About this Author
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
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Category Archives
July 15, 2008
Posted by Derek
Now, if I were still doing metabolic disease work, I'd be all over this target: CAMKK2, which is mercifully short for "Ca2+/calmodulin-dependent protein kinase kinase 2". (Kinase nomenclature has been out of hand for years, in case you're wondering).
CAMKK2 is right in the middle of a lot of pathways that are known to be important for regulation of appetite and glucose levels, namely ghrelin, AMPK, and NPY. These have been rather hard to approach directly with small molecules, or (in the case of NPY) hitting them hasn't been enough by itself. That's the problem with a lot of potential therapies for obesity, as I've mentioned here before. As a behavior, eating is full of overlapping backup redundant pathways, since we're all descendants of creatures that ate whatever they could, whenever they could. The ones whose feeding could be easily shut down or interrupted didn't make it this far.
So even though the field is littered with things that haven't worked out, perhaps a target like this, which seems to be more upstream, might have a better chance of success. We're definitely going to find out. Given the number of companies interested in this area, and the number with kinase expertise, someone's going to be able to take a good swing at this one. The benefits might go beyond weight loss - animals given a known inhibitor (STO-609, a Sumitomo compound) were also resistant to the bad effects of a high-fat diet, putting on less weight than controls and showing better glucose control.
Of course, the fact that Sumitomo had a compound years ago that hits this target so well makes you wonder what ever happened to it. I can't find much about why it didn't progress, but you can be sure that other people are asking that same question right now. . .Update: see this comment for more on this topic. . .
Comments (11)
+ TrackBacks (0) | Category: Diabetes and Obesity
June 18, 2008
Posted by Derek
I’ve done a fair amount of work against drug targets for metabolic disorders, so a recent letter in Nature caught my eye. The authors have used an ingenious technique to determine the number and age of the adipocytes (fat cells) that an individual has, and have tracked that cell population year by year.
One thing that comes out is confirmation of the fact that people basically set their number of fat cells during childhood and/or adolescence, and that number is then constant through their adult life. Several subjects in this study put on or took off weight during it, but that made no real difference to their number of adipocytes. And though liposuction does reduce the number of fat cells (by brute force!), they’re back to their original count after three years or so. So weight changes, as other studies have also indicated, are almost entirely due to individual fat cells becoming larger and smaller.
But that doesn’t mean that you’ve got the same fat cells all the way through. Most interestingly, this study found that about 8% of the adipocyte population turns over every year, which is a higher fraction than anyone realized. Half the fat cells in the body, then, have been replaced after about eight years have gone by. That also means that the stable total number results from a balance between adipocyte death and new cell formation, and it would certainly be interesting to know how these are tied together so well. The authors suggest that this relatively high turnover could be a potential target for weight loss drugs. If we could figure out how, say, to keep the fat cell population from being renewed so exactly, their numbers might naturally decrease. (On the other hand, perhaps the rate at which they die would drop to keep the balance – no one knows yet).
So, how do you tell how old a fat cell is, anyway? That’s the ingenious part I mentioned above, and it involves the same sort of techniques used in radiocarbon dating. The amount of carbon-14 in the atmosphere is relatively constant, with a few minor variations over the last fifty thousand years or so. Well, relatively constant except for the 1950s and 1960s, when we as a species reset the counter but good by atmospheric testing of atomic and nuclear weapons. Those tests released a much larger than usual amount of 14C into the world - in 1963 the count had doubled over normal background - and that's since cycled into the biosphere through uptake by plants and other living creatures.
That process has sent the atmospheric levels of radioactive carbon down steeply over the years, but there’s plenty of signal to detect, and we know just how much it’s gone down every year. In effect, every year of the last 50 or 60 has an anomalous carbon-14 reading, and each one is unique and vintage-dated. We take up the carbon through our food, and as a cell is formed, the particular carbon isotope signature of your body at the time is in all its parts. Many of these are recycled constantly – but the DNA isn’t. Extracting the DNA from cells and looking at the carbon-14 levels through mass spectrometry gives you a “production date” stamp for when that cell was born. (See here for a longer discussion of carbon isotope mass spectrometry as it relates to detection of banned steroid hormone use, specifically in the Floyd Landis case. That post, by the way, led to the longest comment thread ever seen on this blog). The same technique is being used for other cell populations as well.
The confirmation that the number of fat cells seems to be set before adulthood also ties in with the obesity trends seen in the general population. The great majority of obese adults were also obese as children, and the great majority of non-obese children do not become obese as adults. What factors set this adipocyte count in a person’s early life, and how many of them are environmental and could be modified, will be very useful to know. . .
Comments (7)
+ TrackBacks (0) | Category: Diabetes and Obesity
June 16, 2008
Posted by Derek
About a year ago, I wrote about GSK's attempt to sell the lipase inhibitor orlistat over the counter as Alli:
"So my forecast for Alli is strong sales - for a while. Then it takes a dive, never to scale those heights again, as the word gets out. And the demand continues to grow for a weight-loss drug that works. . ."
Thanks to Pharmalot, this week we find this AP story which seems to confirm that suspicion. Sales for Alli aren't up to GSK's hopes, and the company is declining to say how much repeat business there is after people have tried it out, which says all that needs to be said. And this after one of their biggest marketing campaigns ever.
What still throws me is that an analyst quoted in the piece still talks about it as a drug that should, in theory, be a big seller. As that post from last summer makes clear, I've never once understood that, since Roche never could make it a huge seller as Xenical. You'll never be able to get around the unpleasant side effects of a pancreatic lipase inhibitor, as far as I can see, and you'll never be able to advertise one without mentioning them.
I think that the new, slimmed-down GSK organization is wasting money on this whole idea. But hey, Marketing thinks it's a great opportunity. . .
Comments (12)
+ TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity
May 8, 2008
Posted by Derek
Every few years, you hear talk of a renaissance in natural products-based drug discovery. Well, this news should postpone the next round of optimism for a bit longer: Merck is cutting their natural products program entirely. They've had a long history in that area, but no more. That C&E News item includes an interesting detail:
"The company disclosed that it would also be closing its 50-year-old natural products drug discovery operation based in Madrid after a Merck executive inadvertently included the plan in a PowerPoint presentation to an audience that included Merck employees."
Smooth move. I'm sure some interesting e-mails were exchanged around Rahway and Madrid after that one. When, when will we get the powerful regulatory oversight of PowerPoint technology that the masses have cried out for these many years?
