to make the call of whether the cost, and the statin side effects, are worth it. That’s not an easy one (for one thing, there was a statistically significant difference in the number of Crestor-treated patients showing diabetic symptoms in this trial). And when a drug shows harmful side effects, we should make the call in the same way. I just don’t see the two situation treated in a similar manner much of the time, though.

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

September 26, 2008

Prasugrel Today?

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Posted by Derek

I wrote back in the summer about the FDA's delayed decision on Lilly's potential anticoagulant blockbuster Effient (prasugrel). Well, those three months have zipped right by, and the agency is supposed to rule today.

Prediction, for what it's worth: I think the drug will be approved, but with label restrictions for the group(s) that seemed to respond best to it in trials - who may have been. at least partly, the groups that could put up with the associated bleeding the best, too. So no elderly patients, no low-weight ones, and no one with a history of stroke or TIA. That'll cut down the market for the drug, definitely, but not as much as if it doesn't get approved at all, right? I think the FDA will require Lilly to keep a careful eye on how Prasugrel performs in the real world while they wait on the results of the next trial to come in, with a possible label-language change to come at that point.

I'll give that option about a 70% chance. The 30% chance is that they delay things yet again, since the agency has been in a delaying risk-averse mood these days. We'll know soon. This new policy of not issuing those irritating "approvable" letters has made this sort of thing rather more tense, hasn't it?

Comments (6) + TrackBacks (0) | Category: Cardiovascular Disease | Regulatory Affairs

July 22, 2008

Vytorin: Another Round of Nasty Results

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Posted by Derek

Merck took the unusual step of delaying its earnings release yesterday until after the close of the market. A report on another clinical study of Vytorin (ezetimibe), their drug with Schering-Plough, was coming out, so they put the numbers on hold until after the press release yesterday afternoon. Naturally, this led to a lot of speculation about what was going on. A conspiracy-minded website vastly unfriendly to Schering-Plough suspected some sort of elaborate ruse to drum up publicity.

But that sort of thinking doesn't take you very far, unless you count the distance you rack up going around in circles. As it turned out, the SEAS trial (Simvastatin and Ezetimibe in Aortic Stenosis) was, in fact, very bad publicity indeed for the drug and for both companies. In fact, a real conspiracy would have made sure that these numbers never saw the light of day, or were at least released at 6 PM on a Friday. But no, the spotlight was on them good and proper.

This trial studied patients with chronic aortic stenosis, which is a different condition than classic atherosclerosis. The two have enough similarities, though, that there has been much interest in whether statin treatment could be effective. The primary endpoint, a composite of aortic valve and general cardiovascular events, was missed. Vytorin was no better than placebo. It reached significance against one secondary endpoint, reducing the risk of various ischemic events, but not in any dramatic fashion.

That's not necessarily a surprise, since there's not a well-established therapy for aortic stenosis (thus the trial design versus placebo). As several commenters to the conference call after the press conference pointed out, this shouldn't change clinical practice much at all. But it's not what Merck and Schering-Plough needed to hear, that's for sure, because the sound bite will be "Vytorin Fails Again".

Actually, the sound bite will be even worse than that. There are a lot of headlines this morning about another observation from the SEAS trial: that significantly more patients in the treatment arm of the study were diagnosed with cancer. That's a red warning light, for sure, but in this case we have at least some data to decide how much of one.

For one thing, as far as I know there have been no reports of increased cancer among the patients taking Vytorin out in the marketplace - of course, one could argue that this might have been missed, but if the effect were as large as seen in the SEAS study, I don't think it would have been. Analyses of the earlier Vytorin trials and the ongoing IMPROVE-IT trial versus Zocor have also shown no cancer risk, and the latter trial is continuing. So for now, it would appear that either this was a nasty result by chance, or (a longer shot) that there's something different about the aortic stenosis patients that leads to major trouble with Vytorin.

None of these scientific and statistical arguments, and I mean none of them, will avail Schering-Plough and Merck. Among people who've heard of Vytorin at all, the first thing that will come to mind is "doesn't work", and after today's headlines, the second thing that will come to mind is "cancer". Just what you want, to put out press releases that your compound, even though it failed to work again, isn't actually a cancer risk. You really couldn't do worse; a gang of saboteurs couldn't have done worse. Of course, there's no such gang: the companies themselves authorized these trials, thinking that there were home runs to be hit. But all these sidelines - familial hypercholesteremia, aortic stenosis - have only sown fear, confusion, and doubt. The only thing that I can see rescuing Vytorin as a useful drug is for the IMPROVE-IT results to show really robust efficacy in its real-world patients. And I wonder if even that could be enough.

Comments (19) + TrackBacks (0) | Category: Business and Markets | Cancer | Cardiovascular Disease | Clinical Trials | Toxicology

June 24, 2008

Prasugrel: Come Back This Fall

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Posted by Derek

This week was supposed to reveal the FDA's decision on Dai-Ichii Sankyo and Eli Lilly's anticlotting drug prasugrel. That one's in the same chemical class as Plavix (clopidogrel), and works by the same mechanism. Since Plavix did about eight billion dollars of business last year, and the anticlotting area seems to be a limitlessly huge market in general, you can understand why another drug is entering the space.

Both clopidogrel and pasugrel are prodrugs - their structures, as they come out of the bottle, are inactive. But they're converted by cytochrome P450 enzymes in the liver to their active forms, which bind irreversibly to the P2Y12 purinergic receptor on platelets. The clopidogrel link above shows the active form - that thiophene ring gets broken open, and a reactive SH is exposed. The P2Y12 receptor mediates platelet aggregation, so shutting it down extends clotting time.

A few points: for one, you'll note that the structures of the two drugs are very similar indeed. Is pasugrel just a "me-too", then? Well, it certainly is trying to do the same thing by the same mechanism, but as I've said here many times, it's hard to sell a drug unless you can point to some difference. The advantage that prasugrel has is that its metabolic activation takes place through a broader number of liver enzymes, so more of the active metabolite is produced across a wider patient population. And it is indeed about ten times more potent in humans - which may, though, prove to be its downfall.

In the clinic, the large TRITON-TIMI trial ran the two drugs head to head in over 13,000 patients, which is certainly the expensive (and definitive) way to go. The end result was that the prasugrel-treated group had fewer cardiovascular problems of all kinds (good!), but more episodes of severe bleeding (bad!). Overall mortality was the same between the two groups, and that's where the arguing has started. There's a lot of room to break down the numbers more thoroughly to see if there's some real benefit to the drug (or alternatively, to show that it really isn't any more useful than Plavix).

Of course, this is the job of the FDA. And now it seems that they've chosen to punt, delaying their decision by three months. Since the companies don't seem to have been asked to submit any more data, this seems to be an internal wrangle at the agency. I'm not sure what they're going to accomplish by holding their heads and moaning for another quarter, unless the hope is that the numbers can be crunched in some direction which will offer enough of a fingerhold to justify a decision. This is a very, very close call.

If I had to predict - and hey, I write this blog, so I've got a license to do that sort of thing - I'd say that the agency will ultimately approve the drug, but with label restrictions. In the end, they'll turf the problem over to the cardiologists, but with enough warning language on it that no one should be surprised if patients bleed out on occasion. The best outcome would be for some sort of clinical sign to indicate which patients should avoid the drug. The FDA will probably head in that direction, since it appears that the majority of bleeding problems occurred in the oldest and/or lowest-body-weight groups in the trial.

Update: but is that the case? Looking at the NEJM paper, it appears that patients not in these groups did have better efficacy with prasugrel, which improves the numbers. But the hazard ratio for major bleeding was 1.42 in the risky patients (>75 years old, or body weight < 60 kilos, or history of stroke/TIA), but still 1.24 in the ones outside these groups. So it's not at all fair to say that most of the bleeding events were in the risky patients - frankly, it looks like everyone bled, but the healthier cohort just responded better to the drug at the same time. That complicates my guess in the above paragraph, and raises the worst-case chance that the FDA might want to wait until the current trial comes in. What a mess. . .

There's another 10,000 patient study underway which might clarify the situation, or might just emphasize what a tied-up tangle it all is. In the end, I think that the FDA will let the drug be sold until that one finishes up, with the option to revise its opinion when the data come in. The three-month delay will serve to show how seriously they're taking all the safety issues - a big political consideration these days - and to work up the most bulletproof labeling they can come up with.

Comments (12) + TrackBacks (0) | Category: Cardiovascular Disease

June 5, 2008

Merck, Vioxx: Seventeen and Three

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Posted by Derek

You may or may not have noticed, but slowly and quietly, Merck has been getting many of the large Vioxx judgments against it overturned on appeal. These cases made huge headlines when they were first tried, but the articles that tell the end of the story have not, for the most part, made the front page.

This is one reason that the company was finally able to settle a huge number of pending lawsuits for much less than many people thought likely. Merck seemed to like its chances, considering the cases they’d won and the way things looked in the appeals courts, and the amount of money they were able to settle for finally became a better deal for them than the alternative of fighting out every case. Of course, now people are starting to wonder if the company settled too soon - opinions differ.

It's important to note, though, that some of these reversals have been less than total victories for Merck. The first Texas case falls into that category, but the New Jersey punitive damages were thrown out based on the idea of pre-emption. A state jury, the appeals court ruled, can't decide if Merck defrauded the federal government when it got Vioxx approved. (We'll be revisiting that part of the argument when Wyeth v. Levine and Warner-Lamber v. Kent get decided).

But in the end, what looked for a while like an avalanche that might sweep the company away has come down to . . .what? Twenty cases went to juries, and Merck has now prevailed, to a large degree, in 17 of them, including all the largest awards. The Vioxx affair has still been a big financial hit, and it’s definitely had effects on Merck, but it hasn’t been quite the disaster it looked like being. Well, not financially - the company's reputation has taken a fearsome beating, and the drug industry as a whole hasn't come out of the business looking any better, either.

I can’t claim to have kept a cool head through the thing. There really was a period where the entire Vioxx affair could have taken a different turn – if Merck had lost a string of jury trials at the start, a settlement would have been much harder to arrange, and would have cost (naturally) a huge amount more. But fighting the first wave of cases to an expensive draw and appealing every verdict that went against them turned out to be the right strategy. Of course, any rational observer would have wished for a world where the whole business never would have taken place, but that's not where we find ourselves.

But, as you’ll have noticed, the preceding paragraphs are written from a point of view that’s pretty sympathetic to Merck. Zooming out to a more neutral view, what do we have? Vioxx certainly did some people a great deal of harm. The clinical data that led to its withdrawal make it extremely likely that some people experienced heart attacks, fatal in some cases, because they took the drug. Where the arguing starts is when you start pinning numbers to that last sentence. Vioxx’s bad effects, though real, were also small compared to the number of people who took it. (And the arguing continues when you try to balance its bad effects with the good that it did for the patients who really needed it, who were surely, though, a small subset of the people who actually were on the drug).

Those last two sentences point to some of the problem. If Merck had not tried to make Vioxx the pain drug for everyone in the world with any kind of inflammation pain, it’s quite possible that its cardiovascular effects would never have been noticed. And it’s worth remembering that they were noticed during a trial for a completely different indication, the possibility that COX-2 inhibitors might have a protective effect against colon cancer. Only after that trial flashed an unmistakable statistical warning did everyone go back to Merck’s earlier data and start arguing about what could or should have been noticed before.

The problem is that many other drugs have data that, in retrospect, look like trouble. It’s just that in many cases, the trouble never appears, either because it never rises to the level of being noticed, or it never was really there to begin with. There are drug candidates that cause bad effects in one out of every ten people who take them, and those never make it out of the clinic. (Most of the ones causing trouble at that level don’t even make it into the clinic in the first place). The ones that cause trouble at one in a hundred get weeded out, too, if that trouble is bad enough. The one in a thousand, one in ten thousand, one in a hundred thousand levels are where the difficulty is, because clinical trials have an increasingly difficult time picking up those problems. They’ll show up, if they do, after a drug comes to market.

But why stop there? There’s no reason not to believe that there are drugs that also cause direct harm, but only to one out of every million patients. Or ten million, or hundred million. Some unlikely combination of genetic and environmental factors comes up – we really don’t know enough to rule that sort of thing at all. We call those drugs “safe”, but “safe” means “causing harm at too low a level to see”. Every single drug in the world has bad side effects, from the bottom of the scale (hideous old last-ditch chemotherapy drugs that are one step away from World War One battlefield agents), all the way up to the top. It's just a question of how often they turn up.

Comments (9) + TrackBacks (0) | Category: Cardiovascular Disease | Toxicology

May 13, 2008

In Which I Hate A Wonder Drug

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Posted by Derek

Schering-Plough has had its share of troubles over the years, but the company has also seen itself saved by some pretty unlikely compounds. Vytorin (ezetimibe) is the example I’ve spoken about here, and if the drug doesn’t seem like a savior at the moment, well, you have to keep in mind that it was the biggest thing for them since Claritin went off-patent ten years ago.

Now there’s another one potentially coming up. Expectations are building for a thrombin receptor antagonist compound, SCH 530348. And I have a history with this one, too: while the labs down one hallway from me were discovering ezetimibe, down the other hallway they were laying the foundation for this one. There’s a big difference, though, in the way I saw the two.

This thrombin antagonist is an unlikely drug for several reasons. For one thing, its structure is not the sort of thing most medicinal chemists would go out of their way to make. But there’s a good reason for that: to a first approximation, it wasn’t made with medicinal chemistry in mind. 530348 is based on a natural product called himbacine, whose fame, such as it is, rests on its properties as a semi-selective muscarinic antagonist. And that’s how Schering-Plough got interested in this class of compounds; thrombin had nothing to do with it.

At the time (early to mid 1990s) the company had a team working on Alzheimer’s disease, and I’ll go ahead and mention again that I was one of the people involved. (Five minutes on SciFinder would tell you that, anyway). We were quite interested in selective muscarinic antagonists, particularly for the m2 subtype, and himbacine was at the time one of the more selective compounds with that profile. So one of the group leaders at the company, Sam Chackalamannil, decided to synthesize it and do some SAR around the structure.

That was no small undertaking. Himbacine’s not one of the most complex natural products by any means, but it’s no stroll to the beach, either, especially when compared to the usual sorts of drug structures. It took a lot of time, a lot of ingenuity, and (most importantly) a lot of effort to do it. And I. . .well, I thought this was a terrible idea.

I really did. By the time himbacine itself got made, the project team had muscarinic compounds that were more selective and more potent (and a lot easier to make, to boot). I would listen to Chackalamannil’s people presenting their long, difficult routes during meetings, and I’d sit there imagining the company going slowly bankrupt if everyone adopted this approach, the revenue slowly sinking as the number of JACS communications rose. I couldn’t see the point, and although I don’t think I ever quite had the nerve to say so to Chackalamannil himself (hi, Sam!), I said it to plenty of other people.

So, is it time for me to eat crow? Well, one plateful, at least. Some of the himbacine analogs hit in the high-throughput screen for thrombin activity, to everyone’s surprise, and some further compounds (now shed of their muscarinic activity) were even better. The drug discovery effort culminated in 530548, which now might be about to benefit a huge number of people and make the company a ton of money, if everything goes well.

Of course, if these things hadn’t hit in the thrombin assay, I could have remained secure in my opinion. After all, they were never worth very much as muscarinics, as far as I know. (Of course, our muscarinic compounds, in the end, never were worth very much as Alzheimer’s drugs, which is something to keep in mind). So that’s the question: how likely is it for molecules like this to work? It’s very hard to answer that, but given this data point, I guess the answer is “at least a little more likely than I thought”. The very fact that they didn’t look like most other things in the screening deck was probably in their favor. I still think that these compounds were a long shot, but this is a business that lives on long shots. This one came through, and congratulations to everyone involved.

Comments (8) + TrackBacks (0) | Category: Alzheimer's Disease | Cardiovascular Disease | Drug Development

April 29, 2008

Cordaptive Q and A

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Posted by Derek

So why is Merck's stock dropping - again?
The FDA just unexpectedly handed them a "not approvable" letter for their latest drug, Cordaptive. Actually, we should stop calling it that, since they also told the company that they're not going to approve that name, either. What Merck's going to do with all their promotional freebies now, I can't imagine.

What's Cordaptive, or whatever it's called, anyway?
That's Merck's newest cardiovascular drug - although the active ingredient isn't new. It's niacin, also known as vitamin B3. It's been known for many years that niacin can both lower LDL cholesterol and raise HDL, as well as lowering triglycerides - in fact, it's probably one of the only things that can do all of those significantly at the same time.

So this is a rip-off, then? Merck's trying to sell vitamin B for $20 a pill?
No, it actually isn't, at least not to the extent you're thinking. The problem with niacin as a cholesterol therapy is that you have to take whopping amounts of it to see an effect. And there's a side effect - flushing of the face, which is basically uncontrollable blushing that can last for hours in some cases. That may not sound like much, but the great majority of people who take niacin at these levels have a problem with it, and a lot of people discontinue the therapy rather than put up with it. If the drug is taken for a few weeks, the flushing reportedly eases off some, but not everyone makes it to that point. By all reports, it's very irritating - and since patients can't feel their cholesterol being high, but can feel their faces burning and turning red, they solve the problem by not taking the niacin.

So why doesn't Cordaptive do the same thing?
A lot of people have tried to find a way to keep the lipid effects of niacin and get rid of the flushing. Merck added a prostaglandin receptor antagonist, laropiprant, to try to block the pathway that leads to the vascular effects. And it seems to help quite a bit, which made the combination a potential winner. Abbott already has Niaspan, a slow-release version of niacin, which also has reduced flushing problems and does about $600 million of sales a year. Niacin therapy itself seems to be pretty safe, although you do want to make sure that liver and kidney function are normal before you start, so the only big question has been what blocking that DP1 receptor might do on the side: can you take that pathway out without causing more trouble?

Well, can you?
Apparently not. Actually, that should be "apparently there isn't enough evidence to say yet" - that's probably more in the spirit of the FDA's letter. They want to see more information about the drug. Problem is, the FDA treats this (properly) as a matter between the agency and the drug company, so they aren't saying what the problem is. And Merck, for its part, isn't saying, either. Investors feel rather left out in these situations - perhaps the most striking one in recent years was Sanofi-Aventis's absolute wall of silence for months about why the FDA wasn't approving their potential blockbuster Acomplia (rimonabant).

Why's this so unexpected, if there wasn't enough evidence given to the FDA?
Well, there seems to have been enough evidence in the same pile of data for the European Union, whose regulators approved recommended the drug for approval a few days ago. Merck must have felt reasonably confident that they'd get the same treatment here. No such luck. And as just mentioned, we don't know if the problem is not enough evidence of efficacy, not enough evidence of safety, or a bit of each.

Why don't you people just make cholesterol-lowering drugs that work better, then, so there's no doubt about efficacy?
Would that we could. Statins basically only lower LDL - they don't raise your HDL. And if you push the statins too hard, patients start coming down with rhabdomyolysis, and you don't want that - ask Bayer. Raising HDL has proven to be a real challenge, too. There are a lot of ideas about how to do it, but the most obvious ones aren't working out too well - ask Pfizer.

OK, then, why don't you just make safer versions of what you already have?
Would that we could. But in almost every case, we have no idea of how to do that. For the most part, either the safety concerns are tied up with the beneficial mechanism of the drug, or they're occurring through side pathways that we don't understand well and don't know how to avoid. And some of those are things that you don't even get a read on until your drug gets out into the market, which is no way to do things, either.

So, why is the drug business considered such a safe bet?
Now, that one I don't have an answer for. Unless it's the conviction that people are always going to get sick, which I guess is a pretty safe bet. And that's coupled with a conviction, apparently, that we're always going to be able to do something profitable about that. And some days, I have to wonder. . .

Comments (18) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Drug Development | Toxicology

April 4, 2008

Another Cholesterol Medication Goes Down (Or Does It)?

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Posted by Derek

This is turning into Cardiovascular Week around the blog, I have to say, and not in a good way. The latest news is the failure of a drug candidate from Takeda, TAK-475 (lapaquistat). They were in the lead in the field of squalene synthase inhibitors for cholesterol lowering (many other companies have taken a crack at this target, and dropped out along the way)., and their compound once had hopes of being a pretty big deal.

Not any more. In retrospect, the bell sounded late last year, when the company had to stop dosing at their highest level. Elevated transaminase levels were being seen in the treatment groups as the dose went up, which is a sure sign of trouble, as in liver damage trouble. Some investors seem to have held out hope for the compound to show enough efficacy at the lower doses, but Takeda has announced that the safety/efficacy ratio doesn’t justify taking the drug forward.

Liver enzymes are definitely one of those things you worry about when you go into man. There are all sorts of assays that are supposed to give you a read on that problem beforehand, and it’s safe to assume that Takeda ran them. But you’re never sure until you hit humans. Animals can react very differently to some compounds, although that can go either way. But if you set off liver enzyme trouble in rats or dogs your compound is probably dead, no matter how it might act in humans. You won’t get the chance to find out, most of the time.

The alternative is to use human liver tissue, but cultured human liver cells rapidly lose their native abilities and become untrustworthy as a model for the real world. Human liver slices are another alternative, but those are rather hard to come by, as you can well imagine, and the data from them have a reputation for being hard to interpret and hard to reproduce. No, for now, there’s no way to really know what will happen in humans without, well, using humans.

The big question that always gets asked in these failures is whether this is a compound-specific effect, a compound class effect, or a mechanistic effect. Most of the time it’s one of the first two. There are particular compounds, and particular structural series, that are known to be Bad News for liver enzymes. There will be some lingering doubt, though, because there’s plenty of squalene synthase activity in the liver, and it’s not impossible that any compound that hits it could cause the same trouble.

