About this Author
College chemistry, 1983
The 2002 Model
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: email@example.com
March 24, 2014
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.
+ TrackBacks (0) | Category: Cardiovascular Disease
January 27, 2014
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
+ TrackBacks (0) | Category: Cardiovascular Disease
January 16, 2014
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Regulatory Affairs
November 14, 2013
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!
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Pharmacokinetics
October 24, 2013
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.
+ TrackBacks (0) | Category: Cardiovascular Disease
October 16, 2013
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials
July 12, 2013
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | The Dark Side
May 9, 2013
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.
+ TrackBacks (0) | Category: Cardiovascular Disease
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Why Everyone Loves Us
April 4, 2013
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.
+ TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease
March 19, 2013
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.
+ TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Drug Development | Drug Industry History | Toxicology
February 15, 2013
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.
+ TrackBacks (0) | Category: Cardiovascular Disease
January 25, 2013
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.
+ TrackBacks (0) | Category: Alzheimer's Disease | Cardiovascular Disease | Clinical Trials | Drug Development | Drug Industry History
December 21, 2012
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology
December 14, 2012
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?
+ TrackBacks (0) | Category: Cardiovascular Disease
August 31, 2012
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development | Drug Industry History | The Central Nervous System
August 30, 2012
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. . .
+ TrackBacks (0) | Category: Cardiovascular Disease
August 29, 2012
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. . .
+ TrackBacks (0) | Category: Aging and Lifespan | Cardiovascular Disease | Diabetes and Obesity
June 29, 2012
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology
May 30, 2012
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).
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May 18, 2012
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.
+ TrackBacks (0) | Category: Alzheimer's Disease | Cardiovascular Disease | Diabetes and Obesity
May 17, 2012
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.
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May 7, 2012
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials
February 29, 2012
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Regulatory Affairs | Toxicology
November 30, 2011
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. . .
+ TrackBacks (0) | Category: Cardiovascular Disease | Drug Industry History
November 22, 2011
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?
+ TrackBacks (0) | Category: Cardiovascular Disease | Diabetes and Obesity | Drug Industry History | Regulatory Affairs | The Central Nervous System
November 18, 2011
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Drug Development | Toxicology
November 15, 2011
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. . .
+ TrackBacks (0) | Category: Biological News | Business and Markets | Cancer | Cardiovascular Disease | Press Coverage
November 14, 2011
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.
+ TrackBacks (0) | Category: Cardiovascular Disease
July 22, 2011
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.
+ TrackBacks (0) | Category: Cardiovascular Disease
June 9, 2011
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Press Coverage
May 27, 2011
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials
May 18, 2011
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?
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Regulatory Affairs
May 10, 2011
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. . .
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials
January 20, 2011
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development
January 13, 2011
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. . .
+ TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Clinical Trials | Drug Development
November 19, 2010
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. . .
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology
October 21, 2010
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?
+ TrackBacks (0) | Category: Cardiovascular Disease | Patents and IP
July 13, 2010
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | The Dark Side | Toxicology
June 28, 2010
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. . .
+ TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | The Dark Side
June 23, 2010
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.
+ TrackBacks (0) | Category: Cardiovascular Disease
June 14, 2010
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. . .
+ TrackBacks (0) | Category: Cancer | Cardiovascular Disease
June 9, 2010
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | The Central Nervous System
May 27, 2010
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials
May 5, 2010
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | Toxicology | Why Everyone Loves Us
March 30, 2010
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.
+ TrackBacks (0) | Category: Animal Testing | Cardiovascular Disease | Clinical Trials | Drug Assays | The Scientific Literature
March 26, 2010
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. . .
+ TrackBacks (0) | Category: Cancer | Cardiovascular Disease | Clinical Trials | Drug Industry History
March 15, 2010
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | Drug Assays
February 24, 2010
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | The Dark Side | Toxicology
January 4, 2010
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Drug Industry History
November 19, 2009
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Regulatory Affairs
November 16, 2009
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?
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials
October 2, 2009
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | The Central Nervous System
September 22, 2009
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. . .
+ TrackBacks (0) | Category: Cardiovascular Disease | Regulatory Affairs | Toxicology
June 8, 2009
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials
June 4, 2009
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. . .
+ TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Clinical Trials | Drug Industry History
May 20, 2009
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.
+ TrackBacks (0) | Category: Cardiovascular Disease
May 13, 2009
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.
+ TrackBacks (0) | Category: Aging and Lifespan | Biological News | Cardiovascular Disease | Diabetes and Obesity
May 5, 2009
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development | Drug Industry History | Toxicology
May 1, 2009
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. . .
+ TrackBacks (0) | Category: Biological News | Cardiovascular Disease | Toxicology
April 2, 2009
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.