The main thing I remember about Merck's operation in Madrid was when they made a big splash about ten years ago with a weird looking indole/quinone thing that directly activated the insulin receptor. It made the cover of Science and all sorts of press releases, and my biology colleagues starting pestering me immediately. "Hey, you chemists keep saying that there's no point in running a small-molecule screen against the insulin receptor!"
Well, as it turned out, we were right. I assured my co-workers on the next floor that the Merck compound was one of the least likely drug candidate structures I'd ever seen, and that I'd be intensely surprised if it went anywhere. In fact, I told them, seeing it on the cover of Science actually decreased the likelihood that it was anything useful. If Merck really had a small-molecule insulin mimetic, I reasoned, the program would be a real stealth bomber, for fear of sending all sorts of other companies into the same chemical space too quickly. This one had all the signs of the people involved saying "You know, the only thing this stuff is good for is getting on the cover of Science"
So it proved, eventually. The compounds never went anywhere. It looks like the most recent natural product-derived compound that Merck got onto the market was Cancidas (caspofungin), and that was seven years ago. Mevacor (lovastatin) will stand as the modern high-water mark of Merck's natural product work - presumably from now on.
Comments (20)
+ TrackBacks (0) | Category: Diabetes and Obesity | Drug Industry History
April 25, 2008
Posted by Derek
I don’t want to say that this is a trend, but I notice that GSK is saying that they’re going to leave Sirtris more or less alone as well (as Takeda has said they’ll do with Millennium). The researchers in both shops should feel good about that, and not only because they’ll be keeping their jobs. They’re getting a vote of confidence in the most meaningful way that a large company can give that to its employees: by paying you money and not messing with you.
Of course, these deals have two sides to them. I don’t know what it’s like in Takeda back in Japan – my contacts inside the Japanese pharmaceutical industry aren’t extensive. But I think that some of the people at GSK (where I do know a lot of people) are wondering just what motivated their company to spend $720 million on Sirtris rather than on them.
It’s a fair question, even though I don’t have a problem myself with the Sirtris deal (as I said yesterday). But the sirtuins themselves are targets that anyone can work on, and you’d assume that a big outfit like GlaxoSmithKline could, if they wanted to, make a big push into the area and find some interesting things. So why didn’t they? The most obvious reason would be Sirtris had already done a good deal of that work, and it was more economical for GSK to buy it than to redo it. Another possibility is that the chemical space for drug-like hits in that area may not be very spacious, and that Sirtris may have already carved out a good piece of that real estate.
There’s also a bit of Glaxo history to deal with. The company had already, about fifteen years ago, decided to make a great big push into a promising new research area: nuclear receptors. They set up a whole research institute and did a huge amount of good science trying to figure out how these things worked, what they were good for, and how to get drugs that affected them. I got interested in the field in the late 1990s, and it became clear to me very quickly that Glaxo’s effort was the most serious of the bunch (and that included some really substantial research going on at Merck, Lilly and some other outfits). The company had teams of people who seemed to do nothing else than study the structures of these things, generate reams of X-ray data, synthesize huge lists of ligand molecules of every kind you could want, and so on. Just run "Glaxo nuclear receptor" through PubMed to see what I mean.
And what did it get them? From what I can see, not much. Avandia (rosiglitazone) is a nuclear receptor ligand (for PPAR-gamma), but its activity had already been discovered, and it was in clinical trials without a known mechanism. Figuring out how it worked was one of the Glaxo team’s early triumphs. But Avandia has turned out to be famously troublesome, and no others have come to market, despite multiple tries in the clinic. The huge amount of time and money the company spent generated a lot of interesting science, but appears (at least to me) to have brought in not one dime of revenue. (No doubt someone from GSK will correct me if I’m wrong).
So you can see how the company might be wary of starting a big internal effort to explore a massive, complex, and risky new field of biology. Politically and psychologically, it’s probably easier for them to structure this in terms of an acquisition.
Comments (15)
+ TrackBacks (0) | Category: Aging and Lifespan | Business and Markets | Diabetes and Obesity | Drug Industry History
April 10, 2008
Posted by Derek
As mentioned yesterday, I would have to say that Mannkind is in big trouble. I’d never heard of the company until the Wonder Drug Factory was closing back in Connecticut, but Mannkind was moving some of their operations into the state around then and interviewed a number of my former colleagues.
The whole inhaled-insulin idea had already taken some pretty severe blows. The massive failure of Exubera was the biggest, although a creative person could always argue that a better product with a more convenient delivery system could succeed in its place. But then Novo Nordisk and Eli Lilly (serious diabetes players, both of them) got out of the area before they’d even launched, deciding that it was better to write off their whole investment than to try to bring it to market. That didn’t help, which is one reason that Mannkind stock was down in the single digits, despite the company's efforts.
Well, as of yesterday it’s down in the really low single digits. And I honestly can’t see how they’re going to revive their flagship program if the Pfizer lung cancer data are real. The FDA is going to be very, very cautious about allowing any sort of inhaled insulin trials to proceed. I’d think that you’d have to show that your product is different from Exubera in its carcinogenic risk just to get one off the ground, and frankly, I have no idea how you’d do that. Anything that could will take years to develop and validate.
This latest result also shows some of the real difficulties and risks of drug development. After all, Pfizer and Nektar spent a very long time developing Exubera. The product was delayed and delayed while more and more clinical work was done. But in a slow-starting condition like lung cancer, those years may still not enough to quite pick things up by the time a product makes it to market. Think of what might have happened if Exubera had been a success. . .
And that brings us back to the regulatory pre-emption topic of the other day. This illustrates why either extreme of that argument is untenable. On the make-‘em-pay side, you have trial lawyers arguing that if companies just wouldn’t put defective products on the market, well, they wouldn’t have anything to worry about, would they? Test your drugs correctly and things will be fine! But Exubera’s pre-approval life was as long and detailed as could be. The testing went on and on – and after all, insulin itself has been on the market for more than half a century. What more would a company need to say something is safe?
Then there’s the other side – total pre-emption, which says that the FDA is there to regulate and sign off on safety and efficacy, and by gosh we should have them do it. Once this mighty agency gives its stamp of approval, that settles it. But again, the FDA put Exubera through all kinds of paces. If every drug took that long and cost that much to develop, we’d be in even worse shape than we are now, believe me. So what’s the agency to do?