There are a number of other inhibitors out there – interestingly enough, they may have other uses besides lowering cholesterol. For some time, it’s been thought that such compounds might be useful antibiotics, since many bacteria need cholesterol synthesis pathways to survive. And there’s a recent report in Science putting this to the test in a particularly relevant system, particularly virulent strains of Staphylococcus aureus.

The “aureus” part of the name refers to the yellow hue that many strains of the bug exhibit, which seems to be correlated with how nasty they are as an infectious agent. The color comes from staphyloxanthin, a pigment that seems to be used as a defense agent by the bacteria by neutralizing reactive oxygen attacks from a host’s immune system. As the current work shows, the first enzyme in the biosynthetic pathway for staphyloxanthin (known as CrtM) has a lot of structural similarities to human squalene synthase. The authors prepared a number of known squalene synthase inhibitors from the literature, and found that one class of them (the phosphonosulfonates) also inhibit CrtM.

They went further, showing that one of these compounds (a BMS clinical candidate from about ten years ago) actually works quite well as an antibiotic in vitro and in an in vivo mouse model. I'm not sure why this compound didn't go further, but perhaps it (and the others in its class) will have a second life in the antiinfectives world. . .

Comments (8) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development | Infectious Diseases

April 3, 2008

Whose Guess Is Better?

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Posted by Derek

I was having a discussion the other day about which therapeutic areas have the best predictive assays. That is, what diseases can you be reasonably sure of treating before your drug candidate gets into (costly) human trials? As we went on, things settled out roughly like this:

Cardiovascular (circulatory): not so bad. We’ve got a reasonably good handle on the mechanisms of high blood pressure, and the assays for it are pretty predictive, compared to a lot of other fields. (Of course, that’s also now one of the most well-served therapeutic areas in all of medicine). There are some harder problems, like primary pulmonary hypertension, but you could still go into humans with a bit more confidence than usual if you had something that looked good in animals.

Cardiovascular (lipids): deceptive. There aren’t any animals that handle lipids quite the way that humans do, but we’ve learned a lot about how to interpolate animal results. That plus the various transgenic models gives you a reasonable read. The problem is, we don’t really understand human lipidology and its relation to disease as well as we should (or as well as a lot of people think we do), so there are larger long-term problems hanging over everything. But yeah, you can get a new drug with a new mechanism to market. Like Vytorin.

CNS: appalling. That goes for the whole lot – anxiety, depression, Alzheimer’s, schizophrenia, you name it. The animal models are largely voodoo, and the mechanisms for the underlying diseases are usually opaque. The peripheral nervous system isn’t much better, as anyone who’s worked in pain medication will tell you ruefully. And all this is particularly disturbing, because the clinical trials here are so awful that you’d really appreciate some good preclinical pharmacology: patient variability is extreme, the placebo effect can eat you alive, and both the diseases and their treatments tend to progress very, very slowly. Oh, it’s just a nonstop festival of fun over in this slot. Correspondingly, the opportunities are huge.

Anti-infectives: good, by comparison. It’s not like you can’t have clinical failures in this area, but for the most part, if you can stop viruses or kill bugs in a dish, you can do it in an animal, or in a person. The questions are always whether you can do it to the right extent, and just how long it’ll be before you start seeing resistance. With antibacterials that can be, say, "before the end of your clinical trials". There aren’t as many targets here as everyone would like, and none of them is going to be a gigantic blockbuster, but if you find one you can attack it with more confidence than usual.

Diabetes: pretty good, up to a point. There are a number of well-studied animal models here, and if your drug’s mechanism fits their quirks and limitations, then you should be in fairly good shape. Not by coincidence, this is also a pretty well-served area, by current standards. If you’re trying something off the beaten path, though, a route that STZ or db/db rats won’t pick up well, then things get harder. Look out, though, because this disease area starts to intersect with lipids, which (it bears saying again) We Don't Understand Too Well.

Obesity: deceptive in the extreme. There are an endless number of ways to get rats to lose weight. Hardly any of them, though, turn out to be relevant to humans or relevant to something humans would consider paying for. (Relentless vertigo would work to throw the animals off their feed, for example, but would probably be a loser in the marketplace. Although come to think of it, there is Alli, so you never know). And the problem here is always that there are so many overlapping backup redundant pathways for feeding behavior, so the chances for any one compound doing something dramatic are, well, slim. The expectations that a lot of people have for a weight-loss therapy are so high (thanks partly to years of heavily advertised herbal scams and bizarre devices), but the reality is so constrained.

Oncology: horrible, just horrible. No one trusts the main animal models in this area (rat xenografts of tumor lines) as anything more than rough, crude filters on the way to clinical trials. And no one should. Always remember: Iressa, the erstwhile AstraZeneca wonder drug from a few years back, continues to kick over all kinds of xenograft models. It looks great! It doesn’t work in humans! And it's not alone, either. So people take all kinds of stuff into the clinic against cancer, because what else can you do? That leads to a terrifying overall failure rate, and has also led to, if you can believe it, a real shortage of cancer patients for trials in many indications.

OK, those are some that I know about from personal experience. I’d be glad to hear from folks in other areas, like allergy/inflammation, about how their stuff rates. And there are a lot of smaller indications I haven’t mentioned, many of them under the broad heading of immunology (lupus, MS, etc.) whose disease models range from “difficult to run and/or interpret” on the high side all the way down to “furry little random number generators”.

Comments (9) + TrackBacks (0) | Category: Animal Testing | Cancer | Cardiovascular Disease | Diabetes and Obesity | Drug Assays | Drug Development | Infectious Diseases | The Central Nervous System

April 2, 2008

Vytorin Numbers

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Posted by Derek

Thanks to a tip from “Jack Friday” of the Pharmagossip blog, I’ve read this paper which appeared in Atherosclerosis this past summer. A large multi-center team put a lot of work into studying the Vytorin combination (ezetimibe and simvastain, the cholesterol absorption inhibitor and a classic HMG CoA reductase inhibitor) in 72 healthy male subjects. I was initially excited about it, because reading the abstract it seems as if they’ve found a real difference between taking the combination versus taking the drugs by themselves, which is rather a hot topic these days. But read on.

The subjects were divided into three groups, receiving 10 mg/day ezetimibe (basically Zetia monotherapy), 40 mg/day simvastatin (Zocor monotherapy) or the combination (Vytorin). The results? Well, LDL cholesterol went down in all groups, as expected – this much was known already. (Total cholesterol was down as well, but this was basically all due to LDL reduction). Ezetimibe alone lowered LDL by 22%, simvastatin by 41%, and the combination lowered it by 60%: so far, so good. Those are just the kinds of numbers that convinced people to go on Vytorin in the first place.

Cholesterol synthesis showed an interesting pattern, but one that makes sense. Simvastain lowered it, as well it should – that’s the whole rationale for a statin in the first place. But ezetimibe actually increased it, which could be interpreted as the body’s attempt to get back to previous cholesterol levels after the dietary supply was cut off. The combination was a wash, as you’d expect – the two canceled each other out. These results have been found in other studies as well.

Meanwhile, cholesterol absorption was the flip side of endogenous synthesis. Ezetimibe lowered it (again, as well it should!), and simvastatin had essentially no effect. The combination, then, showed an overall lowering of cholesterol absorption – no surprises, and this, too, has been seen in other work.

The gene for the surface LDL receptor showed a different pattern. Ezetimibe by itself didn’t do much to its expression levels, but simvatatin sent it up (and thus the combination sent it up, too). When they looked at the actual LDL-receptor protein, though, none of the three regimens had an effect. The abstract for the paper makes more out of this than the paper itself does, to my eyes. The abstract singles out the combination therapy as upregulating the gene but not protein expression, as if that were some new effect, but simvastatin alone does the exact same thing. I didn’t see anything particularly surprising here, and the bottom line is that none of the three treatments did anything to LDL receptor protein levels, which is how real clinical effects would be expected show up.

The differences these investigators found with Vytorin as compared to its two components seem to me to be either already known, completely reasonable and expected, or so small that it’s uncertain if they exist. I have a feeling that that’s why this work was published in Atherosclerosis - a perfectly good journal, mind you, but if something dramatic had shown up, I’ll bet they could have made New England Journal of Medicine, JAMA, The Lancet, Nature Medicine or the like.

Overall, this study just seems to be confirmation of why Merck and Schering-Plough felt safe in making a big marketing play for Vytorin. If lowering LDL is good, and if lowering LDL is the reason that people take statins, then Vytorin does it even more. If you were shown these results without knowing that they were for Vytorin, you'd think that someone had discovered a real blockbuster of a new cholesterol-lowering drug. So we’re right back to asking why ENHANCE didn’t show a benefit in artery wall thickness. And that, no one knows.

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

April 1, 2008

Vytorin: It's A Pity

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Posted by Derek

Ezetimibe, known as Zetia and as the key component of Vytorin, was invented by friends and colleagues of mine. It was the first drug I ever saw discovered after I joined the drug industry. The initial discovery of the whole compound class happened around the corner from my lab, and the compound that became ezetimibe itself was synthesized down the hall. So, no, I’m not taking the current news about it very well. The situation is still quite confused, but there looks to have been enough stupidity, greed, and plain bad luck involved to make anyone despair. Read on – but I should warn you, I’m probably just going to get madder and madder as the post continues.

As anyone unfortunate enough to be holding Merck or Schering-Plough stock already knows, both companies took a pounding yesterday after the American College of Cardiology issued its recommendation on the use of Vytorin (ezetimibe / simvastatin). This call was based on the now-infamous ENHANCE trial, which was just published in the New England Journal of Medicine. The main points of the study had already come out in January, of course, but a closer look at the data has done nothing to help explain its results: no improvement over existing therapy. Addition of the cholesterol absorption inhibitor to the statin appears to have done nothing to help clear arteries (based on measurement of intima-media thickness) over what could be done with the statin alone. Ezetimibe seems to have had no bad effects, fortunately, but no good ones, either.

The ACC’s verdict is that Vytorin should only be used as a last resort, and that patients currently taking it should strongly consider going back to plain statin therapy. Based on these study results, that seems like a reasonable recommendation. There’s a large outcome trial (IMPROVE-IT) underway comparing the two treatments, but we’re not going to see results from that one for another three years at the earliest. Until then, there doesn’t seem to be any reason to recommend Vytorin. (There may not be any reason to recommend it afterwards, either, but we’ll have to wait to see about that). Fortunately for everyone involved, no one seems to have been harmed, outside of the insurance companies who have paid out for Vytorin for the last few years – they not doubt have their own views on the subject.

It’s important to remember that this result is indeed a surprise, since the combination definitely does do a better job at lowering LDL. (As an editorial in the NEJM puts it, this "dramatically contradicts our expectations"). You’d think that extra LDL reduction would be associated with a better outcome, but one of the panelists at the ACC, Dr. Harlan Krumholz, points out (PDF) that hormone therapy lowers LDL as a side effect, but isn’t associated in that case with better atherosclerosis outcomes, either. Does that mean that there’s more to the effect of statins than just lowering LDL, too? That possibility has to be taken seriously. The non-lipid effects of inhibiting HMGCoA reductase, the statin target, may be part of the answer, although the authors of the NEJM paper are reluctant to make that their whole explanation.

What they suggest instead is disturbing. The study may have been doomed from the start. The ENHANCE subjects were not taken from the general population, but rather were patients with a genetic abnormality in LDL handling, familial hypercholesterolemia. The idea was that these patients would be even more likely to show a benefit from Vytorin. But as the NEJM authors make clear, this may at one time have been a good patient population to show benefits in, but now the great majority of people with this condition are treated with statins starting at an early age. This, naturally, has an effect on their arterial walls. So the subjects of this trial may have already had a head start on reducing their arterial thickness, which means there may well have been a limit on what any particular therapy could have accomplished. Instead of being a better group to demonstrate your LDL-lowering powers in, they could well be worse.

If that’s true, there is, in fact, a chance that the IMPROVE-IT trial could show a clear benefit for Vytorin, since it’s being run in a broader population. (Just watch the confusion if that happens). But what will that mean? The results will be far too late to help Merck and Schering-Plough, and will be a clear disservice to the patients that could have benefited from the drug before then. ENHANCE would then turn out to have been a huge mistake.

But not content with that, the companies have managed to make it into a complete disaster. The controversy has been whether Merck and Schering-Plough sat on the results of the trial or spent extra time trying to find a way to make them look more appealing. This has drawn the attention of Sen. Charles Grassley and an investigative committee, which is the sort of thing that no company can wish for. Yesterday Grassley released some of the text of his letters to the management of both companies, and these include quotes from e-mails sent by John Kastelein, the lead investigator on ENHANCE. They do not look good, not by any stretch of the imagination:

” Is it correct that SP has decided not to present at AHA, but to await the two other, completely unvalidated, endpoints, which analysis is going to take us straight into 2008??!!??

If this is true, SP must have taken this decision without even the semblance of decency to consult me as PI of the study. I can tell you that if this is the case, our collaboration is over…This starts smelling like extending the publication for no other [than] political reasons and I cannot live with that.”

In another e-mail, Kastelein expresses more frustration that the results would not be presented at that AHA meeting (as indeed they weren’t, in the end), and says that ”. . . you will be seen as a company that tries to hide something and I will be perceived as being in bed with you!”

Schering-Plough, for its part, says that these statements are taken out of context, but good grief, what other context could that possibly be? Kastelein has also backed off, saying that he wasn’t accusing the company of “deliberately withholding data for political reasons”, but again, it’s hard to read those excerpts in any other way. These days, no one should make statements in e-mail that they’re not comfortable seeing printed in the Wall Street Journal, which is where I got these.

And does it need to be said that this is exactly, I mean exactly the kind of thing that the drug industry does not need? Vytorin as a drug is easy to forgive – the combination makes perfect sense, and the fact that it didn’t show a good result in ENHANCE took everyone by surprise. (And, as mentioned above, it may in the end turn out to be a good therapy in the end). But the marketing of Vytorin is perhaps another thing – the companies really made a huge aggressive push to get as much of the cholesterol-lowering market as they could. That’s no sin by itself, unless business is a sin, but if you’re going to push that hard, you’d better make sure that you’re standing on something firm.

This trial definitely wasn't that sort of foundation, and the fallout from it has been made much, much worse by its handling. It's distressing to me that the management at Merck and Schering-Plough would even take the chance, in this climate, of being seen as data-massaging study-burying slime. What words do I find if that's what they turn out to be?

Ezetimibe was (and is) a wonderful scientific story in the drug discovery labs, and its development is a testament to some very dedicated and persistent people. What a pity that it's all come to this.

Comments (19) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Press Coverage | The Dark Side | Why Everyone Loves Us

March 13, 2008

Pfizer vs. the NEJM: A Legal Showdown

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Posted by Derek

Today (March 13) at 3 PM EST, there's a hearing scheduled on a legal motion that could change the way scientific results are published in this country. Pfizer is being sued over injuries that plaintiffs believe came from their use of Celebrex, one of the world’s only remaining Cox-2 inhibitor drugs. (I saw a Celebrex tv ad the other day, a surreal thing which was basically a lengthy recitation of FDA-mandated side effect language accompanied by jazzy graphics). Everyone with a Cox-2 compound is being sued from every direction, as a matter of course. The company is, naturally, casting around for any weapon that comes to hand for its defense, as did Merck when that same sky began to come down on them.

But Pfizer’s lawyers (DLA Piper LLP of Boston) are apparently (your choice, multiple answers permitted) more aggressive, more unscrupulous, or more clueless than Merck’s. Among the points at issue are several papers from the New England Journal of Medicine. According to the motion, which I paid to download from PACER, two of the particularly contentious ones are this one on complications after cardiac surgery and this one on cardiac risk during a colon cancer trial. So Pfizer has served the journal’s editors with a series of subpoenas. They’re seeking to open the files on these manuscripts – reviewer comments, reviewer names, editorial correspondence, rejected submissions, the lot. What are they hoping to find? Oh, who knows – whatever’s there: ”Scientific journals such as NEJM may have received manuscripts that contain exonerating data for Celebrex and Bextra which would be relevant for Pfizer's causation defense” say the lawyers. The journal refused to comply, so Pfizer has now filed a motion in district court in Massachusetts to compel them to open up.

What's particularly interesting is the the journal has, to some extent, already done so. According to Pfizer's "Motion to Compel", the editors "produced a sampling of forms identifying the names of manuscript authors and their financial disclosures, correspondence between NEJM editors and authors regarding suggested editorial changes and acceptance and rejection letters". The motion goes on to say, though, that the editors had the nerve to ignore the broader fishing expedition, only releasing documents for authors specifically named in the subpoenas, not "any and all" documents related to Celebrex or Bextra. They also withheld several documents under the umbrella of peer review and internal editoral processes. Thus, the request to open up the whole thing.

I’ve never heard of this maneuver before. Staff members of the NEJM gave depositions in the early phases of the Merck litigation, since the journal was in the middle of the Vioxx fighting. (They’d “expressed concern” several times about the studies that had appeared in their own pages and passed through their own review process). But even then, I don’t think that Merck wanted to open up the editorial files, and you’d think that if anyone had something to gain by it, they would.

Pfizer’s motion seems to me more like a SLAPP, combined with standard fishing expedition tactics. Their legal team doesn’t seem to think that any of this will be a problem, at least as far as you can tell from their public statements. They say in their motion that they don’t see any harm coming to the NEJM if they comply – heavens, why not? Reviewers will just line up to look over clinical trial publications if they think that their confidentiality can be breached in case of a lawsuit, won’t they? And the rest of the scientific publishing world could look for the same treatment, any time someone published data that might be relevant to someone’s court case, somewhere. Oh, joy.

Pfizer’s motion states that ” The public has no interest in protecting the editorial process of a scientific journal”. Now, it’s not like the peer review process is a sacred trust, but it’s the best we’ve been able to come up with so far. It reminds me of Churchill’s comment about democracy being the worst form of government until you look at the alternatives. I realize that it’s the place of trial lawyers and defense teams to scuffle around beating each other with whatever they can pick up, but I really don’t think that they should be allowed to break this particular piece of furniture.

And I can’t see how the current review process won’t get broken if Pfizer’s motion is granted. The whole issue is whether the journal's editors can claim privilege - if so, they don't have to release, and if not, they most certainly do. This can't help but set a precedent, one way or another. If there's no privilege involved in the editorial process, a lot of qualified and competent reviewers will start turning down any manuscript that might someday be involved in legal action. (Which, in the medical field, might be most of them). The public actually does have an interest in seeing that there is a feasible editorial process for scientific journals in general, and I hope that the judge rules accordingly.

In the meantime, for all my friends at Pfizer and for all the other scientists there with integrity and good sense: my condolences. Your company isn’t doing you any favors this week.

(One of the first mentions of all this was on the Wall Street Journal’s Health Blog. The comments that attach to it are quite interesting, dividing between the hands-off-peer-review crowd and a bunch of people who want to see the NEJM taken down a few pegs. I can sympathize with that impulse, but there has to be a better way to do it than this. And there’s more commentary from Donald Kennedy, editor of Science, here (you can pretty much guess what he thinks about this great idea).

Comments (18) + TrackBacks (0) | Category: Cardiovascular Disease | The Scientific Literature | Toxicology | Why Everyone Loves Us

March 4, 2008

Off Target? Which Target Did You Mean?

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Posted by Derek

Here's a snapshot for you, to illustrate how little we know about what many of our compounds can do. I was browsing the latest issue of the British Journal of Pharmacology, which is one of many perfectly respectable journals in that field, and was struck by the table of contents.

Here, for example, is a paper on Celebrex (celecoxib), but not about its role in pain or inflammation. No, this one, from a group in Turin, is studying the drug's effects on a colon cancer cell line, and finding that it affects the ability of the cells to stick to surfaces. This appears to be driven by downregulation of adhesion proteins such as ICAM-1 and VCAM-1, and that seems to have nothing particular to do with COX-2 inhibition, which is, of course, the whole reason that Celebrex exists.

This is a story that's been going on for a few years now. There's been quite a bit of study on the use of COX-2 drugs in cancer (particularly colon cancer), but that was driven by their actual COX-2 effects. Now it's to the point that people are looking at close analogs of the drugs that don't have any COX-2 effects at all, but still seem to have promise in oncology. You never know.

Moving down the list of papers, there's this one, which studies a well-known model of diabetes in rats. Cardiovascular complications are among the worst features of chronic diabetes, so these folks are looking at the effect of vascular relaxing compounds to see if they might provide some therapeutic effect. And they found that giving these diabetic rats sildenafil, better known as Viagra, seems to have helped quite a bit. They suggest that smaller chronic doses might well be beneficial in human patients, which is definitely not something that the drug was targeted for, but could actually work.

And further down, here's another paper looking at a known drug. In this case, it's another piece of the puzzle about the effects of Acomplia (rimonabant), Sanofi-Aventis's one-time wonder drug candidate for obesity. It's become clear that it (and perhaps all CB-1 compounds) may also have effects on inflammation and the immune system, and these researchers confirm that with one subtype of blood cells. It appears that rimonabant is also a novel immune modulator, which is most definitely not one of the things it was envisioned as. Do the other CB-1 compounds (such as Merck's taranabant) have such effects? No one knows, but it wouldn't come as a complete surprise, would it?

These are not unusual examples. They just serve to show how little we understand about human physiology, and how important it is to study drugs in whole living systems. You might never learn about such things by studying the biochemical pathways in isolation, as valuable as that is in other contexts. But our context in the drug industry is the real world, with real human patients, and they're going to be surprising us for a long time to come. Good surprises, and bad ones, too.

Comments (8) + TrackBacks (0) | Category: Cardiovascular Disease | Diabetes and Obesity | Drug Development | Toxicology

February 8, 2008

A Look Under the Hood

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Posted by Derek

There’s an excellent article in Nature Reviews Drug Discovery that summarizes the state of the HDL-raising drug world. It will also serve as an illustration, which can be repeated across therapeutic areas, of What We Don’t Know, and How Much We Don’t Know It.