+ TrackBacks (0) | Category: Cardiovascular Disease
March 17, 2009
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Diabetes and Obesity | Regulatory Affairs
December 2, 2008
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?
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November 12, 2008
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.
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November 10, 2008
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.
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September 26, 2008
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?
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July 22, 2008
Merck took the unusual step of delaying its earnings release yesterday until after the close of the market. A report on another clinical study of Vytorin (ezetimibe), their drug with Schering-Plough, was coming out, so they put the numbers on hold until after the press release yesterday afternoon. Naturally, this led to a lot of speculation about what was going on. A conspiracy-minded website vastly unfriendly to Schering-Plough suspected some sort of elaborate ruse to drum up publicity.
But that sort of thinking doesn't take you very far, unless you count the distance you rack up going around in circles. As it turned out, the SEAS trial (Simvastatin and Ezetimibe in Aortic Stenosis) was, in fact, very bad publicity indeed for the drug and for both companies. In fact, a real conspiracy would have made sure that these numbers never saw the light of day, or were at least released at 6 PM on a Friday. But no, the spotlight was on them good and proper.
This trial studied patients with chronic aortic stenosis, which is a different condition than classic atherosclerosis. The two have enough similarities, though, that there has been much interest in whether statin treatment could be effective. The primary endpoint, a composite of aortic valve and general cardiovascular events, was missed. Vytorin was no better than placebo. It reached significance against one secondary endpoint, reducing the risk of various ischemic events, but not in any dramatic fashion.
That's not necessarily a surprise, since there's not a well-established therapy for aortic stenosis (thus the trial design versus placebo). As several commenters to the conference call after the press conference pointed out, this shouldn't change clinical practice much at all. But it's not what Merck and Schering-Plough needed to hear, that's for sure, because the sound bite will be "Vytorin Fails Again".
Actually, the sound bite will be even worse than that. There are a lot of headlines this morning about another observation from the SEAS trial: that significantly more patients in the treatment arm of the study were diagnosed with cancer. That's a red warning light, for sure, but in this case we have at least some data to decide how much of one.
For one thing, as far as I know there have been no reports of increased cancer among the patients taking Vytorin out in the marketplace - of course, one could argue that this might have been missed, but if the effect were as large as seen in the SEAS study, I don't think it would have been. Analyses of the earlier Vytorin trials and the ongoing IMPROVE-IT trial versus Zocor have also shown no cancer risk, and the latter trial is continuing. So for now, it would appear that either this was a nasty result by chance, or (a longer shot) that there's something different about the aortic stenosis patients that leads to major trouble with Vytorin.
None of these scientific and statistical arguments, and I mean none of them, will avail Schering-Plough and Merck. Among people who've heard of Vytorin at all, the first thing that will come to mind is "doesn't work", and after today's headlines, the second thing that will come to mind is "cancer". Just what you want, to put out press releases that your compound, even though it failed to work again, isn't actually a cancer risk. You really couldn't do worse; a gang of saboteurs couldn't have done worse. Of course, there's no such gang: the companies themselves authorized these trials, thinking that there were home runs to be hit. But all these sidelines - familial hypercholesteremia, aortic stenosis - have only sown fear, confusion, and doubt. The only thing that I can see rescuing Vytorin as a useful drug is for the IMPROVE-IT results to show really robust efficacy in its real-world patients. And I wonder if even that could be enough.
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June 24, 2008
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.
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June 5, 2008
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.
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May 13, 2008
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.
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April 29, 2008
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. . .
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April 4, 2008
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. . .
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development | Infectious Diseases
April 3, 2008
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”.
+ TrackBacks (0) | Category: Animal Testing | Cancer | Cardiovascular Disease | Diabetes and Obesity | Drug Assays | Drug Development | Infectious Diseases | The Central Nervous System
April 2, 2008
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.
+ TrackBacks (0) | Category: Cardiovascular Disease
April 1, 2008
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Press Coverage | The Dark Side | Why Everyone Loves Us
March 13, 2008
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).
+ TrackBacks (0) | Category: Cardiovascular Disease | The Scientific Literature | Toxicology | Why Everyone Loves Us
March 4, 2008
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Diabetes and Obesity | Drug Development | Toxicology
February 8, 2008
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development | Toxicology
January 14, 2008
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. .
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Press Coverage
September 2, 2007
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Drug Development | Drug Industry History
June 11, 2007
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | The Central Nervous System | Toxicology
May 31, 2007
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | Press Coverage
May 25, 2007
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Diabetes and Obesity | Press Coverage | Why Everyone Loves Us
May 24, 2007
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | Toxicology
April 1, 2007
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Drug Development
March 20, 2007
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. . .
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development
December 11, 2006
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Snake Oil
December 6, 2006
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.
+ TrackBacks (0) | Category: Cardiovascular Disease | Drug Development | Pharmacokinetics | Toxicology
December 4, 2006
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?
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology
December 3, 2006
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