The truth, as far as I can see, is that no one can guarantee the safety of a new drug. If you want to take that further, guaranteeing the safety of an existing drug isn’t possible, either. Every known drug is capable of causing trouble at some dose, and every known drug is capable of causing trouble at its normal dose in some people. Every new drug has the possibility of doing things no one ever anticipated, once it gets into enough patients for enough time. Every single one.
Complete safety doesn’t exist, and never has. You can have more safety, if you’re willing to take enough time and spend enough money. But you can take all the time we have on earth, and spend all the money available, and you still won’t be able to promise that nothing bad will ever happen. Pretending that either the drug companies or the regulatory agencies can make that fact go away is a position for fools and demagogues.
Comments (12)
+ TrackBacks (0) | Category: Diabetes and Obesity | Drug Development | Toxicology
April 9, 2008
Posted by Derek
I don't usually do more than one post a day, but this really caught my eye. In an ongoing review of Pfizer's (now discontinued) inhaled insulin (Exubera), an increased chance of lung cancer has turned up among participants in the clinical trials. Six of the over four thousand patients in the trials on Exubera have since developed the disease, versus one of the similarly-sized control group. Six isn't many, but with that large a sample size, it's something that statistically can't be ignored, either.
The concerns would have to be, naturally, that this number could increase, since damage to lung tissue might take a while to show up. This, needless to say, completely ends Nektar's attempts to find another partner for Exubera. Their stock is getting severely treated today (down 25% as I write), but things are even worse for another small company, Mannkind, that's been working on their own inhaled insulin for years now (down 58% at the moment).
There's no guarantee that another inhaled form would cause the same problems, but there's certainly no guarantee that it wouldn't, either. Whether this is an Exubera-specific problem, an insulin-specific one, or something that all attempts at inhaled proteins will have to look out for is just unknown. And unknown, in this case, is bad. It's going to be hard to make the case to find out, if this is the sort of potential problem waiting for your new product. Inhaled therapeutics of all sorts have taken a huge setback today.
Comments (19)
+ TrackBacks (0) | Category: Cancer | Clinical Trials | Diabetes and Obesity | Toxicology
April 3, 2008
Posted by Derek
I was having a discussion the other day about which therapeutic areas have the best predictive assays. That is, what diseases can you be reasonably sure of treating before your drug candidate gets into (costly) human trials? As we went on, things settled out roughly like this:
Cardiovascular (circulatory): not so bad. We’ve got a reasonably good handle on the mechanisms of high blood pressure, and the assays for it are pretty predictive, compared to a lot of other fields. (Of course, that’s also now one of the most well-served therapeutic areas in all of medicine). There are some harder problems, like primary pulmonary hypertension, but you could still go into humans with a bit more confidence than usual if you had something that looked good in animals.
Cardiovascular (lipids): deceptive. There aren’t any animals that handle lipids quite the way that humans do, but we’ve learned a lot about how to interpolate animal results. That plus the various transgenic models gives you a reasonable read. The problem is, we don’t really understand human lipidology and its relation to disease as well as we should (or as well as a lot of people think we do), so there are larger long-term problems hanging over everything. But yeah, you can get a new drug with a new mechanism to market. Like Vytorin.
CNS: appalling. That goes for the whole lot – anxiety, depression, Alzheimer’s, schizophrenia, you name it. The animal models are largely voodoo, and the mechanisms for the underlying diseases are usually opaque. The peripheral nervous system isn’t much better, as anyone who’s worked in pain medication will tell you ruefully. And all this is particularly disturbing, because the clinical trials here are so awful that you’d really appreciate some good preclinical pharmacology: patient variability is extreme, the placebo effect can eat you alive, and both the diseases and their treatments tend to progress very, very slowly. Oh, it’s just a nonstop festival of fun over in this slot. Correspondingly, the opportunities are huge.
Anti-infectives: good, by comparison. It’s not like you can’t have clinical failures in this area, but for the most part, if you can stop viruses or kill bugs in a dish, you can do it in an animal, or in a person. The questions are always whether you can do it to the right extent, and just how long it’ll be before you start seeing resistance. With antibacterials that can be, say, "before the end of your clinical trials". There aren’t as many targets here as everyone would like, and none of them is going to be a gigantic blockbuster, but if you find one you can attack it with more confidence than usual.
Diabetes: pretty good, up to a point. There are a number of well-studied animal models here, and if your drug’s mechanism fits their quirks and limitations, then you should be in fairly good shape. Not by coincidence, this is also a pretty well-served area, by current standards. If you’re trying something off the beaten path, though, a route that STZ or db/db rats won’t pick up well, then things get harder. Look out, though, because this disease area starts to intersect with lipids, which (it bears saying again) We Don't Understand Too Well.
Obesity: deceptive in the extreme. There are an endless number of ways to get rats to lose weight. Hardly any of them, though, turn out to be relevant to humans or relevant to something humans would consider paying for. (Relentless vertigo would work to throw the animals off their feed, for example, but would probably be a loser in the marketplace. Although come to think of it, there is Alli, so you never know). And the problem here is always that there are so many overlapping backup redundant pathways for feeding behavior, so the chances for any one compound doing something dramatic are, well, slim. The expectations that a lot of people have for a weight-loss therapy are so high (thanks partly to years of heavily advertised herbal scams and bizarre devices), but the reality is so constrained.
Oncology: horrible, just horrible. No one trusts the main animal models in this area (rat xenografts of tumor lines) as anything more than rough, crude filters on the way to clinical trials. And no one should. Always remember: Iressa, the erstwhile AstraZeneca wonder drug from a few years back, continues to kick over all kinds of xenograft models. It looks great! It doesn’t work in humans! And it's not alone, either. So people take all kinds of stuff into the clinic against cancer, because what else can you do? That leads to a terrifying overall failure rate, and has also led to, if you can believe it, a real shortage of cancer patients for trials in many indications.
OK, those are some that I know about from personal experience. I’d be glad to hear from folks in other areas, like allergy/inflammation, about how their stuff rates. And there are a lot of smaller indications I haven’t mentioned, many of them under the broad heading of immunology (lupus, MS, etc.) whose disease models range from “difficult to run and/or interpret” on the high side all the way down to “furry little random number generators”.