The last big event in this drug space was the catastrophic failure of Pfizer’s torcetrapib, which wiped out deep into Phase III, taking a number of test patients and an ungodly amount of money with it. Ever since then, people have been frantically trying to figure out how this could have happened, and whether it means that the other drug candidates in this area are similarly doomed. There’s always the chance that this was a compound-specific effect, but we won’t know until we see the clinical results from those others. Until that day, if you want to know about HDL therapies, read this review.

I’d guess that if you asked a thousand random people about that Pfizer drug, most wouldn’t have heard about it, the same as with most other scientific news. But many that had might well have thought it was a cholesterol-lowering drug. Cholesterol = bad; if there’s one thing that the medical establishment has managed to get into everyone’s head, that’s it. The next layer of complexity (two kinds of cholesterol, one good, one bad) has penetrated pretty well, but not as thoroughly. A small handful of our random sample might have known, though, that torcetrapib was designed to raise HDL (“good cholesterol”).

And that’s about where knowledge of this field stops among the general population, and I can understand why, because it gets pretty ferocious after that point. As with everything else in living systems, the closer you look, the more you see. There are, for starters, several subforms of HDL, the main alpha fraction and at least three others. And there are at least four types of alpha. At least sixteen lipoproteins, enzymes, and other proteins are distributed in various ratios among all of them. We know enough to say that these different HDL particles vary in size, shape, cholesterol content, origin, distribution, and function, but we don’t know anywhere near as much as we need to about the details. There’s some evidence that instead of raising HDL across the board, what you want to do is raise alpha-1 while lowering alpha-2 and alpha-3, but we don’t really know how to do that.

How does HDL, or its beneficial fraction(s) help against atherosclerosis? We’re not completely sure about that, either. One of the main mechanisms is probably reverse cholesterol transport (RCT), the process of actually removing cholesterol from the arterial plaques and sending it to the liver for disposal. It’s a compelling story, currently thought to consist of eight separate steps involving four organ systems and at least six different enzymes. The benefits (or risks) of picking one of those versus the others for intervention are unknown. For most of those steps, we don’t have anything that can selectively affect them yet anyway, so it’s going to take a while to unravel things. Torcetrapib and the other CETP inhibitors represent a very large (and very risky) bet on what is approximately step four.

And HDL does more than reverse cholesterol transport. It also prevents platelets from aggregating and monocytes from adhering to artery walls, and it has anti-inflammatory, anti-thrombotic, and anti-oxidant effects. The stepwise mechanisms for these are not well understood, their details versus all those HDL subtypes are only beginning to be worked out, and their relative importance in HDL’s beneficial effects are unknown.

At this point, the review article begins a section titled “Further Complications”. I’ll spare you the details, but just point out that these involve the different HDL profiles (and potentially different effects) of people with diabetes, high blood pressure, and existing cardiovascular disease. If you’re thinking “But that’s exactly the patient population most in medical need”, you are correct. And if it’s occurred to you that this could mean that an HDL drug candidate’s safety profile might be even more uncertain than usual, since you won’t see these mechanisms kick in until you get deep into the clinical trials, right again. (And if you thought of that and you don’t already work in the industry, please consider coming on down and helping us out).

Much of the rest of the article is a discussion of what might have gone wrong with torcetrapib, and suffice it to say that there are many possibilities. The phrases “conflicting findings”, “remain to be elucidated”, “would be important to understand” and “will require careful analysis” feature prominently, as they damn well should. As I said at the time, we’re going to learn a lot about human lipidology from its failure, but it sure is a very painful way to learn it.

And that is the state of the art. This is exactly what the cutting edge of medical knowledge and drug discovery looks like, except for the fact that cardiovascular disease is relative well worked out compared to some of the other therapeutic areas. (Try central nervous system diseases if you want to see some real black boxes). This is what we’re up against. And if anyone wants to know how come we don’t have a good therapy yet for Disease A or Syndrome B. . .well, this is why.

Comments (3) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development | Toxicology

January 14, 2008

Vytorin, Holed Under the Waterline

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Posted by Derek

Merck and Schering-Plough have released the data on a study of genetically high-LDL patients taking a statin alone (Zocor, simvastatin) or the combination of the statin and Schering-Plough's cholesterol absorption inhibitor (Vytorin, simvastatin and ezetimibe). Vytorin has a good share of the market, and has already been shown to lower cholesterol.

And so it did this time: the Vytorin patients showed a 58% decrease in LDL, while the Zocor group showed a 41% reduction. But this trial went further, looking at the growth of atherosclerotic plaques. You'd figure that a greater decrease in LDL would mean a greater decrease in the size and growth of plaques.

You'd be wrong. The Vytorin group's carotid arteries, measured in a standard way (intima-medial thickness, IMT) came out as 0.0111 mm, while the Zocor group's came out as 0.0058 mm. This is making the headlines as "twice as bad as Zocor", but the difference actually isn't statistically significant (p = 0.29). Steve Nissen of the Cleveland Clinic is quoted as saying that this is "as bad a result for the drug as anybody could have feared", but that's not quite right. If that p value had been, say, 0.01, that would be worse. Strictly speaking, you can't call the two groups different. They don't seem to have been different in cardiovascular outcomes.

But here's the real point: that's bad enough. The whole point of Vytorin is that it's supposed to be more effective than a statin alone, and what you can say about this trial is that it sure didn't prove that. But that carotid artery thickness is definitely a concern - the numbers appear to have big error bars on them, but they're certainly not pointing in a good direction. And it's going to be difficult, perhaps impossible, to ever know if that effect is real, because it'll be mighty hard to get another trial of this sort off the ground after results like this. How can you enroll a treatment group for a drug that has been shown to have no benefit?

Well, OK, there's that LDL reduction. But the downstream clinical data (the artery measurements and outcomes) overrule that. The point of taking a cholesterol medication is not to make your lab test numbers go up and down, the point is to have fewer heart attacks and strokes. We use those blood lipid numbers as a convenient surrogate, but it's been obvious for a long time now that we have, to put it delicately, an imperfect understanding of their relevance. Data closer to real mortality and morbidity outcomes will win.

Now what? This is clearly terrible news for Merck and (especially) for Schering Plough. The companies already were under pressure for having taken so long to work up the data for this trial, which delay ended up just drawing even more attention to these bad results. Now, how do you go out and sell Vytorin (or Zetia, the cholesterol absorption inhibitor alone)? Why do insurance companies have motivation to pay for it? And when are we ever going to understand the complexities human lipid behavior and cardiology?

More on ezetimibe, written in happier days, here , here, here, and here. .

Comments (35) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Press Coverage

September 2, 2007

Renin, Wherefore Art Thou, Renin?

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Posted by Derek

I notice that the first marketed renin inhibitor seems to be doing fairly well. That's an interesting phrase, "first marketed renin inhibitor". . .

This is a good example of what drug discovery can be like. Renin is a fine drug target – it’s been known for a long time as a key component of blood pressure regulation, and that’s a condition affecting a huge market whose treatment provides a real medical benefit. What more do you want?

OK, let’s make it even more attractive. It’s not that hard to set up a renin assay, and the protein is well-studied. The counterscreens and secondary assays are not a problem; hypertension is fairly well understood. And if you screen for renin inhibitors, you generally find chemical matter to start off with, too. Protease inhibitors vary quite a bit in their drug-likeness, but they’re certainly not impossible on the face of them.

But even after all this, I would not like to be asked to count how many renin inhibitors have been reported over the years, never to be seen again. The first reports I can find go back to the early 1980s. Given the lead time for these things, I can safely assume that these compounds were being made around the time I went the my high school Junior Prom (theme: “Saturday Night Fever”, natch – it was 1978, after all). And here we are in 2007, and the first one has finally made it to market. It wasn't easy, either - the compound was left for dead years ago, and was only kept going by some ex-Novartis people who started their own company and licensed the compound back to Novartis when it finally made it through the rough spots.

So, what’s the problem? Many compounds have been done in by poor behavior in living models (distribution, absorption, and so on). Getting oral bioavailability in this area has been a lot harder than anyone thought, and even the current drug is no great winner in that category. Projects start and stop, difficulties occur, and the years go by. And other mechanisms for going after hypertension have, of course, come to market, starting with the ACE inhibitors (which come from roughly the same disco era as the first run of renin compounds). They took the gigantic market that an early-1980s renin inhibitor would have had, but even so, I don’t think a year has gone by since that someone in the industry hasn’t been working on one. (There's still room to think that a renin compound would have a better profile than the existing drugs, though). And here we are: 2007. A sobering thought, that is.

Comments (4) + TrackBacks (0) | Category: Cardiovascular Disease | Drug Development | Drug Industry History

June 11, 2007

Rimonabant, Out In the Light

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Posted by Derek

The FDA briefing documents for Wednesday's discussion of Accomplia / Zimulti (rimonabant) have been posted, and they're an interesting read indeed. As everyone in the industry knows, this drug was once looked on as the next potential record-breaker, and writing the first part of this sentence in that verb form tells you a lot about what's happened since. It's the first antagonist targeting the cannabinoid CB-1 receptor, and at one point it looked like it was going to make people lose their excess weight, shed their addictions, and for all I know refinance their mortgages.

But then the delays hit in the US - long, long ones, delays which made fools of everyone who tried to predict when they would be over. And the drug meanwhile made it to market in Europe, where it has very quietly done not very much.

Now we may be seeing some of the reasons for the FDA'a "approvable" letter over a year ago. It's not efficacy - the FDA's briefing summary states that:

"Rimonabant 20 mg daily vs. placebo was associated with statistically and clinically
significant weight loss. Rimonabant 5 mg daily vs. placebo was associated with
statistically significant but clinically insignificant weight loss. . .rimonabant 20 mg daily vs. placebo was associated with a statistically significant 8% increase in HDL-C and a statistically significant 12% decrease in TG levels. There were no significant improvements in levels of total or LDL-C in the rimonabant 20 mg daily vs. placebo group. . .rimonabant 20 mg compared with placebo was associated with a statistically significant 0.7% reduction in HbA1c in overweight and obese subjects with type 2 diabetes taking either metformin or a sulfonylurea."

Not bad - just the sort of thing you'd want to go after the whole obesity/diabetes/cardiovascular area, you'd think. But the problem is in the side effects, and one in particular:

"The incidence of suicidality – specifically suicidal ideation – was higher for 20 mg
rimonabant compared to placebo. Similarly, the incidence of psychiatric adverse events,
neurological adverse events and seizures were consistently higher for 20 mg rimonabant compared to placebo. . ."

They're also concerned about other neurological side effects, and seizures as well. The seizure data don't look nearly as worrisome, except in the obese diabetic patients, for whom everything seems to be amplified. And all of this happens at the 20-mg dose, not at the 5 (which doesn't do much for weight, either, as noted above). And for those who are wondering, yes, on my first pass through the data, I find these statistics much more convincing than I did the ones on the Avandia (rosiglitazone) association with cardiac events.

I had my worries about rimonabant a long time ago, but not for any specific reason. It's just that I used to work on central nervous system drugs, and you have to be ready for anything. Any new CNS mechanism, I figured, might well set off some things that no one was expecting, given how little we understand about that area.

But isn't it good to finally hear what the arguing is about? Sanofi-Aventis has been relentlessly tight-lipped about everything to do with the drug. I can see why, after looking at the FDA documents, but this isn't a problem that's going to go away by not talking about it. The advisory committee meeting is Wednesday. Expect fireworks.

Comments (10) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | The Central Nervous System | Toxicology

May 31, 2007

The Avandia Wars Continue

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Posted by Derek

GlaxoSmithKline is breaking out the data to respond to the Nissen and Wolski NEJM paper on the possible cardiovascular risks of Avandia (rosiglitazone). In a letter published by The Lancet (PDF), the company's chief medical officer, Ronald Krall, defends the drug (and the company):

"GlaxoSmithKline did similar meta-analyses in 2005 and 2006 and found hazard ratios in the same direction as Nissen and Wolski. However, all these results are highly dependent on the methods used and the studies included, given the small number of events reported. For example, the actual number of myocardial infarctions in the Nissen and Wolski meta-analysis yields a very low frequency of events (0·6%), and the absolute difference in rates of myocardial infarctions between rosiglitazone and controls is less than 0·1%.

These observations support a view expressed by Nissen and Wolski them-selves: “a meta-analysis is always considered less convincing than a large prospective trial designed to assess the outcome of interest.”

He then goes back over the data in the three large trials that bear on the question. Reanalyzed data from the ADOPT study still do not show a statistically meaningful cardiovascular risk for rosiglitazone versus the other two diabetes drugs in the trial (metformin and glibenclamide). (There's no placebo group - this is one of those head-to-head comparisons of a drug versus its strongest competitors, a type of study that some people believe never takes place). The second completed study, DREAM, looked at co-administration of rosiglitazone and the ACE inhibitor ramapril. There were four groups - placebo only, rosi and placebo, ramapril and placebo, and rosi plus ramapril. The first three showed no difference in cardiovascular events, but the last one did, for unknown reasons.

These two studies are in the Nissen/Wolski meta-analysis, of course, but as I noted originally, it was the sum of the smaller studies that gave them their cardiovascular warning. But when the statistically less powerful trials show one thing that isn't borne out by the larger ones, the issue is (at the very least) still in doubt. The letter also points out that the company's database mining of managed-care patients taking rosi has shown no increase in cardiovascular risks.

Other controlled studies are ongoing, the (now highly awaited) RECORD and another one called ACCORD. Both are designed from the start to address cardiovascular outcomes (which are a major complication in diabetic patients). Krall's letter lifts the veil a tiny bit on RECORD, saying that the independent review board has now completed an interim analysis of its cardiovascular data and concluded that the trial should continue. This would not be the case, you'd have to presume, were the numbers to clearly show increased CV deaths in the treatment group.

My take on this is that the company has a pretty strong case so far, certainly strong enough to wait for the ongoing trials to settle the issue. What never fails to disappoint me, though, is the way that stories like this are jammed into ready-made templates. Depending on the editorial writer, the appearance of the NEJM paper became "FDA Corrupt, Broken: Snores While Dangerous Drugs Kill Thousands", or "Giant Drug Company Sells Heart Attack Poison, Doesn't Give Hoot". Or maybe just "Drug Approval System Completely Broken - Again".

Now, Steve Nissen does sound the alarm a lot, but I have no doubt that his intentions are honorable. His paper, to me, was the equivalent of saying "Hey, you people may have a problem here. Did you know that?" GSK's response, then is "Yeah, we've looked at that, too, but we don't see it. Are you sure your numbers are good?" Meanwhile, the studies which should answer the question for good are already years into their runs. If this is our standard for a broken drug approval system, we've certainly become mighty fastidious over the years. For what it's worth, The Lancet agrees.

Comments (11) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | Press Coverage

May 25, 2007

More Avandia, And More on Marketing

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Posted by Derek

Insider, author of the Pharmagossip site, sent along this link to an article on Avandia at the Health Care Renewal site, flagged as "essential reading". After looking it over, I don't think I agree, and I thought it might be worthwhile to explain why.

The HCR piece quotes extensively from this New York Times article, headlined "Years Ago, Agency Was Warned of a Drug's Risks". Its focus is a letter that Dr. John Buse of UNC (now president-elect of the American Diabetes Association) sent to the FDA in 2000 on the possible cardiovascular risks of Avandia. Reading HCR's summary is a somewhat different experience than reading the original article, though - for one thing, you miss out on the part about how even now Dr. Buse isn't calling for Avandia to be be taken off the market. Rather than finding the Nissen New England Journal of Medicine paper to be the smoking gun he's been waiting for, he advocates waiting for the GSK cardiovascular risk study to be completed before making any decisions.

The HCR article has some good points in it, but to my ear they're phrased oddly. For example, it advocates a skeptical attitude toward the marketing claims made by drug companies, which is very good advice. But that's very good advice for evaluating the marketing claims of companies in every other industry, too. They're trying to sell you something. They will present their product in the most favorable light possible, whether that product is a car, a diabetes drug, or a burrito.

And that's the part that drives some people crazy, because it seems wrong to have potential life-saving drugs handled the same way as pickup trucks and enchiladas. They're not, though: the reason we can argue about drug company marketing is that drugs already have something that almost no other product has, which is a body of statistically valid comparison data. No data exist as to the long-term advantages and disadvantages of consuming a given brand of burrito versus its competition or versus an alternative meal. Cars are somewhat more data-rich, thanks to government and insurance company testing, and frequency-of-repair databases like those kept by Consumer Reports. But that's about the highest standard for comparison data outside of the drug industry, and you'll look in vain for P values and other tests of statistical significance, because there aren't any. In short, marketing claims in virtually every other industry can go relatively unchallenged, because there's little to measure them against.

So, that's why one of the things that I dislike about the Health Care Renewal piece is the hand-rubbing now-we've-got-'em tone that I detect in it. You don't have to go far to find it from plenty of other sources, either, which is why people like me are perhaps too touchy on the subject.

Comments (26) + TrackBacks (0) | Category: Cardiovascular Disease | Diabetes and Obesity | Press Coverage | Why Everyone Loves Us

May 24, 2007

Avandia: Trouble or Not?

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Posted by Derek

Steve Nissen has (once again) made waves with an analysis of cardiovascular risk. This time the subject is Avandia (rosiglitazone), a therapy for diabetes that's the oldest PPAR-gamma drug on the market. A meta-analysis of 42 reported clinical trials of the drug led to the conclusion that rosiglitazone is associated with a statistically significant risk of cardiac events.

The similarities to the Vioxx situation are what have made headlines (and what sent GlaxoSmithKline's stock down about 8% on the day the paper was released). But there are some important differences. Merck's ran into the Vioxx numbers in their own clinical data - the arguing has been whether they recognized the effects earlier (or should have), but it was a specific trial of theirs that led to the statistics that sank the drug. A meta-analysis is a much different beast, since you're trying to fit a large number of different trials, run in different ways for different reasons, into the same framework. Not everyone trusts them, even when the analysis is performed by someone as competent as Nissen, who does mention the limitations of the approach in the paper:

"Our study has important limitations. We pooled the results of a group of trials that were not originally intended to explore cardiovascular outcomes. Most trials did not centrally adjudicate cardiovascular outcomes, and the definitions of myocardial infarction were not available. Many of these trials were small and short-term, resulting in few adverse cardiovascular events or deaths. Accordingly, the confidence intervals for the odds ratios for myocardial infarction and death from cardiovascular causes are wide, resulting in considerable uncertainty about the magnitude of the observed hazard. Furthermore, we did not have access to original source data for any of these trials. Thus, we based the analysis on available data from publicly disclosed summaries of events. The lack of availability of source data did not allow the use of more statistically powerful time-to-event analysis. A meta-analysis is always considered less convincing than a large prospective trial designed to assess the outcome of interest."

And that's what's happening here. A number of people at large diabetes treatment centers aren't ready to buy into a cardiovascular risk for Avandia yet, because they're wary of the statistics. There's a large cardiovascular outcome trial of the drug going on now, which won't wrap up until 2009, but several people seem to want to wait for that as a more definitive answer.

If Nissen's data hold up - and statistically, I'm definitely not up to the task of evaluating his approach - then we might be looking at a Vioxx-like risk level. Out of some 14,000 patients on the drug in the various studies, there were 86 heart attacks in the treatment groups, and 72 in the controls. That comes out to be statistically significant, but (as you can see) the problem is that Type II diabetics have a high background rate of CV problems. Looking at Nissen's Table IV, it also seems clear that most of the significance he's found comes from the pooling of the smaller studies. The larger trials are nowhere near as clear-cut, which makes you wonder if this effect is real or an artifact.

I'm certainly not prepared to say one way or another, and I just hope that the ongoing trial settles the question. It's certainly not unreasonable to imagine a PPAR gamma drug having this side effect, but if this were a strong mechanism-based phenomenon the numbers would surely be stronger. If a risk is confirmed, though, we'll then be faced with a risk-benefit question. Does the glycemic control that Avandia provides lead to enough good outcomes to offset any cardiovascular risk over a large population? If you think getting the current numbers is a tough job, wait until you try to work that one out.

Comments (19) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | Toxicology

April 1, 2007

The HDL Compost Pile

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Posted by Derek

There's a good article at Forbeson the various attempts to improve cardiac outcomes by raising HDL levels. Matthew Herper and Robert Langreth round up the latest disappointing results, starting with Pfizer's torcetrapib and going on from there. It isn't an appealing sight.

You'd have thought that raising HDL would be a lot more effective than this, wouldn't you? Think of all the associated evidence that's piled up over the years saying that high HDL levels are cardioprotective. We in the industry have been betting hundreds and hundreds of millions of dollars on the hope that we knew enough to make useful drugs out of this information, and by golly, we appear to have been wrong.

This is just one more example, in what appears to be a literally endless series, of how scientific issues get more complicated the more you learn about them. There is clearly an awful lot that we just don't understand about HDL and cardiac risk, for example. Trying to treat the varying distributions of the many different sorts of HDL particles as if they were all one unit has not been fruitful, to put it mildly, so right in front of us the field divides, branches, and fans out into fuzziness: How many different sorts of HDL are there, and how do we tell them apart? What causes different types to be produced or eliminated? What time scale does this happen on, and how do all these things vary between individuals and populations? What do the various HDL species do, individually and in concert, to affect atherosclerosis and other cardiovascular conditions? How on earth can we come up with drugs to differentiate among them, assuming we ever figure out which ones to go after? We are remarkably far away from answers to any of these questions.

Our business is already dependent to an unnerving degree on rolls of invisible dice. If anyone gets an HDL-directed therapy to work in the next few years, their success will surely have an even greater share of plain good luck in it than usual. We're all going to have to know a lot more about lipoproteins before we can safely reach for our wallets in this area. For now, an awful lot of development money has been irrevocably shredded, and earning it back will be quite the job.

Comments (8) + TrackBacks (0) | Category: Cardiovascular Disease | Drug Development

March 20, 2007

AGI-1067: Dead or Alive?

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Posted by Derek

Pfizer's enormous torcetrapib failure last fall wasn't the only time a company has come to grief in the cardiovascular area, and it's not going to be the last one, either. That's been proven this week by a much smaller company, Atherogenics, and their lead drug, AGI-1067 (partnered with AstraZeneca).

The company is targeting expression of the VCAM-1 protein in blood vessels. That's an immunoglobin that seems to be involved in the adhesion of various blood cell types to the vessel walls, and as such is considered a very interesting target for atherosclerosis. AtheroGenics has been working on a series of drug candidates that interfere with the expression of VCAM-1 (through blocking an oxidative pathway in the endothelial cells) and could thus slow the development of arterial plaques (or reduce the size of plaques that had already formed).

Such is the hope, anyway. AGI-1067 behaved well in animal models, and went through numerous Phase I trials in combination with other cardiovascular agents. That link will also take you through the Phase IIa and IIb trials, which showed some real effects in reduction of plaque volume. Those results led to this Phase III trial (with the acronymn ARISE), which expanded the number and variety of patients while looking at real-world endpoints.

That's just how things should work. You see if the drug is tolerated, alone and with the therapies it's going to be given with. Then you check some primary endpoints, to see if the mechanism you're targeting is really being affected. Finally, you see if that's actually going to do a real number of patients any good: I, II, and III. And, unfortunately, III is where the Atherogenics drug ran into trouble.

They missed their primary endpoint, which was a composite score of cardiovascular adverse events - death, heart attack, stroke, angina, etc. Overall, AGI-1067 was no better than placebo when given along with the standard drugs for this patient population. There's no way to call that good news, and no one's even trying. At the same time, though, the company claims to have seen positive effects in some disease states. What subgroups those are, and how positive those effects were, won't be known until next week's meeting of the American College of Cardiology in New Orleans. It's impossible to say if this is just wishful thinking, or a drug worth salvaging.

That's just what the people at AstraZeneca have to decide. The company's pipeline could use some help (not that this distinguishes them very much these days), so they don't want to walk away from something promising. At the same time, they can't afford to throw good development money after bad, either. But the stakes are much, much higher for AtheroGenics, since this physiological pathway is basically the platform for the entire company. There are doubtless some very difficult and unpleasant meetings in progress, not the tiniest bit of fun for anyone involved. My. . .well, heart, goes out to everyone involved. . .

Comments (7) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development

December 11, 2006

Torcetrapib: The Foil-Lined Hat Perspective

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Posted by Derek

Since I've been getting some more less-than-friendly email from Kevin Trudeau fans recently, I thought I'd take a minute to point out something that may not have been generally appreciated. What does the complete failure of a drug like Pfizer's torcetrapib say about the evil-pharma conspiracy theories that Trudeau and his type like to spin?

I mean, think it through: Pfizer spends hundreds of millions of dollars, only to find that their drug has unexpected toxicity. Not the horrible, chemical-weapon toxicity that the conspiracy mongers talk about, mind you: 11 deaths per thousand versus 6 deaths per thousand. But development stops immediately, as it should, the very day that Pfizer's executives get the news. Two days after trumpeting the compound as the biggest thing in their pipeline, they pull it and walk away from the billions of dollars that could have been.

How, exactly, does this fit the Evil Conspiracy worldview? Isn't this, according to Trudeau, exactly the same as all the other drugs already on the market? Why would a company walk away from all that cash just because of a measly little figure like 5 excess patient deaths per thousand? If you believe Kevin Trudeau, everyone who takes anything is being poisoned already.

I know I'm going to regret making this offer, but here goes: I'd be interested in hearing a Trudeau-ite explain this one to me. If you buy into his story, why any drug ever fails in the clinic must be a real head-scratcher, since you'd think that the Evil Pharma Overlords would be able to hocus the data enough to make any sort of toxic junk look good. And this one must seem especially weird.

So tell me, you folks who are convinced that I and all my colleagues in the drug industry are poisoning the world: why did torcetrapib fail? Ground rules: you have to know what torcetrapib is, and you have to have some basic understanding of what it was (in theory) supposed to do. ("Improve cholesterol to try to prevent heart attacks" is enough of an answer for that one - there's a free one for you). And you have to be able to spell Pfizer, and to have read at least one news story about the drug's demise. Have at it in the comments section.

Comments (55) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Snake Oil

December 6, 2006

Bigger And Greasier

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Posted by Derek

Several people have remarked on how large and greasy a molecule torcetrapib is, and speculated about whether that could have been one of its problems. Now, I have as much dislike of large and greasy molecules as any good medicinal chemist, but somehow I don't think that was the problem here.

For the non-medicinal-chemists, the reason we're suspicious of those things is that the body is suspicious of them, too. There aren't all that many non-peptidic, non-carbohydrate, non-lipid, non-nucleic acid molecules in the body to start with - those categories take care of an awful lot of what's available, and they're all handled by their own special systems. A drug molecule is an interloper right from the start, and living organisms have several mechanisms designed to seek out and destroy anything that isn't on the guest list.

An early line of defense is the gut wall. Molecules that are too large or too hydrophobic won't even get taken up well. The digestive system spends most of its time breaking everything down into small polar building blocks and handing them over to the portal circulation, there to be scrutinized by the liver before heading out into the general circulation. So anything that isn't a small polar building block had better be ready to explain itself. There are dedicated systems that handle absorption of fatty acids and cholesterol, and odds are that they're not going to recognize your greaseball molecule. It's going to have to diffuse in on its own, which puts difficult to define, but nonetheless real limits on its size and polarity.

Then there's that darn liver. It's full of metabolizing enzymes, many of which are basically high-capacity shredding machines with binding sites that are especially excellent for nonpolar molecules. That first-pass metabolism right out of the gut is a real killer, and many good drug candidates don't survive it. For many (most?) others, destruction by liver enzymes is still the main route of clearance.

Finally, hydrophobic drug molecules can end up in places you don't want. The dominant solvent of the body is water, of course, albeit water with a lot of gunk in it. But even at their thickest, biological fluids are a lot more aqueous than not, especially when compared to the kinds of solvents we tend to make our molecules in. A hydrophobic molecule will stick to all sorts of things (like the greasier exposed parts of proteins) rather than wander around in solution, and this can lead to unpredictable behavior (and difficulty getting to the real target).

That last paragraph is the one that could be relevant to torcetrapib's failure. The others had already been looked at, or the drug wouldn't have made it as far as it did. But the problem is that for a target like CETP, a greasy molecule may be the only thing that'll work. After all, if you're trying to mess up a system for moving cholesteryl esters around, your molecule may have to adopt a when-in-Rome level of polarity. The body may be largely polar, but some of the local environments aren't. The challenge is getting to them.

Comments (19) + TrackBacks (0) | Category: Cardiovascular Disease | Drug Development | Pharmacokinetics | Toxicology

December 4, 2006

Too Near the Sun?

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Posted by Derek

One thing that the Pfizer debacle makes you wonder about is: were they trying too hard? Torcetrapib seems to have done a fine job raising HDL on its own - so it was only natural to think of combining it with an LDL-lowering statin. If it turns out, though, that the fatal problems that have turned up were the result of the combination therapy, what then? Will the story be that Pfizer brought the roof down on itself by trying to extend the profitable lifetime of Lipitor?

It turns out that we can answer that question. What if the compound had been developed by a company that didn't have a statin of its own to promote? We don't have to wonder: that's the situation with the Roche/JTT compound. Roche has no statin in its stable. But when you look at the trials they they've been running, well. . .

. . .patients will be randomized to receive either CETP inhibitor (900mg po) or placebo po daily for 24 weeks, with concomitant atorvastatin 10 to 80 mg daily. . .

. . .This study will evaluate the efficacy and safety of three doses of CETP Inhibitor when co-administered with pravastatin. . .

. . .Patients eligible to participate in the extension study will continue on the treatment they were originally assigned to ie CETP inhibitor (900mg po) or placebo daily, with concomitant daily atorvastatin (10 to 80mg po). . .

So why the constant statin drumbeat? There's actually a good reason. As it happens, monotherapy trials of torcetrapib seemed to show that it could lower LDL a bit on its own - but only in patients without high triglycerides. Unfortunately, most of the patient population for the drug has high triglycerides, so there you are. You could always try to make the argument that HDL elevation alone might be beneficial, but no one's quite sure if that would be enough, especially given that lowered LDL has been shown to be beneficial in cardiac outcomes.

Roche, of course, is at the moment just packed with people who'd like to know what (if anything) there is about the statin/CETP combination that could turn awful. I wonder how long it'll be before we find out?

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

December 3, 2006

The Torcetrapib Catastrophe

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Posted by Derek

This is a complete clinical disaster: the world's largest drug company just ditched their potential biggest drug. And this comes two days after a press conference where they talked about how they were planning to submit it for approval within months. Development of torcetrapib, the cholesteryl-ester transfer protein inhibitor designed to raise HDL levels, has been halted. Last week, that sentence would have been the subject of nightmares at Pfizer, but now it's the top of the news. No alarm clock buzz will make it go away. If you're looking for an example of just how difficult drug development is, look no more.

The story broke on Saturday: the 15,000-patient trial that was underway (half on Lipitor, half on Lipitor plus torcetrapib) showed excess deaths in the combination group (82 versus 51). That figure's impossible to ignore or explain away, and now the problem will be to explain what caused it. There are other CETP inhibitors in development, such as JTT-705 (from Japan Tobacco and Roche) and one from Merck as well. Both these companies have just had a tremendous shock, since we don't know (yet) if the patient deaths were due to CETP inhibition itself, the combination of it with the HMG CoA reductase inhibition of the statin, an off-target effect of torcetrapib with the statin, or just an off-target effect of the drug on its own. I'm sure that intense reviews of all the clinical data are going on. Things just got much more complicated.

As for Pfizer, they now have a monstrous hole in their near-term pipeline. Looking back, they've had a terrible run the last couple of years, with a number of promising drugs dropping on them, but nothing compared to this. I don't think anyone's had one to compare with this, at least in terms of the expectations for a drug. I was just talking with some people from the company last week (along with many of my colleagues), looking into employment possibilities. After this, I think we may have to keep moving. I don't think that Pfizer's going to be in the mood for hiring.

Comments (47) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials

December 1, 2006

Pfizer's Sizing

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Posted by Derek

I've been remiss in not commenting on Pfizer's reduction of its sales force. (Back almost two years ago I speculated on why they might (or might not) do such a thing).

The first thing to keep in mind is that even with these layoffs, Pfizer's sales organization still looks like the crowd scene from "Gandhi". They're not giving up their position as a marketing monster - rather, it looks like they've just decided that they could be a somewhat more effective marketing monster if they didn't have their sales reps scraping each other's fenders in physicians' parking lots.

But I have to cheer on any drug company decision that doesn't just involve Getting More Humongous. I've thought for a long time that the Humungous strategy (though initially attractive) has its limits, and that these limits are necessarily hard to discern while you're crossing them. Sales forces scale a lot better than research productivity, but you can go too far even there. Perhaps now we can put a number on it.

Pfizer's going to be an interesting place over the next couple of years. They were out beating the drum for their late-stage pipeline, but the part of it that everyone's watching is torcetrapib, their HDL-elevating compound that they're hoping to sell mostly) in combination with Lipitor. A mighty bolus of clinical data on that combination is coming next spring, and it had better look good. There have been concerns about effects on blood pressure, and no one's going to happy until those are quantified better.

The company's talking about all sorts of restructuring plans, but these will surely be adjusted (for better or worse) based on the torcetrapib situation. For purely selfish reasons, I hope that they don't feel the need to release any research staff any time soon. . .

Comments (11) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease

November 17, 2006

Ah, the Heck With the Error Bars

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Posted by Derek

OK, here's a stumper: are there any anti-inflammatory medications that don't have cardiovascular side effects? Aspirin's GI bleeding effects have been known for decades, various NSAIDs have had warnings turn up over the years, the COX-2 drugs are somewhere over there in that huge cloud of legal and statistical dust, and now a study says that one of the last left standing, naproxen, may have cardiac effects as well.

Or does it? This is an attempt to get some useful data out of a large Celebrex trial, looking to see if it had protective effects against Alzheimer's disease, and the whole thing was stopped early when all the COX-2 cardiovascular risks became an issue. As this article makes clear, Steve Nissen isn't convinced, and he's not a person who keeps his worries about drug safety all bottled up inside. His point is that the trial's statistical validity was ruined by the early halt, and that larger epidemiological studies don't back up its conclusion. I should note that he's now running a massive trial addressing this issue as well.

Contrast that with this quote from one of the new paper's authors:

"Particularly for safety data, 'truth' may come in small doses. We firmly believe that results from trials should be published regardless of the direction, magnitude, or statistical significance of the observed results," said Barbara Martin of the John Hopkins University School of Public Health, who worked on the study.

Let me tell you, that kind of thing makes me very nervous. Regardless of the magnitude or statistical significance? That's not a way to arrive at the truth. That's a tornado passing over a pig farm

Comments (14) + TrackBacks (0) | Category: Cardiovascular Disease | Toxicology

November 14, 2006


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Posted by Derek

Just a few days after I commented on the troubles that Isis Pharmaceuticals has had developing antisense DNA therapies, they've popped up with impressive clinical cardiovascular clinical data. Their latest hope, ISIS 301302, has shown some strong LDL-lowering effects, both as a single agent and in combination with statin therapy.

It's aimed at the production of a key LDL-transporting lipoprotein, apoB-100, which target the company correctly describes as "undruggable" through standard med-chem approaches. Of course, the RNA people are hot on its trail, too (these guys, for example). It's a good opportunity for these approaches, since the protein is of clear biochemical importance, and the site of its synthesis is in the liver and gut wall. Those, of course, are the first tissues that an oral drug sees, and (in the case of many antisense and RNAi attempts) the last ones, too. Going after something that lives there is a good strategy.

On a different topic, welcome more additions to the blogroll, such as Totally Medicinal, a med-chem blogger who's concentrating on the synthetic chemistry end of things. And there's Xcovery, a good kinase-o-centric site for those who can't get enough of 'em.

We now return you to our regularly scheduled site closure, already in progress. I've started a new category, "Closing Time", where my posts on that topic will go. There are a lot of odd blogworthy issues and loose ends associated with shutting down an operation like this. I'll be writing on them in the coming weeks, since many people will (fortunately) not have experienced the process firsthand.

Comments (6) + TrackBacks (0) | Category: Blog Housekeeping | Cardiovascular Disease

October 26, 2006

It Should Work. It Just Doesn't.

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Posted by Derek

The late-stage clinical failure of a small company/big company drug partnership story gets told over and over, and today it was the turn of Renovis and AstraZeneca. Renovis had come up with a candidate (NXY-059) for post-stroke therapy that targeted free-radical oxidative damage. Initial clinical trials were fairly positive, but this latest one, a larger and more rigorous effort, totally failed to demonstrate any benefits for the drug.

They've got plenty of company. I've lost count of the number of neuroprotective drug candidate failures I've heard about during my time in industry. It's humbling, like much of drug discovery is when you look at it closely. I mean, if you get your information from the newspapers or (God help you) television news segments, you'd think that we know just how tissues are damaged after an event like a stroke, which means we know just how to block the process, so all it takes it just sending in some drug to keep it from happening. The folks in the lab coats should be whipping one right out any day now.

Nope. Hasn't worked out. Excitatory glutamate toxicity for example, was all the rage about ten years ago, but a number of Phase II and III wipeouts showed that even if these drugs could work (a big if), they would have to be given very, very quickly, which isn't clinically realistic. Since that run of failures, a new set of standards were developed to try to improve the quality of clinical candidates and trials in the field. The Renovis drug is one of the first to come in under those criteria, but little good did they do in this case. Neuroprotection is hard.

Comments (6) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | The Central Nervous System

September 4, 2006

Plavix Plot Twists

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Posted by Derek

The mighty Plavix battle has taken another unexpected twist. In the last installment, Canadian generic company Apotex had snookered (a completely accurate description) Bristol-Meyers Squibb and Sanofi/Aventis into an ill-advised agreement that ended up destroying the drug's patent protection. Apotex had begun gleefully shipping their generic, while the two larger companies sought relief in court from what appears to have been largely a problem of their own making.

To my surprise, that relief has been granted. Last week, a judge issued an injunction against further sales by Apotex in the U.S. until the patent infringement trial is completed. That's not even going to begin until early next year, and you can be sure that BMS and S-A are going to drag it out as much as possible. No legal bills can compare with the hit they've taken over generic Plavix. Sanofi-Aventis, for example, has lowered its profit forecast to a 2% increase over last year, instead of 12%, claiming that Apotex has clogged up all the distribution channels with their generic. I'm a little sceptical of the size of that effect - it's not unheard of for companies to unload other types of bad news under a convenient banner, given the chance - but there's no doubt that it's been a nasty experience.

Apotex may have just had its moment of glory, at least as far as Plavix is concerned. I'm sure that they made money during this adventure, so if they were going to lose the patent case anyway, they're still ahead. No doubt they'd have been even happier to go on selling it, but they'll take what they can get.

Meanwhile, the Federal Trade Commission is making threatening noises about investigating other pay-the-generic-to-go-away deals. The courts have ruled that such deals are legal if they don't push past the patent expiration of the drug, so I'm not sure what the FTC is going to be able to do. But they're clearly unhappy about the situation. For my part, I'd as soon see the generic companies go ahead and challenge the patent-holding ones, as long as the decisions are made in a competent legal venue. By which I mean, not like the one that upheld Ariad's patent. Keeping everyone on their toes is a good thing, as long as it's done fairly.

Comments (10) + TrackBacks (0) | Category: Cardiovascular Disease | Patents and IP

September 1, 2006

Merck: Unfigure-outable

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Posted by Derek

So, how are things going with the Merck/Vioxx situation? Short answer: confusingly. Earlier this month, Merck's winning verdict from last November was thrown out, and the whole case will have to be retried next year. To balance that out a bit, this week one of the company's big losses had its $51 million dollar award overturned - the judge says that Merck is still liable, but that the award was "grossly excessive".

To add to the uncertainty, another Merck loss in RioGrande City, Texas is coming under scrutiny. Today's Wall Street Journal has a front-page article (subscription link) reporting that one of the jurors in that trial had a history of borrowing money (thousands of dollars worth) from the plaintiff, a fact that certainly didn't come out during the voir dire. Merck, needless to say, is looking into having this verdict thrown out as well.

All this makes it impossible to say just what's happening. The reversals (and coming re-reversals, for all I know) just make it even harder to grasp. Even without these backtracks, the whole business is moving on a slower-than-human-attention-span time scale, which is the problem with a lot of important issues. Watching grass grow and paint dry can actually be very useful, but we're not equipped to do it very well.

For the time being, anyway, the flood of damaging information and bad decisions coming from Merck's side seems to have receded, perhaps because there wasn't much left to accomplish in that line. Interestingly, if you were a Merck shareholder before the Vioxx disaster hit, you're still underwater - but if you bought afterwards, you've done extremely well. This seems to reflect (understandable) panic at first, followed by relief that the company was capable of winning a case or two and not immediately disappearing beneath the flood waters. But if we're going to try every case at least twice, I don't see the stock making much headway for a while.

Comments (3) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Toxicology

August 10, 2006

The Great Plavix Disaster

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Posted by Derek

I've been remiss in not covering the Plavix situation, which is quite a story. The huge-selling anticoagulant is marketed in the US by Bristol-Meyers Squibb and in the rest of the world by Sanofi-Aventis. It's been the target of the Canadian generic firm Apotex, who've maintained that key parts of its patent coverage are invalid. They won the right from the FDA back in January to sell their generic form - but keep in mind that the FDA is not concerned with patent law, only the drug's manufacturing standards and identity with the original version.

The company was in the middle of their patent suit with BMS and S-A, and were holding back to see how that would go. In March, though, a deal was cut: Apotex agreed to wait until 2011, the lifetime of the (unchallenged) patent, and in return they got paid by the larger firms and received a guarantee that they wouldn't be undercut until then.

Paying generic firms to go away is not unheard of, but companies can put themselves at risk when such deals are made too blatantly. This one fell apart, big-time, last month. Not only was it rejected by various state attorneys-general, but a criminal investigation was launched into the whole matter.

The ceiling tiles really began to rain down at that point. There was a clause in the agreement that if the deal didn't go through, Apotex could start selling its generic version with five days notice, and that's exactly what they've started doing as of earlier this week. The generic isn't all that much cheaper, but it's enough to torpedo the branded version.

What's more, it appears that BMS and Sanofi-Aventis limited their potential recourse. Under the usual rules, they'd be able to sue and obtain triple damages if they won, but they seem to have waived that right, along with several others. This would seem to be an indicator of just how much they wanted to keep the generic off the market, and how hard a bargain Apotex drove. It's enough to make you wonder if Apotex factored in, up front, the chance of the whole thing being rejected and decided to give their rivals enough rope with which to hang themselves.

Update: as pointed out in the comments, the CEO of Apotex is making it sound like that was exactly the plan. Perhaps he's laying it on a bit thick, but he's in a position to, isn't he?

Shares of both Bristol-Meyers Squibb and Sanofi-Aventis took a fine hammering, as you can well imagine, since Plavix represents about 30% of BMS's profits. (Here's a read-'em-and-weep chart). Apotex is privately held, which is a shame in a way, because it would have been something to see what the trading in their stock would have been like. Sanofi may try to obtain an injunction to stop the generic sales, but no one seems to think that it will be granted - partly because of all those Apotex-favoring terms that the companies agreed to originally.