Comments (8)
+ TrackBacks (0) | Category: Animal Testing | Cancer | Cardiovascular Disease | Diabetes and Obesity | Drug Assays | Drug Development | Infectious Diseases | The Central Nervous System
March 12, 2008
Posted by Derek
Well, I wish I hadn’t been right about this one. Last month I spent some time expressing doubts about Merck’s new obesity drug candidate taranabant, a cannabinoid-1 ligand similar to Sanofi-Aventis’s failed Acomplia (rimonabant). S-A ran into a number of central nervous system side effects in the clinic, and although they’ve gotten the drug approved in a few markets, it’s not selling well. US approval, now long delayed, looks extremely unlikely.
I couldn’t see why Merck wouldn’t run into the same sort of trouble. If a report from a Wall St. analyst (Aileen Salares of Leerink Swann) is correct, they have. Merck’s presenting on the compound at the next American College of Cardiology meeting (at the end of this month in Chicago), and information from the talk has apparently leaked out in violation of the ACC's embargo. There appears to be some difficulty both on the efficacy and side effect fronts – bad news all around.
The company was aiming for a 5% weight loss, but only reached that at the highest dose (4 mg). The report is that CNS side effects were prominent at this level, twice the rate of the placebo group. The next lower dose, 2 mg, missed the efficacy endpoint and still seems to have shown CNS effects. According to Salares, nearly twice the number of patients in the drug treatment group dropped out of the trial as compared to placebo, citing neurological effects which included thoughts of suicide.
While there’s no confirmation from Merck on these figures, they’re disturbingly plausible, because that’s just the profile that got rimonabant into trouble. If this holds up, I think we can say that CB-1 ligands as a CNS therapeutic class are dead, at least until we understand a lot more about their role in the brain. Two drugs with different structures and different pharmacological profiles have now run into the same suite of unacceptable side effects, and the main thing they have in common is CB-1 receptor occupancy. There’s always the possibility that a CB-1 antagonist (or inverse agonist) might have a use out in the periphery – they could have immunomodulatory effects – but anyone who tries this out would be well advised to do it with a compound that doesn’t cross the blood-brain barrier.
And as for taranabant, if the data are as reported I don’t see how Merck can get this compound through the FDA. Even if they did, by some weird accident, I don’t see why they’d pull the pin on such a potential liability grenade. Can you imagine what the labeling would have to look like in order to try (in vain, most likely) to insulate the company from lawsuits? That makes a person wonder how on earth the company could have been talking about submitting it for approval later this year, which is what they were doing just recently. They must have had these numbers when they made that statement – wouldn’t you think? And they must have immediately realized that this would be trouble – you’d think. If that Leerink Swan report is correct, the company’s recent statements are just bizarre.
Comments (29)
+ TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | The Central Nervous System | Toxicology
March 4, 2008
Posted by Derek
Here's a snapshot for you, to illustrate how little we know about what many of our compounds can do. I was browsing the latest issue of the British Journal of Pharmacology, which is one of many perfectly respectable journals in that field, and was struck by the table of contents.
Here, for example, is a paper on Celebrex (celecoxib), but not about its role in pain or inflammation. No, this one, from a group in Turin, is studying the drug's effects on a colon cancer cell line, and finding that it affects the ability of the cells to stick to surfaces. This appears to be driven by downregulation of adhesion proteins such as ICAM-1 and VCAM-1, and that seems to have nothing particular to do with COX-2 inhibition, which is, of course, the whole reason that Celebrex exists.
This is a story that's been going on for a few years now. There's been quite a bit of study on the use of COX-2 drugs in cancer (particularly colon cancer), but that was driven by their actual COX-2 effects. Now it's to the point that people are looking at close analogs of the drugs that don't have any COX-2 effects at all, but still seem to have promise in oncology. You never know.
Moving down the list of papers, there's this one, which studies a well-known model of diabetes in rats. Cardiovascular complications are among the worst features of chronic diabetes, so these folks are looking at the effect of vascular relaxing compounds to see if they might provide some therapeutic effect. And they found that giving these diabetic rats sildenafil, better known as Viagra, seems to have helped quite a bit. They suggest that smaller chronic doses might well be beneficial in human patients, which is definitely not something that the drug was targeted for, but could actually work.
And further down, here's another paper looking at a known drug. In this case, it's another piece of the puzzle about the effects of Acomplia (rimonabant), Sanofi-Aventis's one-time wonder drug candidate for obesity. It's become clear that it (and perhaps all CB-1 compounds) may also have effects on inflammation and the immune system, and these researchers confirm that with one subtype of blood cells. It appears that rimonabant is also a novel immune modulator, which is most definitely not one of the things it was envisioned as. Do the other CB-1 compounds (such as Merck's taranabant) have such effects? No one knows, but it wouldn't come as a complete surprise, would it?
These are not unusual examples. They just serve to show how little we understand about human physiology, and how important it is to study drugs in whole living systems. You might never learn about such things by studying the biochemical pathways in isolation, as valuable as that is in other contexts. But our context in the drug industry is the real world, with real human patients, and they're going to be surprising us for a long time to come. Good surprises, and bad ones, too.
Comments (8)
+ TrackBacks (0) | Category: Cardiovascular Disease | Diabetes and Obesity | Drug Development | Toxicology
February 25, 2008
Posted by Derek
My piece on Merck last week seems to have touched a few nerves, if some of the comments and e-mails I’ve received are any sign. To clarify things: I agree that Merck is still doing some excellent science, as they always have. And they still have a lot of good people there, as they always have. Those aren’t the problems. And they’re still introducing some innovative drugs, arguably more than a lot of other companies, and that’s not the problem, either. These are all are admirable things.
And Vioxx, as I said here at the time, was not, in my opinion, necessarily a bad drug. It and the other COX-2 inhibitors have a real place in the pharmacopeia. The problem is that Merck – or, to put the usual face-saving perspective on it, Merck’s marketing department – oversold the stuff. The prospect of an aspirin-sized market was too much for them to resist, so the company pushed Vioxx just about as hard as they possibly could.
Yep, Vioxx was for all kinds of patients, all kinds of pain, all the time – and under those conditions, whatever side effects were there were finally revealed. It’s the company’s bad luck (not to mention the bad luck of their patients) that those effects were as potentially severe as they were. Even so, the increased risk of a heart attack with Vioxx use is extremely small in any absolute sense. For people with severe pain who can’t get relief with other drugs, I think a COX-2 inhibitor is absolutely worth it.