It's difficult to see how this could have worked out more horribly for the two big companies here: their best-selling drug is under attack five years early, they've signed away their rights to do much about it, the analysts are downgrading their stock and the financial rating agencies are looking at lowering their credit ratings, and the criminal investigation is rolling right along. Short of a meteor strike or a plague of frogs, I'm not sure what else could go wrong. And the worst part is, they brought it on themselves. Their patent position should have been stronger in the first place to protect a compound of this importance, and they shouldn't have pushed the envelope so much with their go-away payments to Apotex. It didn't have to be this way. Did it?

Comments (37) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Patents and IP | The Dark Side

July 26, 2006

Pfizer Recalculates

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Posted by Derek

That Pfizer article I was blogging about yesterday made much of their new HDL-raising therapy, torcetrapib, and the company's plans to only sell it as a combination therapy with Lipitor. That's been a controversial idea, naturally, given the number of people (and the number of insurance companies) who would rather be able to take it alone or with the statin of their choice.

But according to today's New York Times, Pfizer has dropped the idea. Torcetrapib (I await announcement of its brand name, so I don't have to type that) will be available alone as well as in combination.

The drug is an inhibitor of cholesteryl ester transfer protein, CETP, which is mostly bound to HDL particles in the blood. It spends its days shuffling cholesteryl esters and triglycerides among different lipoproteins, generally evening things out among the various lipoprotein fractions. But cholesteryl esters mostly come in as a component of HDL, so the overall effect of CETP is to transfer the cholesterol compounds away from HDL to LDL and other fractions. (Triglycerides, for their part, tend to be moved in the opposite direction). If you could inhibit CETP, the HDL-bound fraction of total cholesterol should increase, and that it does. And since it's been known for some time that loss-of-function mutations in CETP seem to be cardioprotective, the mechanism seems pretty sound. The drug is expected to be huge.

So why did Pfizer about-face? The Times article quotes a Pfizer official as saying that all the criticism was certainly a factor - "We didn't appreciate how this would be perceived", he said. That sounds rather unlikely to me, given that a child of ten would have been able to immediately appreciate how Pfizer's bundling strategy would be perceived. No, I think it's time to apply my general rule that most questions that start with "I wonder how come they. . ." can be answered by "money".

In this case, it may well have been some advance pushback from the various managed-health organizations. Everyone involved knows that this is about the time a decision would have to be made on whether torcetrapib would be sold solo or not, given the regulatory and manufacturing lead times, and I'm sure some strong opinions on the subject were quietly exchanged. Like any other company, Pfizer does nothing, or at least tries to do nothing, that is not in the best interest of Pfizer, and they've no doubt decided that bad publicity is one thing, but putting a possible limit on their new drug's sales potential is quite another.

Comments (3) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease

July 5, 2006

More Statin Skirmishing

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Posted by Derek

The word today is that AstraZeneca and Abbott are going to combine two of their cardiovascular therapies. Crestor, AZ's statin, and a new fibrate, the successor to Abbott's TriCor, will be sold as a single pill. Its name will, I feel sure, end in "-or". This is part of the next wave of cholesterol drugs (and drug mixtures), which are aiming to simultaneously lower LDL (via the statin) and raise HDL (the fibrate's contribution, in this case). A number of other "statin-plus-something-to-raise-HDL" projects are in the works (including a bet-hedging one from AstraZeneca with a totally different drug candidate from a small company called Atherogeneix).

As for these two components, Crestor is a powerful statin indeed, bordering perhaps on too powerful, and if it's possible to describe a billion-dollar drug has having disappointing sales, this is the one. (After all, if you listened to the analysts back before it was introduced, it was supposed to be selling three times that amount by now). And TriCor is a fibrate, one of a mechanistically baffling class of lipid-modifying drugs which have been in use for quite a while now. If you look through the literature, particularly in patent claims, you can see that the idea of combining statins and fibrates has been proposed many times before. It's a sensible combination, although (as with many of these ideas) it's something that you could probably also achieve by taking two separate medications. It would be interesting to know how many people are doing just that at present.

Another thing that would be worth knowing is how well this idea works with Abbott's next-generation fibrate compared to generic fenofibrate, and how well either one would work when combined with, say, generic simvastatin (Zocor) instead of (on-patent) Crestor. That's the flip side of these combination therapies - the insurance companies start to wonder if they can assemble the same sort of thing for a much lower price, and who can blame them? Of course, all this has already occurred to the various companies involved, who will be working hard to show that a single pill is better - that the dosing schedule makes a difference, that patient compliance is better, and so on. Everyone in this field is making sure not to miss any tricks.

AstraZeneca, for example, has been watching Merck and Schering-Plough do well with Vytorin, the combination of Zocor and the cholesterol absorption blocker Zetia, so they ran a trial of their own - Crestor and Zetia. That seems to have done very well indeed, although (as that Matthew Herper Forbes article points out), this was an open-label trial in patients with very high cholesterol numbers to start with.

But A-Z might find themselves arguing that patients should definitely go with a single pill when it's Crestor and the Abbott drug, oh yes, but to feel free to mix and match Crestor with Zetia. That'll be an interesting pitch. And things are just going to get more complicated as time goes on in this area. (Money will do that). But don't forget, the reason that there's so much money involved is that there are a lot of therapies that seem to have value. So it's nerve-wracking (but profitable) to be a drug company in this area, and it's tough to be an insurance company. But if you're a patient, well, it's not as bad as it used to be. . .

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

June 26, 2006

Vioxx: 18 Months to Trouble?

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Posted by Derek

The latest round in the fit-to-never-end saga of the Vioxx APPROVe trial and the New England Journal of Medicine is here. The journal today released a correction of the orginal paper, perspective article on the statistics of the original study, and some inconclusive correspondence about the (recalculated) risks.

The correction is notable for removing the earlier statements that it appears to take 18 months for risk to develop in the study's Vioxx patient group. And since Merck's made a big deal out of that timing, this has already become the headline story. (I can recommend this overview by Matthew Herper at Forbes).

The perspective article, by Stephen Lagakos of Harvard, may be fairly heavy going for someone who doesn't who isn't statistically inclined. I include in that group - please correct me if I'm wrong here - the great majority of newspaper reporters who might be covering the issue (Herper and a few others excepted). I'm no statistician myself, but I spend more time with the subject than most people do, so I'll extract some highlights from Lagakos's piece.

He has a useful figure where he looks at the two incidence curves for the Vioxx and placebo groups. These are the curves that have been the source of so much controversy: whether or not there was an increased risk after 18 months of Vioxx therapy or not, or if the risk was clear from the outset, and so on. As Lagakos points out, in a slap at Merck's public treatment of the graphs:

"It may then be of interest to assess how the cumulative incidence curves might plausibly differ over time. Doing so by means of post hoc analyses based on visual inspection of the shapes of the Kaplan-Meier curves for the treatment groups can be misleading and should be avoided. A better approach is to create a confidence band for the difference between the cumulative incidence curves in the treatment and placebo groups - that is, for the excess risk in the treatment group."

He does just that, at the 95% confidence level. What it shows is that well past the disputed 18-month point, the 95% confidence band still contains the 0% difference line, and there's room around it on both sides. As he summarizes it:

"The graph shows that there are many plausible differences, including a separation of the curves at times both before and after 18 months, and a consistently higher or lower cumulative incidence in the rofecoxib group, relative to the placebo group, before 18 months."

In other words, the data don't really add much support to anyone's definitive statements about Vioxx risks before 18 months. The 95% band only widens out to a plus or minus 1% difference in cumulative incidence rates at a time between 18 and 24 months. At that point, the upper and lower bounds are both creeping up, though, but the band only rises to an all-positive difference between the two groups at the 30-month mark. By the 36-month point, the last in the study, the 95% confidence band is between a 1% and a 4.5% risk difference for Vioxx therapy compared to placebo.

This doesn't help Merck - in fact, since they've made such a lot of noise about this 18-month threshold, it does them quite a bit of damage. But it doesn't directly help the plaintiffs who are suing them, either - the good news for them is that Merck is looking bad again.

Lagakos goes on to talk about what these demonstrated long-term risks can tell us about short-term ones. Assuming that the risk for, say, 12 months of Vioxx is somewhere between the placebo group and the 36-month figure (a reasonable assumption), these figures will set the upper and lower bounds. The most optimistic outcome, then, is that 12 months of Vioxx does nothing to you at all, compared to placebo, even after another two years of observation. And the most pessimistic outcome is that the Vioxx you took continues to increase your risk the same as if you'd been taking it the whole three years (a damage-is-already-done scenario). Although Lagakos doesn't name these as such, you could call these two boundries the Merck line and the Trial Lawyer line, because they correspond to what each side would fervently like to believe is true.

Combining this with his 95% confidence band plot, you end up with a figure that shows that, within 95% confidence, the excess risk for a 12-month treatment could still range anywhere from zero up to the worst that was seen in the full-term-treatment group. So, because this range still includes the no-effect outcome, you can't conclude that a shorter course of Vioxx was harmful. But because it includes the data of the out-to-three-year group, you can't conclude it's safe, either. And that's really the best you can do. If you're not willing to make those starting assumptions, you can't really say anything about the shorter courses of treatment at all.

This is, I think, a valid way of looking at the controversy, but in the end, it's not going to satisfy anyone. It makes me think that both Merck and the lawyers going after them will either: (a) pick their favorite sections from this article and beat each other with them like pig bladders, or (b) ignore it completely. (I think that the first one is already happening, with the advantage, for now, to the lawyers). If Merck can make a successful counterattack that the data don't show that Vioxx was harmful for shorter doses, either, perhaps they can get something out of this. That depends, of course, on people believing a single word that they say. Which they're making more difficult all the time.

Comments (17) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology

May 31, 2006

As Merck Caroms Off Another Tree

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Posted by Derek

You have to figure that Merck is getting tired of restating and re-explaining its Vioxx numbers. I certainly am. The only people who aren't fed up with it, I'm sure, are the hordes of lawyers for the plaintiffs. They're munching popcorn and waving pom-poms as Merck staggers around in circles.

The latest episode is a statistical mixup of the APPROVe trial, which I last wrote about here. In the NEJM publication of the results and in Merck's submission of the data to the FDA, they mention using log(time) as a variable in their primary statistical method. But they report statistical tests in the paper which used a model with plain old linear time as a variable. Merck says that "The results of diagnostic steps specified in that data analysis plan indicate that the linear test is an appropriate method to assess changes in the relative risk over time", although they'd surely rather not have to backtrack and make that argument.

This issue affects the measurement of the change in relative risk over time, not the magnitude of the risk itself. Merck's taking pains to point out that the overall magnitude of those relative risks were described correctly. That's fine, I guess, as far as it goes. The problem is, Merck has already been making a big deal out of that change in risk with time, namely that patients weren't at risk unless they'd been taking Vioxx for at least 18 months. So this is, unfortunately for them, a relevant issue.

What's the difference come to? For the difference between risk levels before and after the 18-month threshold, Merck reported a p-value of 0.01 using linear time, but if you run the method the way it's actually outlined in the paper (log time), you get p = 0.07, which is certainly worse. In fact, in my experience, you start losing your audience at p values of 0.03 or 0.05, and that's what seems to be happening. When Merck says that this error does not affect the conclusions of the study, they're only partly correct. What it affects are the believability of the conclusions, and once again, the revision makes things look worse for them.

Honestly, guys. What's with you these days?

Comments (3) + TrackBacks (0) | Category: Cardiovascular Disease

May 22, 2006

Merck and the Numbers

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Posted by Derek

The New York Times has a good article today on the Vioxx data that I was talking about here last week. Check the graphic of the Kaplan-Meier charts especially; it's a good illustration of the problem. Merck is technically correct that the latest data still don't show a statistically meaningful difference between the Vioxx group and placebo until at least 18 months. As the article makes clear, they're hitting that theme very hard.

But Merck is also living in a dream world if they think that's going to help them much at this point. The problem is, the data look as if they're trending worse from a much earlier stage, and finally reach significance at the later time points. No lawyer in the world is going to walk away from that without driving it into the jury's heads that the danger is plain to see, yes, right there from the beginning, and don't talk to me about p-values when anyone can just look at this chart - your chart! - and see what's really going on. . .etc. We live by statistical arguments in the drug industry, but the people who are being called to jury duty sure don't. If I were one of the plaintiff's attorneys, I'd use the voir dire to make sure that anyone who knew anything about statistics never saw the inside of the jury box.

What's worse, to nonscientists, making statistics the centerpiece of your defense sounds shifty. People don't trust them; it's not for nothing that there are all those variously attributed quotations about "Lies, damned lies, and statistics". Now, if someone asks "Why are you so sure?" about something where I work, the answer "p less than point-oh-oh-five" will stop the questioner in their tracks. Not so in most workplaces, where that answer would make you sound as if you're dodging the question. And let's face it, the only p-values that strong that Merck can show are the ones that work against them.

The other problem is that a statistical approach is valid for large samples, the larger the better. But the jury isn't looking at a large sample. They're not there to decide how much Vioxx might have raised aggregate cardiovascular risk in certain subgroups, they're there to decide if it caused a heart attack in that guy sitting over there. The attorneys are going to keep things as personal as possible.

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

May 17, 2006

Merck's Latest Underwhelming Data

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Posted by Derek

I mentioned yesterday that my opinion of Merck and their handling of the Vioxx cases isn't very high these days. The reason for this is the press release that the company sent out a few days ago on follow-up data to the APPROVe study, which is the one that caused the company to withdraw Vioxx in the first place.

That study was looking at possible use of Vioxx for the prevention of precancerous colon polyps. That may sound slightly insane if you're not following the field, but there's some biochemical rationale that suggests a role for inhibition of COX-2 against colon cancer. (This would be another huge market, naturally, which is why Merck - and Pfizer - have both looked into it). As the world knows, the study also showed clear evidence of an increased cardiovascular risk after 18 months of Vioxx use., and that's what started us all on the bumpy road to where we are today.

The APPROVe study was designed to have a one-year follow-up period to evaluate how long any colon-related benefits persisted. Unfortunately, it wasn't really designed (or powered, as the clinicians say) to address cardiovascular safety, so everyone just has to take what they can from the data we have. Merck, naturally, takes the current data to mean that Vioxx is doing just fine. They point out that in the post-drug follow-up year, the cardiovascular risk for the group that was taking Vioxx doesn't seem to be statistically different from the group that had been taking placebo.

Which is fine, as far as it goes. A more objective look at the data, though, show that they didn't miss statistical significance by all that much. The numbers seem to be all against Vioxx, which is enough to make you wonder if the lights would have truly flashed red in a more statistically appropriate study. As it is, Merck is in the position of saying that a study which wasn't expected to show a statistical difference between Vioxx and placebo heart safety didn't show a difference - and that that's good news.

Even if the numbers had gone the company's way, statistical arguments are a notoriously hard sell for the defense in front of a jury. Having a bunch of muddy but trending-ugly data is one of the worst things that could have happened to Merck, actually. No one knows, from these numbers, just when the effect of Vioxx on cardiovascular risk might wear off. It's a playground for the lawyers - can't you just hear it? "Isn't it true that more patients had heart attacks on Vioxx? Even during the year after they'd stopped taking the drug? No, no, I didn't ask you for a lesson in statistics - just tell me if more people had heart attacks or not!"

No, no courtroom help there. I hope, for Merck's sake, that no one at the company believes there is, and that no one's charging them by the hour to try to convince them otherwise. At this point, they're going to need something better, and I'm not sure where they're going to get it. It's past the time when we can usefully argue about whether Vioxx should have been withdrawn, about what its risk-benefit ratio is, and whether Merck should be facing thousands of lawsuits or not. They are, and more than this latest batch of data will be needed to fight them.

(See also Jim Hu's comments).

Update: According to today's WSJ, things have gotten even muddier. Here's the subscriber link, and this is a Reuters summary.

Comments (11) + TrackBacks (0) | Category: Cardiovascular Disease | Toxicology

May 16, 2006

The New England Journal And Its PR Flacks

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Posted by Derek

The Wall Street Journal ran an interesting article by David Armstrong the other day on the New England Journal of Medicine and the Merck/Vioxx affair. It's subscriber-only on the WSJ site, but the Pittsburgh Post-Gazette picked it up here. It brings up an angle that I hadn't completely considered:

While Merck has taken the brunt of criticism in the affair, the New England Journal's role in the Vioxx debacle has received little attention. The journal is the most-cited medical publication in the world, and its November 2000 article on Vioxx was a major marketing tool for Merck. . .Internal emails show the New England Journal's expression of concern was timed to divert attention from a deposition in which Executive Editor Gregory Curfman made potentially damaging admissions about the journal's handling of the Vioxx study. In the deposition, part of the Vioxx litigation, Dr. Curfman acknowledged that lax editing might have helped the authors make misleading claims in the article. He said the journal sold more than 900,000 reprints of the article, bringing in at least $697,000 in revenue. Merck says it bought most of the reprints.

The article goes on to detail the role of a public relations consultant in the release and timing of the "Expression of Concern", which I've expressed my own concerns about. The journal seems to have been worried about its own name, and seeking to put the focus back on Merck. And some of these efforts may have gone a bit over the line. Remember the infamous missing data?

Perhaps the most sensational allegation in the journal's expression of concern was that the authors of the November 2000 article deleted heart-related safety data from a draft just two days before submitting it to the journal for publication. The journal said it was able to detect this by examining a computer disk submitted with the manuscript.

The statement was ambiguous about what data the authors deleted, hinting that serious scientific misconduct was involved. "Taken together, these inaccuracies and deletions call into question the integrity of the data," the editors wrote.

In reality, the last-minute changes to the manuscript were less significant. One of the "deleted" items was a blank table that never had any data in it in article manuscripts. Also deleted was the number of heart attacks suffered by Vioxx users in the trial -- 17. However, in place of the number the authors inserted the percentage of patients who suffered heart attacks. Using that percentage (0.4 percent) and the total number of Vioxx users given in the article (4,047), any reader could roughly calculate the heart-attack number. . .

. . .Many news organizations, including The Wall Street Journal, misunderstood the ambiguous language and incorrectly reported that the deleted data were the extra three heart attacks -- which, if true, would have reflected badly on Merck. The New England Journal says it didn't attempt to have these mistakes corrected.

So, the matter of the missing heart attacks, which was the subject of a lot of heated language around here, appears to be closed. This sheds an interesting light on last December's "reaffirmation" of concern, where the NEJM made so much of the heart attack data and how it should have been included. Just about everyone who read that came away thinking that the whole fuss was about the deletion of the three MI events in the Vioxx treatment group. As you'll see from the comments to that post, many of us spent our time arguing about whether they should have been included or not, what the clinical cutoff date was, and so on.

We could have saved our breath. The heart attacks weren't deleted from the manuscript, and those who thought that they had been were responding to a well-thought-out public relations campaign. My opinion of the NEJM is not being enhanced by these revelations, let me tell you.

Problem is, my opinion of Merck isn't at its highest level these days, either. More on that tomorrow. . .

Comments (10) + TrackBacks (2) | Category: Cardiovascular Disease | The Dark Side | The Scientific Literature | Toxicology

April 24, 2006

Merck, So Far

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Posted by Derek

So Merck's now gone 3 and 3 in Vioxx litigation. That's a preliminary count, of course, because they're appealing all the cases they've lost. For the same reason, a total of the damages against them doesn't mean very much, either. Does that leave any way to tell how things are going?

Well, you can be sure that with ten thousand or so suits that have been filed against the company so far, that the eventual record is not going to be five thousand up and five thousand down. These things don't take place independently, and there's eventually going to be a run to one side or the other. If Merck starts knocking down some more cases, that'll gradually increase the pressure for settlements in many of the remaining cases (and many others will just evaporate). But if they hit a big losing streak, not only will the existing plaintiffs and their lawyers be more motivated to hang in there, but even more cases will condense out of the vapor phase.

This last loss wasn't a good one to take, since the late defendant was overweight, smoked, had had bypass surgery and took Vioxx (at least as far as his medical records show) for all of seven days. Merck says that this verdict was an aberration which will be reversed. They'd better hope so.

So far, unless I'm quite mistaken, they haven't settled with anyone yet, and they're vowing to take on everyone in court. For that to work, I think that they're going to have to do better than 0.500. If they don't the problem will be keeping the tide from coming in while the appeals process goes on, a process which will start to resemble the Red Queen's race from Lewis Carroll. Even people who think that Merck will come out of this (and I'm one, most days) see the cost to them being around ten billion.

Which is certainly a fine use of the money, isn't it? You could probably discover a drug or two with ten billion dollars, wouldn't you think? But why do that, when you can give it to the lawyers?

Update: a similar analysis from John Simons at Fortune, who says that Merck's only choice is to fight every case.

Comments (23) + TrackBacks (0) | Category: Cardiovascular Disease

March 21, 2006

Nitromed's Slow Decline

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Posted by Derek

Nitromed is a company whose fame, such as it is, comes from the controversy over BiDil (which I wrote about here. It's a mixture of two generic hypertension drugs which more or less flunked the main parts of its original clinical trial, except in the cohort of black patients. You can get burned by subgroup analysis, but Nitromed persevered and last summer won approval for what was probably the first race-based pharmaceutical.

The problem is, it's expensive to launch and promote a drug all by yourself, and BiDil turned out not to sell the way that optimists both outside and inside the company had hoped. The company has had a hard time convincing health insurance organizations to pay for the drug, and they've made noises about how their contract sales force hasn't performed up to expectations. Nitromed hasn't made a dime of profit since BiDil came on the market. The stock was at about 19 when the FDA approved the drug late last June, and rose as high as 24 and change a month or so later. Since then, though, it's been a long, slow slide downhill. (Try Google's new finance section for a neat chart). One wonders if they were able to unload a proposed stock sale back in January at their planned price or not.

Today came the abrupt word that the company's CEO and CFO have resigned, no reasons given. But no reasons had to be, did they? The stock's been rising a bit, apparently from bottom-fishers hoping for a takeover. But who's going to do that? BiDil really doesn't look like a winner so far, and I don't think the company has all that much more to offer besides hopes and dreams. Doubtless many of these research areas took a hit while all the money was spent launching BiDil . If the company has anything else ready for the clinic, I sure haven't heard about it, and the way that web page trumpets their IP rights isn't a good sign. If there were anything else to brag about, that wouldn't be the headline, would it?

Nitromed reminds me of the old story about the fellow who lost three cars playing poker and drawing to inside straights. He lost the first two by not filling his hand - and lost the third one by making the straight. Getting BiDil to the market may have been the company's biggest mistake.

Comments (12) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease

March 13, 2006

The Big Statin Pillow Fight

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Posted by Derek

The American College of Cardiology meeting in Atlanta is the source of all those news headlines today on cholesterol-lowering drugs. It can hard to make sense of all the studies that are being reported - my favorite confused headline so far is "Merck Says Vytorin Beats Zocor", to which the appropriate response is "It had damn well better". Beating Zocor is the whole reason that Vytorin exists, since it's Zocor (simvastatin) plus Schering-Plough's dietary cholesterol absorption inhibitor Zetia (ezetimibe).

The cholesterol-lowering market has long been vicious, but it's getting more so. There's a simple reason: Zocor's going generic this summer. Many managed-care organizations are looking forward to moving patients to the new, cheaper statin as soon as that happens, and companies are trying to come up with reasons to keep that from happening. Merck needs to show that they've got something better than their old drug, and other companies with their still-patented statins want to show that they do more than the generic will, too.

Thus AstraZeneca's big splash with their results for Crestor (rosuvastatin), where they showed arterial plaques actually reversing and getting smaller. I realize that drug-company-sponsored results aren't exactly in the highest standing these days. But the lead investigator on this study was Steve Nissen of the Cleveland Clinic, who is not exactly a tool of the drug industry, unless someone's updated the master list without telling me.

And that's clear from his own comments on the results, as opposed to those in the AstraZeneca press release. While impressed with Crestor's efficacy, Nissen did a good job putting things in perspective.

For example, he points out that he doesn't think that much more plaque shrinkage is even theoretically possible - most of the lipid content of the plaques has probably been taken out by this point. And he also mentions that no, this trial wasn't powered to say whether this effect actually improves long-term morbidity and mortality in patients (although you'd have to think it would, at least a little bit). Most tellingly, he makes the observation that everyone else's statins probably do the same thing if dosed to give a similar degree of cholesterol lowering.

AstraZeneca's argument has long been that gosh, nothing can lower cholesterol like Crestor, and I'm sure that much more in this line is coming. And Merck and Schering-Plough will continue to beat the drum for Vytorin, while Pfizer will never be known for their coyness about the benefits of Lipitor. But the Zocor patent expiration is just a coming-attraction trailer for this market. Its run as the cheapest effective statin in town will go on, arguments and advertising blaring all around it, for about three or four more years. And that's when Lipitor starts going off patent. You can bet that studies are already under way to try to show why people shouldn't switch to its generic when the time comes. . .

Comments (7) + TrackBacks (1) | Category: Cardiovascular Disease

February 22, 2006

NEJM vs. Its Contributors, Round Two

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Posted by Derek

The original "Expression of Concern" editorial over the VIGOR Vioxx trial in the New England Journal of Medicine was an odd enough document already. But today brought an "Expression of Concern Reaffirmed" in the journal, along with replies from the VIGOR authors.

It's going to take some doing to get these folks together, as you'll see. The NEJM's editors, in their "reaffirmation", add a few details to their December 8th expression. Their position is still that there were three heart attacks in the Vioxx treatment group that were not in the data submitted to the journal. And they're not buying the explanation that these took place after the end of the study, either:

"The authors state that these events did occur during the trial but did not qualify for inclusion in the article because they were reported after a "prespecified cutoff date" for the reporting of cardiovascular events. This date, which the sponsor selected shortly before the trial ended, was one month earlier than the cutoff date for the reporting of adverse gastrointestinal events. This untenable feature of trial design, which inevitably skewed the results, was not disclosed to the editors or the academic authors of the study."

Those academic authors (11 of them from seven different countries, led by Claire Bombardier of Toronto) have a reply to all this in the same issue. Regarding those three MI events, they say:

"The VIGOR study was a double-blind, randomized outcomes study of upper gastrointestinal clinical events. We, as members of the steering committee, approved the study termination date of February 10, 2000, and the cutoff date of March 9, 2000, for reporting of gastrointestinal events to be included in the final analysis. Comparison of cardiovascular events was not a prespecified analysis for the VIGOR study. . .the independent committee charged with overseeing any potential safety concerns recommended to Merck that a data analysis plan be developed for serious cardiovascular events. . .As a result, a cardiovascular data analysis plan was developed by Merck. Merck indicated that they chose the study termination date of February 10, 2000, as the cutoff date. . .to allow sufficient time to adjudicate these events. . . (The three events) were neither in the locked database used in the analysis for the VIGOR paper no known to us during the review process. However, changing the analysis post hoc and after unblinding would not have been appropriate."

The authors go on to say that including the three heart attacks does not, in their view, change the interpretation of the safety data. They also take issue with the journal's contention that the three events were deleted from the manuscript, saying that the table of cardiovascular events in the presubmission draft of the paper never included them in the first place.

The two Merck authors on the paper, in a separate letter, make the same point, and also mention that there was an additional stroke in the naproxen-treated group that didn't make the paper for the same reasons. They reiterate that including the three heart attacks wouldn't have changed anything:

". . .The article clearly disclosed that there was a significant different in the rates of myocardial infarction in the Vioxx and naproxen arms of the study and reported these rates as 0.4 and 0.1, respectively, with a relative risk reported as 0.2. The inclusion of the post-cutoff data myocardial infarctions changes the Vioxx rate to 0.5 but does not meaningfully change the relative risk or the conclusion that there was a significant difference between the two arms of the study. Indeed, with such a small number of events (which were not a primary end point of the study) - and with such wide confidence intervals around them - it is difficult to imagine that this small numerical change could affect the interpretation of the data."

Looking at everything together, I'm still coming down on the side of Merck and their academic collaborators in this part of the fight. The post-launch cardiovascular data on Vioxx and its advertising and promotion are worth debating separately, but as for the VIGOR study, I think the NEJM is overreaching. Still, from Merck's viewpoint, I think the damage has already been done. . .

Update: Y'know, it occurs to me that there are a few people who aren't as upset about all this editorial wrangling: the editors of JAMA and the other top-ranked medical journals. They'll be getting some manuscripts that otherwise would have gone to NEJM.

Comments (25) + TrackBacks (2) | Category: Cardiovascular Disease | The Scientific Literature | Toxicology

January 23, 2006

Merck versus the New England Journal

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Posted by Derek

Tuesday and Wednesday of this week are the days when Merck's attorneys are scheduled to question Dr. Gregory Curfman of the New England Journal of Medicine and another unnamed staffer. The journal's handling of the published Vioxx data (the VIGOR study) looks as if it could be a key part of the next trial, which will be in lawsuit-friendly Rio Grande City, Texas, with jury selection beginning this week. Note that the late plaintiff had taken Vioxx for all of seventeen days.

Naturally, both sides are saying that they expect the facts to help them out. The plaintiffs will argue that the recent editorial in the NEJM confirms that Merck was trying to hide the risks of Vioxx, and Merck will argue. . .well, they might argue several things. For one thing, they'll try to show that the journal's suspicions about altered data are unfounded. But I also have to wonder if my theory from last month is going to get aired out, too. Will Merck's attorneys ask if the journal has been approached by representatives of the plaintiffs?

We'll have to wait until the the next trial to see if any of this makes it into the courtroom. For now, I think it's interesting and unusual enough for Merck to be putting a journal editor under oath. They must feel as if they've got a pretty good reason for doing it. And they'd better. . .

For pre-trail reading, here's a law professor from Fordham who says the whole spectacle isn't making our liability law system look very good.

Comments (4) + TrackBacks (1) | Category: Cardiovascular Disease

December 20, 2005

Does Celebrex Have A Future At All?

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Posted by Derek

I have a correspondent who's written me a few times about the Vioxx/Celebrex/NEJM situation, and I thought I'd pass along some of his thoughts. He's not buying my idea that the New England Journal is worried about being sued, for one thing. As he points out, the various liability battles that have taken place over the last twenty years also have had potential for that sort of thing, and no one's done it yet.

And as for Pfizer's big Celebrex trial, he regards it as four years worth of lawsuit insurance, and cheap at the price. That's a reasonable idea, unfortunately, but I wonder if that would slow down a sufficiently motivated member of the plaintiff's bar. After all, they could make the argument that the company clearly had no idea (italics theirs!) if their product posed a cardiovascular risk or not - that's why they had to run a trial, naturally - and meanwhile had recklessly exposed consumers to the dangers of this insufficiently tested drug. . .man, once you start on those italics, it's hard to stop.

However, my correspondent isn't even sure that this is an ethical trial at all. (That Forbes article I linked to the other day had quotes from others raising such concerns). If you believe that COX-2 inhibitors have mechanism-based cardiac risks (a hypothesis publicized best by Garrett Fitzgerald at Penn), then Celebrex isn't going to be able to escape. There's room to argue that the COX-2 drugs don't have as good a gastrointestinal safety profile as had been hoped, either, which would take away another reason for their existence (and another ethical rationale for the new trial). Celebrex had better be good at relieving pain. . .

I should point out that if these effects are real, neither of them are things that would have been obvious earlier in the development of the COX-2 drugs. The rationales for their development were actually quite compelling at the time (just ask the University of Rochester - anyone heard from them recently?) But that's drug development for you. Every single new drug has risks, many of which aren't even known until millions of people take them. Would that it were different, but it isn't.

Comments (4) + TrackBacks (0) | Category: Cardiovascular Disease

December 14, 2005

An Expensive Way Back for Celebrex

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Posted by Derek

Pfizer's going to pull out the stops and spend up to $100 million to try to show that their COX-2 drug Celebrex is worth it. And they're going right to the source: the Cleveland Clinic. The study will be run by Steve Nissen, and he's forbidding the investigators under him from accepting money from all sides: drug companies, securities firms, trial lawyers, the lot. Celebrex will be compared head-to-head in high-cardiac-risk arthritis patients versus naproxen and ibuprofen (no aspirin, because of the near-certainly of bleeding problems at the doses involved).

A disproportionate number of arthritis sufferers are in the higher-risk groups, so this would seem to be an appropriate patient population. They're going to need to round up 20,000 of them, though, which is going to take some time, and the whole study won't finish up until 2009, at the current best guess. (Celebrex doesn't come off patent until 2013, in case you're wondering). I hammer on Pfizer a lot around here, because I think they're too big to be effective as a company. But I have to say that this is one case where being humungous (and, for now, full of cash) is an asset. This is going to be a long a costly trial, and you can count the drug companies capable of funding it on one hand.

Merck's taking a few shots in the press today, since they'd said that a study like this basically couldn't be run. No one would do it unless they felt they had to, that's for sure. But the loss of Vioxx as a competitor may have made this study possible for Pfizer, in that it could allow them to earn back the expense more easily. Celebrex first has to show that it doesn't have the cardiac risks associated with Vioxx (which are tiny, but real). If it doesn't do that, it's dead. But if it makes it past that, and actually works better than the cheaper alternatives, Pfizer will own the market. They'd at worst dominate it over some other COX-2 stragglers like Novartis's Prexige, which I don't think has even been filed for US approval yet. Novartis is on that short list of companies that can afford this kind of clinical expense for a single trial, and they may have to consider doing a big head-to-head with Celebrex if they want to stay in the market. Smaller studies aren't going to cut it in the COX-2 area any more.

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

December 13, 2005

The New England Journal of Legal Immunity?

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Posted by Derek

Why did the New England Journal of Medicine come out with their "expression of concern" last Friday? The more I think about the situation, the more I'm coming to agree with a speculation that I first saw over at Medpundit.

Don't get me wrong: I think Merck had every intention of making their VIGOR data look as good as possible when the study was published. Companies do that, and they should be punished when they push things too far. But if these three MI cases that we're disputing really did occur after the cutoff date for the study, then Merck had every right to exclude them from the data. (They had to be reported to the FDA, though, which is exactly what happened when it came time for approval). So why is the journal so worked up?

I don't know if this was a deliberate attempt (as some have speculated) to affect the outcome of the first Federal Vioxx case (now declared a mistrial). I hope not. But what I do think is that it was an attempt to clear the NEJM as a target of future lawsuits. Look at the sequence of events: the journal discovers the editing discrepency four years ago, but does nothing. Vioxx goes to the FDA for approval, goes on the market, sells in huge amounts, is hit with concerns over cardiac safety, is withdrawn from the market and is the subject of FDA and Congressional hearings. During this whole time, the journal and its editors say. . .nothing. Merck is hit with hundreds, then thousands of lawsuits. The first case goes to trial, and Merck loses with a huge jury award. But they win the second one, as the weeks and months go on. And the New England Journal keeps quiet.

Then the first Federal case starts up, and the journal's editor is brought in to give a deposition. And now the editorial staff springs into action, rushing out an unprecedented comment on a paper from their own journal that manages to publish on a Friday afternoon. All of a sudden, somehow, things couldn't wait.

Could it be that the plaintiff's attorneys, while questioning Gregory Curfman, mentioned that there could be more targets for litigation than just Merck? You run a prestigious journal there. . .probably influenced a lot of physicians to prescribe Vioxx, eh? Didn't see anything odd in the cardiovascular data, you say? Why, that's nearly a tort right there. . . I don't like to think that this is what happened. But it's not impossible, either. The journal's actions look like those of an organization that fears the legal discovery process. And why would you fear that, unless you fear that you'll be sued?

Comments (18) + TrackBacks (1) | Category: Cardiovascular Disease

August 11, 2005

Selectivity: One of Those Flexible Concepts

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Posted by Derek

One of the comments to the last post mentioned that a way to provide the benefits of a combination therapy is to make a drug that hits more than one target. For a while there, this idea was a bit out of fashion, but I think it's been making a comeback.

There are a number of multiple-target drugs on the market already, and the list even includes some where this profile was arrived at deliberately. (That was a joke. I think.) Examples of the planned category include Tracleer (bosentan), a dual endothelin receptor antagonist for pulmonary hypertension, rupatadine, a dual histamine/PAF antagonist for allergy (not yet approved in the US, I think), and Cymbalta (duloxetine), an antidepressant which affects both serotonin and noradrenaline reuptake.

Examples of the non-deliberate class include all sorts of drugs marketed before the 1980s or so. (That's about the time that target-based drug design really took over, as opposed to "see what it does in vivo".) In some therapeutic classes, this is the norm - the activities of CNS drugs in general are known to be extraordinarily messy. The antipsychotics, for example, hit so many receptors that it's basically impossible to figure out just how they work. A more recent example is the cardiovascular drug Pletal (cilostazol), which is both a PDE-III inhibitor and an adenosine uptake inhibitor. Other PDE-III inhibitors didn't work nearly as well, so there was clearly something else pitching in. (There may well be something similar at work with Lipitor, to pick a drug that everyone's actually heard of, although no one's quite sure what the extra activity is.)

There are all sorts of other dual-acting drugs being looked at in earlier phases of development. For the most part, they're going after similar receptor subtypes or related enzymes, since that's where you're most likely to get the cross-reactivity. (A good example would be the PPAR alpha-gamma ligands that many companies have been trying to develop for diabetes.) But the biggest area of multiple-action drugs now is cancer.

You might not know it from reading the popular press, though. A lot of reporters are still a generation behind, going on about the new breed of incredibly selective targeted cancer drugs. Problem is, it's turning out that some of those incredibly selective drugs work only on incredibly small numbers of cancer patients, which is not what everyone had in mind. Over the last few years, efforts have shifted to making drugs that hit a slew of potential cancer targets simultaneously, in hopes that this will show more efficacy, and these are just coming to the FDA now.

Many, many cancer targets are from a large family of broadly similar enzymes (the kinases), so getting multiple activities isn't really all that hard. In fact, getting selective kinase inhibitors was the hard part - looking back, had we but known, we all could have probably skipped that step and gone right to the blunderbusses. But the fear was that these compounds would be too toxic (yeah, even for cancer therapy), so selectivity got priority. Now that it turns out that we don't need to be so picky, it's also becoming clear that the multiple-kinase drugs are tolerated a lot better than we thought. You'll see the word "targeted" thrown around when these agents are discussed, but it should have quotes around it.

Comments (7) + TrackBacks (0) | Category: Cancer | Cardiovascular Disease | Drug Development

July 26, 2005

Merck on Trial

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Posted by Derek

I haven't been talking about the Merck-Vioxx trial, but people are asking me how I think the it's is going. Unfortunately, I have no idea. And, I'd think that most of the people commenting on it in the press have no idea, either, when you get right down to it. All I know about the testimony is what I read in the media, and I'm not willing to accept that data as good enough to use.

The daily reports coming out of Texas are probably about as misleading as a round-by-round commentary of a boxing match. Anyone reporting this story is looking for exciting news, a big quote, a damaging revelation or slip-up. That's what will get the most play, and if there wasn't anything in those categories on a given day, the next best thing will do. A trial is a natural fit for the narrative instincts of most reporters, and that's what the readers expect to see, too.

The similarities to the reporting of an electoral campaign or confirmation hearing should be kept in mind, and a political scandal is the perfect example of the form. Punch! Counterpunch! Attack from the right! Feint from the left! A steady delivery of reasonably sized news chunks keeps the story moving along, the viewers tuned in, and the readers buying papers. Never ignore narrative bias; you're soaking in it.

But, unlike a boxing match, we don't know who's ahead on points so far in the Merck trial. The jury will be influenced by the facts presented to them, but also how they were presented and by whom. All of this will be layered on top of what they already know and the opinions that they already have. I don't presume to know what's going through their minds, because even if I were sitting there in the courtroom with them, I'd surely have a different perspective on the whole matter. If I had to guess, I'd say that Merck has a reasonable chance of getting out of this one. But I'm not putting any money down on that opinion. Merck's got enough on the table for everyone.

Well, fine, you say - but who should win? Grudgingly, I have to admit that I don't know the answer to that one, either. The details of the death in this case aren't all out yet, and I'm not a pathologist. And the details of Merck's internal knowledge and subsequent marketing decisions aren't all out yet, either. I think that their problem was believing what they wanted to believe (a tendency never to be underestimated), but it could end up looking worse (or better) than that.

However, it does seem clear that COX-2 inhibitors have caused, or at least contributed to, some deaths. Balancing those against the benefits they may have had for a much larger group of people is a very difficult calculation, but it's one that you'd have to make before coming to a final judgment on the whole class. The FDA has, of course, decided to leave the drugs on the market, so you know where they finally came down.

But the overmarketing of the drugs (by everyone, not just Merck) is, in the end, how we got into this situation. If COX-2 inhibitors had been prescribed mostly to people who had demonstrated an intolerance to the existing drugs, I doubt if any excess deaths would have been noticeable even had they occurred. (But if that had been the expected market, how many companies would have entered the field at all?)

Things have come to the point where many companies have made the decision not to get involved in huge marketing battles over blockbuster drugs. They're trying to put together a business out of more specialized drugs in less competitive areas, or where there's less direct-to-consumer marketing (which is quite expensive.) The pendulum, perhaps, is swinging back.

Comments (16) + TrackBacks (0) | Category: Cardiovascular Disease

June 30, 2005

Where's the Combo?

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Posted by Derek

Gruntdoc wonders about why a particular combination therapy isn't available yet. Skin infections with methacillin-resistant staphylococcus aureus (MRSA), which I hope I never come any closer to experiencing, are treated with one of several antibiotic combinations, but they're all administered as separate drugs.

The answer is what you might suspect: the FDA would want clinical trials of the single-dose combination, just to make sure that things work the way that they're supposed to. Any company developing the combo would have to recoup those costs, not to mention the costs of then beating the drum for the idea that the new combination is a better idea. But the antibiotics in question are generics, which means that there could be some real cost-containment issues over the use of a more expensive combination.

But we have a rather close example at hand: the recently approve BiDil. (Here's the package insert, in PDF format.) That's a combination of two generics, too, which (famously) shows far better effects in the black population than it did in general clinical trials. Nitromed, the developer of the therapy, had to run some pretty reasonable-sized ones, and they spent a lot of money in the process.

They started by establishing that the blood levels of the two drugs were reasonable when given in combination, and went on to a group of 186 male patients. That trial (with 273 in the placebo group) didn't show a benefit, but hinted at one in the black subjects. The company also ran an 804-patient trial against enalapril, and saw the same trend, which led to the definitive 18-month trial in 518 black patients (with a roughly equal number in the placebo arm.) Keep in mind, this is all for two drugs whose individual efficacy was well-studied.

Note added after original post: Nitromed was after something more than the individual efficacy of each drug. Their hypothesis was that the combination would make the blood-pressure-lowering effect much more pronounced, and that this would translate into clinical benefit as seen in eventual mortality. Why this only seems to be the case in the black population is a head-scratcher. The situation for combination antibiotics would be simpler. So. . .

A combination antibiotic trial wouldn't be as long, or as expensive. But it wouldn't be negligible, either, and it's likely that some companies have run the numbers and decided that the investment would be unlikely to pay off.