But that’s not what you’d think from reading the newspapers, or from listening to the lawyers. It was expedient to paint the company as a bunch of callous poisoners; Merck’s reputation has been hooked to the back of a pickup truck and pulled through a swamp. (They didn't always do themselves much good during that period, either). And while the good name was bouncing off the tree stumps and scooping up the mud, the company had to spend vast amounts of money to deal with all those lawsuits, which is money that presumably could have been used for something else. (OK, some of that is coming from insurance – but think of how much more they’ll be paying for that coverage now).
Which is what worries me about taranabant. I realize, as several commenters to the previous post pointed out, that it may well differ in selectivity and CB-1 receptor activity from rimonabant. If the compound is an inverse agonist instead of an antagonist at the receptor, that could well be good news. Or, you know, it might not be, since we have no idea of what an inverse agonist will do, either. (More on the difference between those terms in a future post). At any rate, discovering new things about human CNS functions while a bunch of lawyers watch doesn’t sound like a good idea. If Merck does end up going down the Vioxx path again, another run through the swamp will do it no good at all.
Comments (23)
+ TrackBacks (0) | Category: Diabetes and Obesity | The Dark Side
February 20, 2008
Posted by Derek
A recent item from InVivoBlog about Merck which brought up some interesting points. They aren’t cheerful ones. The article is largely about Merck’s reputation, which has taken some dents in recent years, to put it lightly. The Vioxx debacle is the main reason for this, but the hits have kept on coming, such as the latest controversy over the release of the disappointing Vytorin study data.
So, although this is a painful question, perhaps it needs to be asked: remember when Merck was above all that stuff? Maybe there should be a “seemed” in that sentence somewhere; that might take some of the sting away. But the company really did have a singular reputation at one time. Depending on your point of view, you could have used words like “insular” or “arrogant” to describe the culture over there, but they were distinctive.
Merck didn’t merge with anyone. They stuck with targets and projects for years and years if they thought something would come out of them. And (until Vioxx) they avoided the sorts of disasters that seemed to hit other companies. That’s gone. Not all gone – they still seem to run on longer timelines over there – but one of the most distinctive things about the company was how it guarded its reputation, and that seems to have slipped down the list. They didn't have to do ad campaigns like this one. The company's trying to convince people, or convince themselves, that things haven't changed, but they're wrong.
The other thing that struck me about the article was about the development of the company’s CB-1 antagonist. That’s the same mechanism as rimonabant, Sanofi-Aventis’s failed wonder drug for obesity. (OK, it’s on the market as Acomplia in several countries, but considering what people had thought it would do, it’s a failure, all right). I question Merck’s judgment in pushing another compound into that area, although these programs do take on a life of their own. And as the In Vivo post points out, Merck’s current reputation of pushing every drug as hard as possible won’t help it when it comes to getting the drug through the FDA.
The biggest problem with rimonabant was the comparison of its side effects to its efficacy. It does seem to help people lose weight, although not to any startling extent, but in a large patient population various psychiatric side effects showed up. Taranabant's side effect profile isn't yet clear. Merck is going to have to tread lightly, but can they? The situation is a bit too much like Vioxx, with a huge, lucrative market out there if you can just expand the patient population. And we can argue about just how bad Vioxx really was, and about its risk/benefit ratio, but that won't change the fact that it was a catastrophe for Merck. The last thing they need is another one. I don't think I would have picked this time to push another CB-1 antagonist forward, but I suppose we don't get to pick that sort of thing. . .
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+ TrackBacks (0) | Category: Diabetes and Obesity | Drug Development | Drug Industry History | The Dark Side
January 18, 2008
Posted by Derek
After Pfizer’s Exubera inhaled-insulin product died so horribly in the market last year, the other companies working in the same space had to be worried. Lilly and Alkermes have had a long-running program, as has a smaller company called Mannkind. But recently, another contender, Novo Nordisk, has announced that they and partner Aradigm have decided to cut their losses. The In Vivo Blog has an excellent roundup.
According to Novo’s CEO, they (like Pfizer) were focusing on prandial insulin because that was basically the only thing they could get to work through inhalation. Now that they’ve seen how well that went over, they’ve decided to spend the money on different proteins (basal insulin, glucagon-like-peptide 1 analogs, etc.) They have a GLP-1 analog in Phase III, but apparently are heading toward the clinic with a second-generation one that can work by the inhaled route.
I wish them luck. We really need new routes of administration for drugs, and every seemingly good candidate has some real problems. There’s a limit to how much compound you can administer transdermally through a patch, for example, and a limit to how quickly it can be administered. Long, slow, continuous delivery is fine, but no one’s going to be marketing an epinephrine patch for anaphylactic shock any time soon. Similarly, you can probably forget about antibiotic-sized total doses, too, because nobody’s skin has enough surface area. (I know, I know, on some people you might think it would work – but if you weigh a lot, you probably need more antibiotic to start with on a mg/kilo basis, and meanwhile your surface area goes up as a square while your volume goes up as a cube, and it’s a losing battle).
No, unless we find some way to make the skin crazily permeable, it’s never going to be a great delivery system. And crazily permeable is just what the skin is not, for good reason. That’s why pulmonary delivery makes sense, to a first approximation. The lungs have huge surface area, just like the small intestine does for oral dosing, because both those organs live to absorb things from the environment (as opposed to the skin). The lungs absorb a gas, unfortunately, as opposed to the small molecules absorbed by the intestines, but a gas is just a special subset of small molecule.
But there’s the downside of the idea. While an oral drug is piggybacking on machinery that’s doing what it’s supposed to be doing, lung delivery is making the organ do something it’s not. (Thus the idea of dosing peptides by this route, since the lungs aren’t a soup of proteolytic enzymes, and pulmonary circulation does not feed your compounds right into the sawmill of the liver). While the intestine absorbs all kinds of stuff, the lungs are there to absorb only one gas and excrete only one. And that primary function of oxygen / carbon dioxide transfer is rather vital, so if you’re going to horn in on it, you’d better be sure that you’re not going to degrade things.
That’s always been the worry with inhalation dosing. We can get around the acute problem of choking the patients, but the chronic problem of potential lung damage is always a worry. Lung function varies quite a bit, too, even under normal conditions, That variation is both patient-to-patient and from time to time – how do you take your inhaled medicine when you have a chest cold, or if you pull a muscle? (And that’s another reason why it’s sort of a grim cosmic joke that insulin turns out to be the big test for peptide drug delivery through the lungs, since its safe dosing window can be so narrow).