Comments (3) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Infectious Diseases

June 6, 2005

A Drug's Target, Finally

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Posted by Derek

Well, a large group from Schering-Plough and Merck have published the definitive paper on the real target of S-P's cholesterol absorption inhibitor, ezetimibe (Zetia), which drug I've spoken about here and here. It's published in the preprint section of the Proceedings of the National Academy of Sciences, which is a pretty nice journal to be in, and (for a number of reasons) not one that drug company research finds its way into all that often.

The drug and its equally active metabolite hit a protein in the intestinal wall called NPC1L1. This was the suspect in the previous publication on this topic, but now they've nailed it down. The authors were able to express the protein in cells and get a radioligand binding assay going for it using the isolated membranes, which turned out to be a pain. Depending on how you prepare the membrane and what detergents you use in the assay, the binding could change by a factor of 5 in what were supposed to be samples of the same thing. Only membranes from the cells that had expressed the protein showed any binding, and this result was extended to whole animals by generating a strain of mice with NPC1L1 knocked out, and intestinal membranes from their cells, in turn, no longer bind ezetimibe at all.

The paper hammers things flat in every direction: a series of ezetimibe analogs that bound with a thousand-fold range of potency on the intestinal membranes showed the same spread when tested in the NPC1L1 expressed-protein binding assay. Interestingly, intestinal membranes from different species showed a wide range of binding behavior, with mouse being the weakest and rhesus monkey by far the strongest, and that exactly parallels the drug's behavior when dosed in these animals. Humans are in the middle, by the way. (I should mention that the best chance to get a correlation this nice is with a drug like ezetimibe, which hardly gets out of the gut at all. Different species can vary so much once a compound gets out into circulation that a direct link to a binding assay is often obscured.)

So, this is the drug's target, beyond doubt. The doubt kicks in very quickly, though, when you ask what NPC1L1 does and why ezetimibe's binding to it blocks cholesterol uptake. The paper advances two hypotheses - that cholesterol binds directly to NPC1L1 - that it's the cholesterol transporter itself. Alternatively, it could be regulating the real transporter, and since Schering-Plough had already investigated a lot of the obvious candidates, that might well be a further unknown protein.

Note how long this all took. Nothing good comes quickly in drug discovery. The first compounds in the ezetimibe series were discovered in 1990/91, and efforts to identify the molecular target went on for many years. How long, you have to wonder, would it have taken to find this important pathway without first finding the compound which illuminated it?

Comments (1) + TrackBacks (0) | Category: Cardiovascular Disease

February 20, 2005

COX-2 Aftermath

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Posted by Derek

Overall, I found the conclusionsn of the FDA's COX-2 committee quite reasonable (and not too far from what I predicted during the day on Friday.) Perhaps their actions will calm things down a bit. After all, they had the chance to bay at the moon, yank everything off the market and call for heads on pikes. But they ended up saying (I'm paraphrasing just a bit): "Y'know, these drugs really do have side effects. But a lot of stuff does. And they do some people some good. Maybe if just the people who really need them take them, things will work themselves out."

This all should make Merck's path forward in their Vioxx lawsuits a little easier. They could still face a punitive-damages avalanche, of course, and a lot of lawyers will be working to get the snowpack loosened up. I assume that the first case will be tried in Mississippi, Texas, or some other jury award paradise - picking the right venue is part of the art.

I'm just glad that the "Toxic drugs! Film at eleven!" momentum has been lost. I think that the industry, the stock market, the public, and (most definitely) the press were really close to panic there for a bit. (Naturally enough, in the last case, since panic sells.) But outside of advertising revenue, it does no one any good. If you make the right decision in that frame of mind, it's generally by accident.

Comments (2) + TrackBacks (0) | Category: Cardiovascular Disease

February 18, 2005

Waiting for the FDA

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Posted by Derek

Well, we're finally coming to the end of the FDA's COX-2 marathon. My predictions will be overtaken by reality soon, but I know that a lot of people are following this, so I'll take a crack at it:

I don't think we're going to see any drugs pulled outright from the US market, but if there is one, it'll probably be Bextra. Assuming it stays on the market, I think that it and Celebrex will pick up additional warnings, along with guidance to prescribe it only to patients who can't tolerate the more traditional anti-inflammatories. The FDA has been trying to do that already, and I think we'll see it emphasized again.

And if those two drugs and Vioxx all suffer from the same risks, which I think is likely the case, then why shouldn't Vioxx come back on the market, as Merck's Peter Kim said the other day? He has a point. After all, the recall was voluntary, not FDA-mandated, and as far as I know, there's nothing keeping Merck from bringing the drug back.

As for Merck's follow-up COX-2 (Arcoxia) and Novartis's Prexige, neither of which is available in the US yet, I think that the FDA will want to see major cardiovascular data. Perhaps they'll let them through, eventually, with the same set of warnings and guidelines I expect to see attached to the current drugs. But if the companies want better terms, they're going to have to show some evidence why they should have them.

So we might end up, after all the mud is washed off the walls, with more COX-2 drugs on the market than we have now. Odd, eh? They'll be fighting inside what's supposed to be (and probably will be, in fact) a smaller market, though. The real financial damage has already been done, because this class of drugs will never be what it was a few months ago. Makes you wonder if a big launch of Arcoxia, et al., is even going to be worth the effort.

Which brings up one more point: in the above, I mentioned prescribing COX-2 drugs "only to patients who can't tolerate the more traditional anti-inflammatories", and I'll bet that many people read that and added ". . .just like they should have all along." And it's true that we probably wouldn't have even seen the cardiovascular side effects in that smaller patient population (nor would we have been bombarded with COX-2 ads, for that matter.)

But that's what companies do - try to broaden their market as much as possible. I think that Merck and Pfizer overdid it in the pain market, true. But keep in mind that some of the bad news about these drugs came from trials of them against other possible targets (colon cancer, for example.) The only way we're going to find out if they work in these indications is to run those trials, and finding bad news instead of good is the risk that we in the industry take. I think it's better to try and lose than to never try. Some may disagree. . .

Comments (4) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Toxicology

December 19, 2004

Boarding Up the Windows

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Posted by Derek

In almost every story about Pfizer's disastrous Friday, you'll find a sentence with this phrase in it: ". . .the company says it has no plans to recall Celebrex. . ." But this statement, taken literally, is surely untrue.

Pfizer definitely does not want to recall Celebrex. They've been in the Red Queen's Race of the pharmaceutical world for a few years now - they have to run as fast as they can to stay in the same place. To me, none of the estimates of how many billion-dollar launches they need have ever seemed attainable, and their method of just going out and buying the biggest drugs they could find has never made sense. Losing Celebrex would put an ugly dent in their strategic plan, even in the eyes of people who believe in it.

Neither do I have enough data to hand (nor, for this kind of decision, enough expertise) to say whether Celebrex even should be recalled. But whether it should or not, I'd say the odds are better than even that it will be. Such is the climate.

And you can be sure that Pfizer has thought about it, about what they'd have to do and how they would do it. You can be sure that someone over in Groton or New London has that job, and you can be equally sure that they didn't get home very much over the weekend. There's a lengthy PowerPoint presentation ready by now that no one wants to deliver. Don't take Pfizer's word for it - there are plans, because there have to be.

Comments (1) + TrackBacks (0) | Category: Cardiovascular Disease

December 17, 2004

The FDA Weighs In

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Posted by Derek

This afternoon the FDA released a statement about the Celebrex news from this morning. This clears things up a bit, but it means that the agency (and Pfizer) have some very hard decisions to make.

There appears to have been a clear dose dependence in the elevated cardiovascular risks. At 400 mg b.i.d. (twice a day), the treatment group showed 3.4 times the risk of the placebo group. At 200 mg b.i.d., the risk was 2.5x. The average duration of treatment was 33 months - pretty substantial, but a lot of people take Celebrex for an extended period for pain relief.

Now, Pfizer has stated that another trial at a similar dose has shown no indication of cardiovascular trouble, and that's true as far as it goes - it's a 400 mg trial, but the drug is dosed q.d. (once a day). How can 400 mg act so differently, taken all at once versus split up? My industry colleagues are already nodding their heads at the probable answer. The difference is coverage.

Coverage, as in how high the blood levels are, for how long - what pharmacologists call AUC (area under the curve) in a blood-level versus time plot. A single 400 mg dose of a typical drug will spike right up as it gets absorbed and hits the bloodstream in a big initial wave, then the line will decay down over several hours, eventually back to uselessly low levels. Ideally, that still works out to decent coverage of the drug's target for a once-a-day dose.

Taking that same drug twice a day at half the dose means that you never hit that maximum level you would in the first dosing regime, but you cover the target longer at pharmacologically active levels. Some drugs work better one way, some the other. And some drugs work differently all by themselves when they're dosed in those two kinds of regimens. It would appear that Celebrex is more worrisome when it covers its targets for longer continuous periods, rather than hitting higher levels but then going away. Perhaps in the latter case things have a chance to get back to normal before the next dose hits, but not in the multiple-dosing protocol.

If this is the case, it's going to be tough figuring out what to do. The FDA is already saying:

"Physicians should consider this evolving information in evaluating the risks and benefits of Celebrex in individual patients. FDA advises evaluating alternative therapy. At this time, if physicians determine that continued use is appropriate for individual patients, FDA advises the use of the lowest effective dose of Celebrex."

I won't mince words: to me, this looks like the first step to pulling the drug. At the very least, I think its use is going to be severely restricted. The fallout? I'll be intensely surprised if Novartis goes ahead with their planned launch of their own COX-2 drug, for one. And Pfizer is looking at some severe trouble, because they're so huge that they need a constant infusion of billion-dollar drugs just to stay where they are. I've never been able to figure out where those were supposed to come from. And I sure can't figure out how they can afford to lose one.

Comments (2) + TrackBacks (0) | Category: Cardiovascular Disease | Toxicology

November 2, 2004

Let's See What the Sharks Think of These Steaks!

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Posted by Derek

I assume that anyone reading this blog today must be looking for something else besides election news or leaked exit poll numbers. How about some drug industry stuff? That I have, but it isn't good. Monday's Wall Street Journal brought a disturbing story about some leaked e-mails and internal memos from Merck and its troubles with Vioxx.

This piece, by Anna Wilde Matthews and Barbara Martinez, led to Merck's stock taking a terrible beating in today's trading, and it's pretty damned easy to see why. If these items are correct, and I've no reason to think that they aren't, Merck is in even bigger trouble than I thought. And believe me, that's really saying something.

It appears that prominent people inside the company not only thought early on that Vioxx had cardiovascular liabilities, but then did everything they could to divert attention and keep the drug on the market for as long as possible. Says the Journal story:

A Merck internal marketing document reviewed by The Wall Street Journal, addressed to "all field personnel with responsibility for Vioxx," provided an "obstacle handling guide." If a doctor said he was worried that Vioxx might raise the risk of a heart attack, he was to be told that the drug "would not be expected to demonstrate reductions" in heart attacks or other cardiovascular problems and that it was "not a substitute for aspirin." This wasn't a direct answer.
One training document is titled "Dodge Ball Vioxx" and consists of 16 pages. Each of the first 12 pages lists one "obstacle," apparently representing statements that might be made by a doctor. Among them are, "I am concerned about the cardiovascular effects of Vioxx" and "The competition has been in my office telling me that the incidence of heart attacks is greater with Vioxx than Celebrex." The final four pages each contain a single word in capital letters: "DODGE!"

There's more, including incidents of Merck coming down hard on academic researchers who presented negative appraisals of the drug. They seem to have gone way over the line - at least, what should be the line - in trying to protect their blockbuster drug. It's ugly and it's disappointing, because I always had a high opinion of the company. This is just the kind of thing that gives my industry a sleazy reputation, and it infuriates me to see how much of it can be deserved.

Naturally, Merck says that the statements in the article are taken out of context. Perhaps some of them are, but it would have to be a pretty unusual context for this stuff not be be what it looks like. And what it looks like is blood in the water for the lawyers, who will now go even more beserk than usual. Who could blame them? Who knows what other things might turn up in discovery proceedings, if goodies like this are already available?

No, I already thought that Merck was in major trouble, but this is going to be one for the record books. Merck is going to be out many, many billions of dollars, far more than they ever made from Vioxx itself. I don't see how the company gets out of this without terrible damage, with most of it done to the cheers of an angry crowd. It's sad, because in many ways Merck has been a great company that's done a lot of good in the world. But not always, and not this time.

Merck has a lot of very bright, very competent, very hard-working researchers. But trouble that's coming is going to lay waste to the good and the bad, the innocent and the guilty. Who will be spared?

Comments (4) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Why Everyone Loves Us

October 19, 2004

Cox-2 Confusion

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Posted by Derek

The COX-2 story is continuing to thrash around, as it will for some time. The latest news has Pfizer's second-generation compound, Bextra, linked to possible cardiovascular risks. This is data from patients who have undergone open-heart surgery, so we can argue about how applicable this is to the general population, but it's still not good news. The whole drug class didn't need any more clouds over it.

At the same time Pfizer has announced a large cardiac trial of Celebrex. Pfizer's positioning this as a trial to look for cardiovascular benefits, actually, but it's going to be hard to shake the impression that they're looking for risks. It'll be interesting to see how quickly they can enroll patients in that one, although odds are we're not going to be able to find that out.

And over at Merck, they've presented data from a study of their own second-generation drug, Arcoxia. In a trial against diclofenac (a classic antiinflammation drug), Arcoxia didn't seem to show an increased risk of heart attack or stroke. But what it did show was a correlation with slightly increased blood pressure, and that's not what Merck or anyone else wanted to hear. You could, in a pessimistic mood, link increased blood pressure to long-term cardiac effects, although there's no way to know if that's what's going on yet.

Remember, the Vioxx problems didn't really show up until the drug had been on the market for some time. You'd think, to read some of the stories (or to hear some of the ads from law firms) that the drug was just mowing down its patients, but that's not what happened. Vioxx's side effects might never have been noticed in the normal course of use - although severe, they're too uncommon to pick up for sure except in a large sample. Patients had to take the drug for over a year to show any problems at all, for one thing.

Without trials specifically designed (and statistically powered) to look for them, the side effects of other COX-2 medications might be invisible. But invisibility isn't an option.

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

October 7, 2004

How Bad Are the Cox-2 Inhibitors, Anyway?

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Posted by Derek

Since Merck pulled Vioxx (rofecoxib) off the market, the big question has been whether its cardiovascular problems are specific or general. Do all COX-2 inhibitors have this liability? If so, do they all have it to the same extent? The analogy that comes to mind is the statins - all of them have been shown, at high enough dosages, to be associated with a potential for rhabdomyolosis, a serious muscle side effect. But Bayer's entry into the class, Baycol, showed it more than the others and had to be pulled.

Pfizer's been saying that they have seen no evidence of trouble for their Celebrex (celecoxib). But there's an interesting perspective in the latest New England Journal of Medicine. (That link will allow you to download a free PDF of the article.) The author, Garret Fitzgerald of U Penn, suggests that there could be trouble enough to go around.

The story involves two signaling molecules formed from the COX enzymes, thromboxane A2 and prostaglandin I2. Aspirin inhibits both COX-1 and COX-2, and suppresses the formation of both of them. The thromboxane, formed by COX-1, causes vasoconstriction and platelet aggregation, while the prostaglandin causes the opposite - it dilates blood vessels and inhibits platelet aggregation.

Neither Vioxx and Celebrex touch the thromboxane A2 pathway, naturally, but they both suppress the formation of prostaglandin I2 in humans. This was a weird result when it came out, because it was assumed that this molecule was made via COX-1 too, which these drugs don't inhibit. It later turned out that it's also made by COX-2 - which at least made sense from the drug standpoint - but that was still odd, because that enzyme wasn't supposed to be in the blood vessels at all.

But it seems that COX-2 can be induced there, especially when the vessel walls are subject to shear stress from blood flow. Problem is, when you inhibit that prostaglandin's formation, you've taken off a brake to platelet aggregation and you've probably caused some vasoconstriction, too. They're trying to make more of the prostaglandin, but the drug is preventing that from happening.

FitzGerald doesn't put any sugar on it:

"We now have clear evidence of an increase in cardiovascular risk that revealed itself in a manner consistent with a mechanistic explanation that extends to all the coxibs. (Emphasis mine - DL) It seems to be time for the FDA urgently to adjust its guidance to patients and doctors to reflect this new reality. . .The burden of proof now rests with those who claim that this is a problem for rofecoxib alone and does not extend to the other coxibs."

Over to you, Pfizer! Uh, Pfizer? Oh. . .I see. . .

Comments (6) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Toxicology

October 3, 2004

More on Merck

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Posted by Derek

I see that some of the Merck/Vioxx coverage has been along the lines of "Company Finally Heeds Warnings of Unsafe Drug." Boy, the tort attorneys have to love that sort of thing. It's true that Merck had some signs that Vioxx could have cardiovascular problems, but there are a lot of drugs, unfortunately, that show rumblings of this sort. Some of them turn out to be false alarms, and some of them turn out to be real. This one turned out to be real with fangs.

If we immediately pulled every drug that showed any indication of trouble, it's for sure that no patients would come to harm. But we wouldn't have very many drugs, either. It's possible that Merck could have moved more aggressively to see if Vioxx had these problems or not - but if companies immediately ran fully-powered studies to address every red light that comes on, we'd have even more enormous costs to make up than we do already. Nothing's free.

Our job, on the discovery and development side, is naturally to try to find things with the largest positive footprint and the smallest negative one. The size of the latter one never goes to zero; it can't. We try to figure out how big it is, but you can never be really sure until after the drug goes onto the market. It's sad, it's unnerving, but it's absolutely true. The mission of the FDA, in an ideal world, would be to ensure that only drugs that can cause no harm make it to market. In the world we find ourselves in, though, the mission is to balance the potential harm a new drug could cause with the good it could do. That's an awfully tough assignment.

And the job of the injury lawyers is to swoop down after the worst happens, cawing about "defective products" and "willful negligence", and bearing away the biggest chunks their beaks can carry. The sky over Merck is getting dark with them right now.

Speaking of carrying away things in beaks, remember the University of Rochester? A group there made some of the early COX-2 discoveries, and on the strength of a patent, wanted a piece of all the earnings of COX-2 inhibitor drugs. The suit failed, after years of wrangling, on the grounds that the patent did not provide any such compounds, nor did it (or could it) describe what such a drug would look like or be composed of. But if they'd won, do you think they'd be willing to pick up some of the liability? Soak up a little of the lawsuit pain? Or were they only in it for the sunny days while the money was flowing? What do you think?

Comments (3) + TrackBacks (0) | Category: Cardiovascular Disease | Drug Development | Toxicology

September 30, 2004

A Day With All the Bark Left On It

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Posted by Derek

The talk at every pharmaceutical company today was Merck's sudden withdrawal of their COX-2 inhibitor Vioxx. Merck has been having an awful time for the last year or two, and this really throws a burning tire on top of the whole heap.

They were running a study to see if Vioxx would help prevent the formation of colon polyps - evidence has been accumulating that COX-2 inhibition would be helpful in colon cancer, and Merck was going to put the idea to a rigorous test. Halfway through the three-year trial, though, things have come to an ugly halt. Not only was there no colorectal effect (at least, none so far), but the treatment group showed roughly twice the rate of serious cardiovascular side effects such as heart attacks and stroke. These doubts had followed Vioxx for several years now, after a JAMA-published analysis which seemed to suggest cardiovascular complications. But Merck contended that this earlier study was controlled against a group taking a cardioprotective drug, and therefore not sufficient evidence. That's not the case any more.

So what's this mean? Well, in the near term, Pfizer is going to rake it in with Celebrex and its successor Bextra. And Novartis will have a more open field to introduce their coming COX-2 drug Prexige. But are these problems confined to Vioxx, or is it a COX-2 mechanism effect that's going to keep showing up? As far as I know, these problems haven't been noted with Celebrex, but it may be incumbent on Pfizer to generate new data to make sure. If the drug is clean, then Pfizer gets my vote as the luckiest drug company I have ever seen, between the unexpected benefits of Lipitor and the unintentional safety of Celebrex.

Meanwhile, Merck is going to face a horrible tsunami of lawsuits. It's 10:20 EST as I write this, and when I search Google for the word "Vioxx", the first two sponsored links on the right side of the page are from tort lawyers already trolling for clients. Lawsuit-centered web domains are already active, and I'm sure that the radio ads will be on the air tomorrow. I hate to say it, but I don't see how Merck makes it through this without firing people at some point. It's a damn shame - even Merck's fiercest competitors respect their research prowess, and I hate to see the company damaged.

And in the long term? Matthew Herper has it right over at Forbes:

"In some sense, every medicine is a ticking time bomb, and existing studies may not be enough to know what is safe and what isn't. The drug development business was already risky and expensive. But it just got even worse."

Just what we needed. Man, sometimes I think I should answered that ad back in the 1980s and learned to drive the big rigs for fun and profit.

Comments (0) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Toxicology

September 2, 2004

The Last Word (For A While) On Me-Too Drugs

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Posted by Derek

What sort of markets breed multiple therapies? The ones with the largest number of potential (paying) patients, for one thing, which shouldn't surprise anyone. Fortunately, that also corresponds pretty well with the markets that could be better served with another drug. The success of the first compound in a new market shows that it can be done, and proves that there's money to be made, and that attracts more companies to the field. The path has been cleared, up to a point - but remember, all the following compounds have to go through the same degree of efficacy and safety testing as the first one did, although the later entries at least know, broadly, how to set up their clinical trials.

But entering an existing market is no guarantee of riches. There are no guarantees of riches. Look at Bristol-Meyers Squibb and their statin, Pravachor, which has been weighed in the balance against Lipitor and been found wanting (with BMS paying for the whole process). Now what? You can be sure that AstraZeneca is beavering away, trying to show that their big statin hope (Crestor) has even more of the effects that Lipitor has shown. It'll need to.