I’ll go into the ups and downs of other potential administration routes in another post. Most of them involve sharp objects, though, so they take on a certain similarity, and have the same only-if-I-have-to reputation.
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+ TrackBacks (0) | Category: Diabetes and Obesity | Drug Development | Pharmacokinetics
December 5, 2007
Posted by Derek
How many hits can a drug – or a whole class of drugs – take? Avandia (rosiglitazone) has been the subject of much wrangling about cardiovascular risk in its patient population of Type II diabetics. But there have also been scattered reports of increases in fractures among people taking it or Actos (pioglitazone), the other drug with the same mechanism of action.
Now Ron Evans and his co-workers at Salk, who know about as much PPAR-gamma biology as there is to know, have completed a difficult series of experiments that provides some worrying data about what might be going on. Studying PPAR-gamma’s function in mice is tricky, since you can’t just step in and knock it out (that’s embryonic lethal), and its function varies depending on the tissue where it’s expressed. (That latter effect is seen across many other nuclear receptors, which is just one of the things that make their biology so nightmarishly complex).
So tissue-specific knockouts are the way to go, but the bones are an interesting organ. The body is constantly laying down new bone tissue and reabsorbing the old. Evans and his team managed to knock out the system in osteoclasts (the bone-destroying cells), but not osteoblasts (the bone-forming ones). It’s been known for years that PPAR-gamma has effects on the development of the latter cells, which makes sense, because it also affects adipocytes (fat cells), and those two come from the same lineage. But no one’s been able to get a handle on what it does in osteoclasts, until now.
It turns out that without PPAR-gamma, the bones of the mice turned out larger and much more dense than in wild-type mice. (That’s called osteopetrosis, a word that you don’t hear very much compared to its opposite). Examining the tissue confirmed that there seemed to be normal numbers of osteoblasts, but far fewer osteoclasts to reabsorb the bone that was being produced. Does PPAR stimulation do the opposite? Unfortunately, yes – there had already been concern about possible effects on bone formation because of the known effects on osteoblasts, but it turned out that dosing rosiglitazone in mice actually stimulates their osteoclasts. This double mode of action, which was unexpected, speeds up the destruction of bone and at the same time slow down its formation. Not a good combination.
So there’s a real possibility that long-term PPAR-gamma agonist use might lead to osteoporosis in humans. If this is confirmed by studies of human osteoclast activity, that may be it for the glitazones. They seem to have real benefit in the treatment of diabetes, but not with these consequences. Suspicion of cardiovascular trouble, evidence of osteoporosis – diabetic patients have enough problems already.
As I’ve mentioned here before, I think that PPAR biology is a clear example of something that has turned out to be (thus far) too complex for us to deal with. (Want a taste? Try this on for size, and let me assure that this is a painfully oversimplified diagram). We don’t understand enough of the biology to know what to target, how to target it, and what else might happen when we do. And we've just proven that again. I spent several years working in this field, and I have to say, I feel safer watching it from a distance.
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+ TrackBacks (0) | Category: Biological News | Diabetes and Obesity | Toxicology
November 28, 2007
Posted by Derek
Novartis must wonder what they did to deserve this one. A few years ago, it looked as if they ruled the potentially lucrative world of dipeptidylylpeptidase-IV (DPP-IV) inhibitors for diabetes. (Note - name of enzyme corrected after brain hiccup - DBL). Novartis seemed to be the first big company to come up with good chemical matter in the area, and they published a whole string of papers while their lead compound went through the clinic.
Then came trouble. Merck turned out to have a big program of their own in the area, which in Merckian fashion they’d kept very quiet about, and they actually beat Novartis to the FDA. And then they beat them to market, because the agency had some questions about the Novartis compound. Those questions have done nothing but multiply. Now the problem appears to be liver tox, one of the last things the diabetic population needs. It’s looking very likely that Novartis’s compound may never get to the market in the US at all.
So here’s a question: if both compounds had made it to market, wouldn’t the people who tally up lists of “me-too” drugs have considered the first compound (from Merck) to be the original, and the Novartis one to be the copycat? After all, they target the same enzyme for the same disease in the same way. (I should mention that a DPP-IV inhibitor itself is just the sort of thing the industry is supposed to be turning out, a completely new way to treat a major and growing public health problem, but we'll pass over that for now).
But these compounds were developed more or less simultaneously, with the two companies racing each other to the market. It’s not like either company sat back and watched the big profits roll in, and said “I need to latch on to some of that – let’s make one of those, too.” The whole thing was done on a risk basis, because while the biochemical rationale behind DPP-IV inhibition makes sense, a lot of things make sense and still go nowhere. No one really knew how the drugs would perform, either in the clinic or in the marketplace.
And take a look at the problems that the Novartis compound has. Like so many other toxicology hits, these came out of the cloudless sky. Well, actually, it’s more accurate to say that the sky over the toxicologists is never cloudless, because you never know what’s going to happen. In this case, Novartis has taken an especially painful and expensive beating, since the drug had advanced so far before the problems began to make themselves clear.
I’d like to ask some of the critics of the industry what they think about this situation. Me-too drugs are a particular arguing point with many of these people, so here we go: does that term apply in this case? If not, then why not? Should companies go after the same target in the same way at the same time? If not, then why not? How do we deal with the fact that any compound can fail at any time, other than turning companies loose to compete with each other and take as many shots at a target as possible? Do you have a better solution – and if not, well, then, why not?
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+ TrackBacks (0) | Category: "Me Too" Drugs | Diabetes and Obesity | Drug Development
November 19, 2007
Posted by Derek
Back in 2005, I worried about taking a new drug to market that had a completely new central nervous system mechanism: Acomplia (rimonabant). CNS makes me nervous. I used to work in the area, and I have a healthy respect for how little we know about it. So when you come in with something new, you have to be worried about what's going to happen, and whether your clinical trials are going to be enough to tell you about it.
And sure enough, the long, long delay at the FDA for the drug, which was (in theory) supposed to be approved in the first half of 2006, turned out to hinge on CNS side effects, among them "suicidal ideation". Now a meta-analysis has come out in The Lancet which suggests that patients taking the drug in Europe (one of the few places you can take it) have a much higher risk of depression.
You have to be careful with meta-analyses. But this one's noteworthy because, as the authors point out, depressed mood was an exclusionary factor for the studies concerned. Yet even after winnowing out those patients, the study patients seem to have been 2.5 times as likely to drop out of the trials due to depression as compared to the placebo groups. The studies totaled 2503 patients on the drug, and 1602 in the placebo groups. Depression showed up in 74 and 22 cases in those groups, respectively, which does seem to be a real effect, especially when you start by excluding anyone who seems depressed.
Compare that with the Avandia meta-analysis that has made much so much news (and come close to sinking the drug completely). Out of 14,000 patients, that one had 86 cardiac events in the treatment groups and 72 in the controls, and this in a population with underlying cardiovascular trouble. Depression is not as serious an outcome as a heart attack, to be sure, but it's nothing you'd sign up for, either. Sanofi-Aventis should stop being upset that they haven't gotten the drug on the market here, and start being glad that the lawyers here didn't get a chance to strip a few billion dollars off of them.
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+ TrackBacks (0) | Category: Diabetes and Obesity
October 22, 2007
Posted by Derek
Pfizer has pulled the inhaled insulin Exubera from the market, and not because of the FDA, and not because of the lawyers. They’re giving up on it because they can’t take the pain any more. The company sold 12 million dollars worth of the stuff so far this year, a horrifyingly tiny amount. That represents about 0.3% of the insulin market, which we can round off to "zero". The ticket out is a mere 2.8 billion dollar charge against earnings. It's the first time I can remember a company pulling a drug just because it was losing so much money - of course, Pfizer is not a normal company, and these are not normal times, especially for them.
There are plenty of post-mortems around, from the front page of the Wall Street Journal onward. (See the Journal’s Health Blog, Matthew Herper’s blog at Forbes, Pharmalot and the folks at Invivoblog for more). I have my own, naturally, since a disaster of this size admits of many interpretations. Here’s what it says to me:
1. Marketing isn’t everything. The next time someone tells you about how drug companies can sell junk that people don’t need through their powerful, money-laden sales force, spare a thought for Pfizer. The biggest drug company in the world, with the biggest sales force and the biggest cash reserves, couldn’t move this turkey. People didn’t want it, and they didn’t buy it.
The flip side of this is that even the drugs that folks love to hate, the ones that no one can figure out why they do as well as they do, must be doing something for some people. Perhaps other, cheaper drugs would do something quite similar, and we can discuss cost/benefit ratios, but you couldn’t sell them if people didn’t feel that benefit in the denominator. Not many people felt it from Exubera.
2. Internal sales estimates can be a joke. People inside the drug companies have known this for a long time, although they’d often rather not think about it. Analysts have known it, too, but they're forced to pay attention to those numbers anyway. But man, look at the magnitude of this one. Just as Warner-Lambert tried to kill Lipitor before they brought it to market (who needs another statin?), Pfizer was telling analysts a few years ago that their projections for Exubera sales (a billion dollars a year) were just too darn low. Two billion a year by 2010, thank you and please correct the error. Only off by a factor of one hundred, and what’s two log units between friends?
Sales forecasts are not science, and they only bear a superficial resemblance to math (where the phrase "imaginary number" is rather more strictly defined). They are guesses, and some of them are good guesses and some of them are awful, and unfortunately when you first look them over, they all smell about the same.
3. Groups aren’t necessarily smarter. This is the flip side of all the “Wisdom of Crowds” stuff, which only works when a lot of people (who think of a lot of different things) all get a crack at a subject. Inside a company, though, diversity of opinion sometimes doesn’t get much respect, and the problem gets worse in areas like marketing (and worse as you go into the higher ranks). Think of what would have happened to a Pfizer exec who forecast a 0.3% market share and a 2.8 billion dollar charge for Exubera when everyone else was revising their figures up a billion. It would have taken a fantastic amount of nerve to make a call that contrarian, and the rewards for being right (if any) would definitely not have been worth it. Even if someone had a terrible suspicion, it was surely much safer to keep quiet.
Groups of people can, in fact, be quite stupid. People will deliberately not bring their minds to bear on a problem, in order to get along with their co-workers, to not stick their heads up, or just to make the damned meetings end more quickly.
4. Pfizer is in vast amounts of trouble. While not an original thought, it's an unavoidable one. We all know the problems they have, and believe it, they do too. But what to do? I remarked a few weeks ago that Pfizer's situation reminded me of a slow-motion film of a train running toward a cliff, and a colleague of mine said "Yeah, me too, but in this case they're still boarding passengers and loading their luggage".
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+ TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity | Drug Industry History
September 6, 2007
Posted by Derek
It’s useful to be reminded every so often of how much you don’t know. There’s a new paper in PNAS that’ll do that for a number of its readers. The authors report a new protein, one of the iron-sulfur binding ones. There are quite a few of these known already, so this wouldn’t be big news by itself. But this one is the first of its kind to be found in the outer mitochondrial membrane, which makes it a bit more interesting.
It also has a very odd structure – well, odd to us humans anyway, for all we know things like this are all over the place and we haven’t stumbled across one until now. There’s a protein fold here which not only has never been seen in the 650 or iron-sulfur proteins with solved structures, it’s never been seen in any protein at all. That’s worth a good publication, for sure.
The part that’ll really throw people, though, is that this protein (named mitoNEET, for the amino acids that make up its weird fold) binds a known drug whose target we all thought we already knew. Actos (pioglitazone) turns out to associate with it, which is a very interesting surprise. We already knew the glitazones as PPAR-gamma ligands. We didn’t understand them as PPAR ligands (no one understands them very well, despite many years and many, many scores of millions of dollars), but that was generally accepted as their site of action.
And now there’s another one, which is going to make the pioglitazone story even more complex. Reading between the lines of the paper, I get the strong impression that the authors were fishing for another pioglitazone binding site, using modified versions of the drug to label proteins, and hit the jackpot with this one. (And good for them - that's a hard technique to get to work). There’s been some speculation that the compound might have effects on mitochondria that wouldn’t necessarily be PPAR-mediated, and this is strong circumstantial evidence for it.
What’s more, I can’t think of any other iron-sulfur proteins that are targets of small molecules. Just last week, I was talking about the diversity of binding sites and interactions that we haven’t explored in medicinal chemistry, and here’s an example for you.