Or look at the erectile dysfunction field. Pfizer showed that it could be a moneymaker with Viagra, and don't believe for a minute that this was obvious beforehand. There were plenty of sceptics, doubtless some of them within Pfizer itself. But Viagra's success attracted a lot of interest around the industry, since many companies had a stable of potential PDE inhibitor leads. Now Bayer (partnered with Glaxo SmithKline) and Icos (partnered with Lilly) are in the field with Levitra and Cialis, respectively. A glance at your e-mail spam will have already familiarized you with both compounds, in case you've somehow missed the massive advertising campaigns.

The hope was the the new compounds, which differ from Viagra (and each other) in side effects, onset, and duration of action, would expand the market even more to people who had never tried Viagra. But as far as anyone can see, neither of them has been the as big a hit as the companies involved might have hoped for. It looks like the size of the market is still roughly the same, only now there are three compounds beating each other up inside the same box. The promotional costs for everyone involved are not trivial, and they would have been a lot easier to bear if a lot more patients had decided to try the therapies for the first time. It doesn't seem to have happened, at least not yet. Those are the breaks. We make money in this business, true, but if you think it comes easy, well, come on down with your leaf blower and scoop some up.

Comments (3) + TrackBacks (0) | Category: "Me Too" Drugs | Cardiovascular Disease

August 31, 2004

Me Too, Part Two

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Posted by Derek

As came up in the comments to the previous post, there's not as much price competition inside a given drug category as you'd think. That's not because we're Evil Price Gougers, at least not necessarily. As I was pointed out yesterday, "me-too" type drugs aren't as equivalent as some people think. The main reason we go ahead with a drug in a category where there's already competition is because we think we have some advantage that we can use to gain market share.

This is a constant worry in every drug development effort where there's already a compound out there. I've personally, many times, been in drug project meetings where we've looked at the best competing compound (one that's either already marketed or well into clinical trials) and said "We haven't beaten them yet. We're not going to make it without some kind of unique selling point." The best of those, naturally, would be superior efficacy or a superior safety profile. Then you have easier dosing, fewer interactions with other drugs, and so on. I need to emphasize this: I have seen drug projects killed because no case for an advantage could be made.

Now, there's room to argue about how much better efficacy a drug needs to be a real advance in the field, or at least a bigger seller. You can argue about any of those possible advantages I listed, and it's true that drug companies push some compounds that aren't exactly huge leaps over the previous state of the art. (You see more of that when there's a case of shriveled pipeline in progress.) But there has to be something, and the bigger the difference, the better it is for us. We're motivated, by market forces, to come up with the biggest advances we can. The sales force would much, much rather be out there with data to show that the new drug beats the competition in a clean fight, as opposed to saying that it beats the old one on points, in a subset of patients, if you massage the data enough and squint hard, and besides it tastes better, too. . .

And as I've pointed out before, we often find out things about compounds long after they've reached the market. Lipitor, as discussed yesterday, is a case in point. I have not been a Lipitor fan in the past. The statin field seemed already pretty well served to me (as it did to a number of people inside Warner-Lambert during the drug's development, frankly.) The drug made its way forward based on efficacy in the clinic: it seemed to do a better job lowering cholesterol and improving the LDL/HDL ratio. How much advantage that is in the long term is another question, but those are the best markers we have.

The whole antiinflammatory c-reactive-protein story about the drug only came up after it was already on the market. The marked differences between it and the other statins, which I have to assume at this point are real, are a pleasant surprise to everyone involved. Warner-Lambert (and then Pfizer) thought it was a better compound, but not to this degree or for these reasons, I'l bet. I'd say that this is another argument for having multiple drugs in the same category. We don't, and can't, know everything that they'll do.

Comments (2) + TrackBacks (0) | Category: "Me Too" Drugs | Cardiovascular Disease | Clinical Trials | Drug Development | Drug Prices

Clinical Trials And What to Do With Them

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Posted by Derek

Allow me to get a little defensive. If I understand some of the critics of my industry, we spend most of our time making "me-too" ripoff drugs rather than doing something that provides any clinical benefit to patients. And, if I have this right, here's how we determine efficacy: we run clinical studies until we get the answer we want, and then we bury all the other ones. (Mind you, we bury the data by giving it to the FDA, but stay with me here.)

OK, now let's try to explain this. Merck has just released a study on its statin drug, Zocor. Following in the footsteps of two other studies with Pfizer's statin, the market-leading Lipitor, Merck dosed patients who had just suffered heart attacks. Lipitor treatment seemed to show a real benefit in these situations, lowering the rate of later cardiovascular trouble, and Merck was hoping for (and no doubt expecting) the same thing.

But they were rudely surprised. At the lower doses of Zocor, they failed to show any benefit at all. And at the highest dose, while they managed to show a lower rate of second heart attacks, they still didn't reach significance versus the placebo group. Worst of all, several of the high-doses patients showed the muscle-weakening condition rhabdomyolosis. That's the bane of statin drugs, and the reason why Bayer pulled their compound (Baycol) from the market. (Just to complicate things, one of Merck's placebo patients showed rhabdomyolosis, too, which is food for thought and should give you an idea of how much fun it is to interpret clinical trial data.)

So what's going on here? Zocor and Lipitor both work by inhibiting HMG-CoA reductase. They hit the same mechanism. Were the patients different? The study's authors say it's possible. The patients in the Lipitor studies seem to have been receiving more aggressive therapy in addition to the drug. Are the drugs different? That's possible, too. Lipitor, as it turns out, seems to lower the inflammation marker C-reactive protein much more than Zocor, and that could potentially make a difference.

But if the drugs are really different, what happens to the idea that Lipitor is just a me-too, yet another statin piling on the profits? If we in the industry hadn't kept banging away at these drugs, we wouldn't have ever known that better ones could be found. Would we? As I've pointed out in the past, if you're going to market a drug in a category where the competition is ahead of you, you'd better have some improvement to point at or set about finding one. Lipitor came into the market under the banner of "lower dose / higher efficacy", and it may be picking up more advantages as time goes on.

Now, if we believe that the drugs aren't different, which will be an interesting thing to try to prove at this point, then we have to figure out how much weight to put on this study. How does it go into the Great Clinical Trial Repository? With an asterisk? Then shouldn't the earlier two studies with Lipitor have one, too? This is the same situation I spoke of before.

And what about this clinical trial data in general? Isn't this the sort of bad news that we're supposed to be sweeping under the rug over here? A full article in JAMA complete with vigorous editorial commentary. . .some rug. Oh, and one other thing: those two earlier Lipitor studies that showed a benefit. One of them was from Pfizer(/Pharmacia), as you'd expect. But the other one was from their competition. Bristol-Meyers Squibb has been trying to prove that their statin, Pravachor, is better than Lipitor, and failing. Where's that damn rug when you need it?

Comments (5) + TrackBacks (0) | Category: "Me Too" Drugs | Cardiovascular Disease | Clinical Trials

March 15, 2004

Pravachol vs. Lipitor Update

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Posted by Derek

In my March 11 piece below, I mentioned the possibility of Pravachol competing on price with Lipitor. But over at Forbes, Matthew Herper has pointed out that it's currently more expensive. What BMS is going to do with this drug, I can't imagine.

There's also a good story in the Newark Star-Ledger about the whole comparative-trial situation. (That paper does a pretty good job with the drug industry, since so many of the big players are right in its back yard.)

Comments (0) | Category: Business and Markets | Cardiovascular Disease | Clinical Trials

March 11, 2004

Ignorance Was Bliss

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Posted by Derek

Just a brief note today about the "PROVE-IT" study that Bristol-Meyers Squibb ran and has now reported on. This was their big shot at Pfizer's Lipitor, their chance to show that their own statin, Pravachor, was just as good or better. The study was big, it was long, and man, was it expensive. It's just the sort of thing that I was talking about when I wrote recently about comparative drug trials.

And it shows why more of them aren't done. Because, as is well known, when you strike at a king, you have to kill him. BMS found, no doubt to their dismay, that Lipitor is actually a better drug. It's not a gigantic difference, and you can still argue about the dosages, but BMS's drug definitely failed to realize the hopes they had for it. Here are two competing views on the issue, one from DB's Medical Rants (keep scrolling up) and one from Medpundit.

Now what? How do they promote it? The question that BMS is going to get is "Why should anyone take your drug instead of Lipitor?" The only thing I can think of is for them to compete on price. "Take Pravachor - it's proven to be sort of, you know, inferior, but it's sure cheaper!" Doesn't quite have that compelling zing, does it?

If comparative drug trials are going to be done, they're either going to have to be required by law - in which case, as I pointed out, we in the industry will pass along those costs to the consumer, thanks - or they'll have to be done by a third party. (In which case it'll be paid for by everyone who pays taxes, not just the eventual users of the drugs involved.) If you're waiting for more companies to do them on their own, you're going to have a long wait. Especially after something like this happens.

I'll leave everyone with a homework question: Can anyone think of another case - I can't - where a company sponsored a study of their product against a competitor, found that theirs fell short, and publicized it? UPDATE: I mean, outside the drug industry. It's happened several times to us (Zyprexa!) I'm talking Ford / Honda, Dell / Gateway examples, and I can' think of one. Admittedly, as I've said before, health care is different, but still. . .

Comments (0) | Category: Business and Markets | Cardiovascular Disease | Clinical Trials

February 25, 2004

Ezetimibe, The Press, and More

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Posted by Derek

Credit where it's due! Yesterday I mentioned the original chemist who started the ezetimibe story, but I should note that the drug itself was synthesized by another former colleague of mine, Stuart Rosenblum. He and a host of others developed a huge series of analogs, which built in more acitivity and greater in vivo stability. Just the way drug development is supposed to work, actually.

This drug is also used as an example in a very interesting front-page Wall Street Journal article yesterday. It's a public version of a debate that's been going on inside the industry for a few years now: has the huge increase in compound screening (and compound synthesis) done any good? The article does a pretty good job discussing the issue, although it does mix the two technologies together a bit. It's a very interesting topic, which I'll return to here soon.

And while you're at it, the same issue of the newspaper has (in the Money and Investing section) a nice piece on how drug companies tend to bury news of clinical failures. Different companies handle this differently, of course, but with some of them you really have to watch closely. The article makes the same point I did a while ago - investing in this industry is more of a gamble than most people think. Don't just buy one company's stock if you're looking at biotech and pharma - there's no way you can really know what's going on. Spread your risk.

These articles confirm the Journal's status as the best newspaper when it comes to covering the drug business. The New York Times tries, and sometimes has good work in it, but isn't in the same class. As for magazines, I'd say that Forbes does very well, as does their online site with its copious coverage from Matthew Herper.

Comments (0) + TrackBacks (0) | Category: Cardiovascular Disease | Drug Assays | Drug Industry History

February 24, 2004

The Beginning? It's Right Past the End. . .

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Posted by Derek

There's a paper in the latest issue of Science from a team at Schering-Plough that may have tracked down how the company's cholesterol absorption inhibitor (Zetia, ezetimibe) works. That news really takes me back.

It's been years now, so it won't do any harm to mention that I used to work there. I had a ringside seat for the early years of that project, because it all happened right around the corner from my old lab. Ezetimibe was discovered fortuitously when one of my colleagues synthesized and sent in the original structures of the class for a project targeting a cholesterol handling enzyme known as ACAT. I believe that the in vitro assay was down that week, so the compounds went into the open slots for mouse testing, where they worked better than anything they'd seen. But when the protein assay came back on line, it was discovered that the compounds had no affinity for ACAT at all. Food for thought, that was.

The chemist involved was named Duane Burnett, and a search for "Burnett DA" in Pubmed will send you to most of the chemistry literature on the subject (along with this review). He had indeed hit on some features of a cholesterol binding site (which was his aim, based on blackboard-level structure modeling - no computers involved.) The compounds seemed to hit an unknown target in the small intestine that helped transport dietary cholesterol. The search for the protein involved began in about 1993, and seems to have concluded successfully in 2002-2003, years later than anyone thought it would take.

In the mid-1990s, all the classic methods for tracking down an unknown binding site were tried. The lead structure was biotinylated, modified with radiolabels, photoaffinity tags, and fluorescent groups (along with various combinations of these.) None of these methods identified the target.

They finally tracked down the protein by brute force genomics, using a cDNA library prepared from rat intestinal lining, coupled with sequence searching for the features you'd expect in a transmembrane protein with a steroid binding site. The evidence seems clear that the protein they've found is a key for ezetimibe's actions, but - most oddly - it still doesn't seem to bind to the protein. That would certainly explain the failure of all those modified compounds to pull out the target, but it does make you wonder what's going on. (Is there another real target? But if so, why wasn't that identified through the modified compounds? And so on.)

It took a lot of nerve to go on with that project, and I have to salute the people who kept it going. As with many other successful projects, there were several points along the way where it seemed like the whole effort was going to fail. As it turns out, ezetimibe is one of the main (few?) bright spots in Schering-Plough's portfolio. Merck, their eventual partner for the drug, values it pretty highly, too. I'm glad I got the chance to see it happen.

Credit where it's due! I should note that ezetimibe itself was synthesized by another former colleague of mine, Stuart Rosenblum. He and a host of others developed a huge series of analogs, which built in more acitivity and greater in vivo stability. Just the way drug development is supposed to work, actually.

Comments (0) + TrackBacks (0) | Category: Cardiovascular Disease | Drug Assays | Drug Industry History

February 5, 2004

Sic Transit Gloria Mundi

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Posted by Derek

So Entremed is finally giving up on its celebrated peptide drug candidates, angiostatin and endostatin. I'm sorry to see what the company, and its employees have been through, but I'm even sorrier when I think about what cancer patients have been through during this story. Especially those of them who read that (in)famous New York Times story back in 1998, with the (in)famous James Watson quote about curing cancer in two years. (He might as well wear a sign: Loosest Cannon in the Room - Come Here For Quotes!)

I wrote about this whole issue back on my Lagniappe site a couple of years ago, which led to an interesting exchange with Mickey Kaus about whether the Times article had been vindicated or not. Kaus is a wonderful political journalist, but would be the first to admit that he's no pharmaceutical expert, and his take was that the focus on angiogenesis made the Times article look better, in retrospect. My contention was that angiogenesis was already known to be a good area to work in. This was thanks in good part, it's true, to Judah Folkman, who was also a main subject of the article. But the emphasis on angiostatin and endostatin was perverse.

By the time the Times ran their front-page above-the-fold horn-honker, legions of people had already decided that Folkman was on to something. And they were working on better compounds to try the theory out. The problem with Folkman's peptides was that they were, well, peptides, and unusually painful ones to work with, at that. Angiostatin and endostatin are not that easy to produce, to purify, to store, or to dose, as opposed to the small molecules that were also already in clinical trials.

Once you dose peptides, they get hammered, chain-sawed, and burned down to the ground. I love coming up with verbs to describe the process, I have to admit. If you saw a plot of blood levels after dosing a typical peptide drug, you'd see just what I mean. It takes a pretty specialized protein to circulate around after an i.v. dose without getting enzymatically ripped to shreds, and as for oral dosing, you can forget it. The gut is very efficient at grinding every protein it sees down to its component amino acids.

So Entremed's compounds were flying into a stiff breeze from the beginning. And, as so often happens, anti-angiogenesis as a cancer therapy has turned out to be more complicated than anyone thought. (If you work in the drug industry, you could take that last phrase and turn it into a keyboard macro to save time. It's practically our motto.) There are many, many possible targets in the field, and we're not that sure which ones are most likely to work. And a lot of them are so biologically similar that it's hard to make selective drugs that work against them, anyway, thus many clinical candidates turn out to have a large and ill-defined footprint. To add to the confusion, different types of tumors express different amounts of these various target proteins, and their relative importance is surely all over the place as well. Not that we know yet, of course. And I'm only talking about the cases where vascularization is thought to be important; many other sorts of tumors are poor candidates for anti-angiogeneic therapies right from the start.

No, these compounds have been doomed for years, as far as I can see. They were long shots even when the Times sent Entremed on its insane ride up to nearly $100/share. I remember scoffing at the article when it came out, and I remember trying to go short the company's stock (couldn't get the shares to borrow.) But while all this was happening, people were getting their hopes up, desperate patients who thought that this might be their chance for survival. How many of them who read that article are still alive today?

I'm normally a pretty optimistic person, but I make an exception for my work. We should never let people get their hopes up. Not until we're really, really sure. We don't know enough. This whole situation wasn't Entremed's fault, and it certainly wasn't Judah Folkman's. This one gets chalked up to the New York Times.

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December 20, 2002

Trials of Trials

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Posted by Derek

As I mentioned yesterday, I think the kind of study that compared diuretics with other hypertension medicines was a very good thing. So why don't we see more of these?

There are several reasons. It's worth thinking about the different levels of testing, and what questions they're designed to answer. At the first level, you have questions about specific drugs - is Drug A safe to take, compared with taking nothing? Does Drug A work, compared with taking a placebo? These are the usual subjects of Phase I and II clinical trials.

There's a third question, namely, how good is drug A versus other drugs that work the same way? That one doesn't get answered as often as it should, because the FDA generally only requires testing against placebo. A debate has been going on about when it's appropriate to run head-to-head trials rather than placebo-controlled, and it happens more often than it used to. Drug companies aren't always eager to try this, because they sometimes fear that the advantages of their new compound may turn out to be more subtle than they'd like. But if they think they've got a clear edge, then a trial like this is just the thing. I think we're going to be seeing more and more FDA requests for these sorts of trials, which will definitely make life harder for drug development, but in a good cause.

Beyond specific drug questions, you get to mechanism issues: Does therapy A work better than therapy B? That's what the diuretic study was designed to answer, and it's the rarest kind of all. It's a situation, though, like the old proverb that says when you strike at a king, you have to kill him. If you run one of these trials and your advantage isn't there, you're probably sunk - and if a safety liability shows up versus the existing therapy, you're completely sunk. This is what happened to Bristol-Meyers Squibb when they run Vanlev (omepatrilat) against Vasotec (enalapril) for hypertension. Vanlev's never going to see the light of day, and neither is any other ACE/neutral endopeptidase inhibitor combination.

As one of the interviewees in Wall Street Journal noted:

Duke's Dr. Catliff says it isn't reasonable to expect the pharmaceutical industry to onduct head to head studies needed to answer questions of both science and money. "It's sort of an all or nothing game," he says. There is a potential gain for the winner, but a huge risk for a loswer. Some results could essentialy kill the market for a drug. "The industry can't afford to take that kind of risk."

Well, whether it's reasonable or not, he's right that companies aren't going to line up to do this sort of study. The business is risky enough already, thanks. No one company is going to try it unless they're forced to (like BMS.) That goes double when you're comparing existing therapies, things that are already on the market. But that doesn't mean that I don't think this kind of study should be done - on the contrary. I think that the NIH's model for the ALLHAT hypertension study could be the way to go - let people run the study who won't be cutting their own throats by running it. It'll be interesting to see if they get a general mandate (and funding) to do just that.

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November 3, 2002

Cholesterol Lowering, One Way or Another

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Posted by Derek

Schering-Plough and Merck have won FDA approval for Zetia, their cholesterol absorption inhibitor that I've spoken about from time to time. That's a big step for them, although approval was pretty much assumed. The drug won't reach its real potential, though, until they can get their combination Zocor/Zetia formulation approved, which is the next big push. (I can highly recommend this article from Forbes, which presents a very accurate portrait of how the drug was developed.)

The two drugs have complementary mechanisms. Zocor is a statin, an inhibitor of an enzyme with the melodious name of hydroxymethylglutarate coenzyme A reductase. It's responsible for a key step in the cascade that synthesizes cholesterol from scratch. Merck was the first company to get one of these inhibitors on the market, and they've done extremely well with them over the years, although their current compound, Zocor, has slipped behind Pfizer's juggernaut Lipitor.

There are a number of statins out there, but one (Bayer's Baycol) was recently pulled from the market. That highlights some of the small (but real) differences between the different compounds: Bayer's compound ran into a similar toxicity problem that has affected the other statins (a rare inflammation of muscle tissue,) but seemingly showed more of it. To the best of my knowledge, no one knows what influences patient susceptibility to this effect, and it's something that hangs a bit over the entire field. Sounds like a good candidate for toxicogenomics, although it's hard to know where to start looking.

Zetia, on the other hand, has nothing to do with HMG-CoA reductase - rather, it inhibits the other source of cholesterol, absorption from the diet. Combine the two, and there really shouldn't be much excess cholesterol left. (I've always wondered what would happen if you really loaded up on both, though, because cholesterol, despite its bad reputation, is essential. Would some endogenous synthetic pathway that we don't even know about suddenly kick in? What would cholesterol deficiency look like, anyway?)

By itself, Zetia doesn't do any better job of lowering cholesterol than a statin does. But in combination with one, you can take the statin at lower doses than you would need it in a monotherapy. This would presumably lead to lower incidence of side effects, so it could be that events have conspired to bring the drug in at just the right time.

One wild card is that HMG-CoA reductase inhibitors may be good for more than lowering cholesterol - for example, there may be a protective effect for Alzheimer's. There's been a cholesterol handling/Alzheimer's link known for some time (a long and knotty subject that I'll take up in some future post.) So here's a question - are the possible side benefits of the statins due to lowered cholesterol only? Or are they due to something else that comes out of inhibiting HMG-CoA reductase? Or is it door number three - some other target entirely that statin-like structures also hit?

There's also the question of how much good lowering cholesterol really does. That's not something that's going to affect Zetia (or Lipitor, or anything else) for a long while. But the dietary fat controversy that Gary Taubes and others have been stirring up makes a person wonder how much good all this cholesterocentricism (new word! you saw it here first!) really does. That's a topic for another day, too!

Comments (0) + TrackBacks (0) | Category: Cardiovascular Disease