This paper raises a pile of questions: what does mitoNEET do? Shuttle iron-sulfur complexes around? (If so, to where, and to what purpose?) Is it involved in diabetes, or other diseases of metabolism? Does pioglitazone modify its activity in vivo, whatever that activity is? How well does it bind the drug, anyway, and what does the structure of that complex look like? Does Avandia (rosiglitazone) bind, too, and if not, why not? Are there other proteins in this family, and do they also have drug interactions that we don’t know about? Ah, we’ll all be employed forever in this business, for as long as people can stand it.
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+ TrackBacks (0) | Category: Biological News | Diabetes and Obesity
August 9, 2007
Posted by Derek
I didn't note it at the time, but Amgen just recently finished buying a smaller company, Alantos. That cost them about $300 million, and for that money they got a diabetes drug in the clinic and a program generating compounds for arthritis and other diseases.
Sound OK, eh? That's the one-line executive summary right there, but look closer: the diabetes drug is a DPP-IV inhibitor. There's nothing wrong with that, except that this one is going to be what, if it makes it to market - fourth in line? Fifth? I've lost count. The Alantos compound may be a good one (Amgen certainly thinks so), but it's a crowded space, for sure.
And the arthritis drugs? Matrix metalloproteinase inhibitors. No, no, it really is 2007, not 1995. MMPs have been the subject of a big old pile of drug development over the years, all of which (to my knowledge) has come to grief. Again, there may be something particularly good about these (Amgen certainly thinks so), but it's a well-trodden space, for sure.
This deal makes me wonder a bit about Amgen's small-molecule pipeline. They don't talk much about it, although they have a lot of people doing traditional med-chem these days. No one seems to know what they're up to, though, and the inlicensing of drugs from such well-known therapeutic classes - ones that have not been particularly difficult to find lead compounds for, yet - is food for thought.
(As a sideline, Alantos, at least in its early days, was a champion of relatively exotic approaches like dynamic combinatorial chemistry, which I'll have to write a post on some day. Anyone know if these compounds came from that kind of work, or is this another case where the neat stuff never generated any drugs?)
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+ TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity
August 8, 2007
Posted by Derek
You know, you can run the biggest marketing behemoth the drug industry has ever seen - but if people really aren't interested in buying your product (and if insurance companies really aren't interested in paying for it), that's not enough.
The evidence? Pfizer's Exubera, the inhaled insulin that for years was thought by some to be one of the Next Big Things. Earlier this year, a "relaunch" of the product was announced, but that doesn't seem to have helped much. Pharmalot passes on the news that one of Pfizer's main suppliers is cutting back production.
This comes after the drug ran up only $4 million in sales in the second quarter, relaunch be damned. And I mean that "only" - compared to what Pfizer and its partner Nektar spent on developing Exubera, a few million dollars is nothing at all. You'd think that if we in the industry were as powerful and as evilly resourceful as our worst critics have us, we'd be able to keep things like this from happening - wouldn't we?
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+ TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity
July 23, 2007
Posted by Derek
Four years ago I wrote about an unusual Roche diabetes compound targeting glucokinase. The odd thing about it was that it made the enzyme more active, which is something you can only rarely hope to do. Enzymes generally run near the top of their specs, unless there's some built-in switch that keeps them damped down until they're needed. That's often phosphorylation, but another trick inside the cell is to keep the concentrations of substrate low (or the concentrations of some inhibitor high). But once they go, they usually go about as fast as they can. This glucokinase example is still about the only one I can think of in drug development, and it's had a fair amount of attention over the years.
Maybe I should switch the tense, though, because reader Daniel H. has informed me that Roche seems to have stopped work on the compound in Phase II. The company had taken their lead compound (R1440) through several different trials, so something seems to have been working, but they don't seem to have given any reasons as to why they abandoned it.
After that much Phase II work, the most likely answer is some sort of toxicity, the kind that comes up too close to the efficacious dose. A company may try several different dosing regimens, combinations with other drugs, or patient populations trying to get around a problem like that, and perhaps what we're seeing is the end of the line. Nothing looked safe enough to spend the really large money on Phase III.
By now, there are several other companies in the same area, and I'm sure they're rather curious about all this, too. Is glucokinase activation dead as a target? As with many questions in this industry, you'll have to have either a lot of money or a lot of patience to find out. And if you want to come down and try drug development yourself, you'll need a lot of both.
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+ TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | Drug Development
July 17, 2007
Posted by Derek
A commentor to my Proteomics 101 post the other day brought up an important point: that before you can have a chance to figure out what a protein is doing, you have to know that it exists. Finding the darn things is no small job, since you're digging through piles of chemically similar stuff to unearth them. What's more, we can't just ignore 'em: some of the low-concentration proteins are also correspondingly important and powerful.
Nasty arguments can erupt over whether a given protein and its proposed functions even exist. Crockery is flying over one of those right now, an insulin-like protein hormone dubbed "visfatin" by its discoverers in Osaka a couple of years ago. Well, in this case the protein probably exists, but does it do what it's advertised to do? An insulin mimic secreted by fat cells would be worth knowing about, but there doesn't seem to be enough of it present in the blood to do much of anything, given how well it binds to its putative targets. There are also reports that some of that data in the Osaka paper are hard to reproduce.
Complicating things even more is the (apparently well-founded) contention that visfatin is a re-discovery of a protein already known as PBEF, which is identical to another protein named Nampt. (Each "discovering" group assigned their own name, a situation that happens so often in biology that people don't even notice it any more).
The whipped topping on the whole thing is a accusation of misconduct by someone in Japan, which led to an investigation by Osaka University, which has now recommended that the original paper be retracted. Its lead author, Iichiro Shimomura, does not agree, as you might well imagine. The points of contention are many: whether the misconduct was real at all, or whether it describes real events that don't rise to the level of misconduct, or whether the conclusions of the paper are invalidated or not by them, and so on.
An early solution appears unlikely. And we still don't know what exactly visfatin/PBEF/Nampt is doing. Next time you wonder how things are going over in the proteome, consider this one.
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+ TrackBacks (0) | Category: Biological News | Diabetes and Obesity | The Dark Side
June 18, 2007
Posted by Derek
If you're wondering why Sanofi-Aventis would spend so much time and money on a tricky, problematic drug like rimonabant, just take a look at the reception of GSK's over-the-counter version of Xenical (orlistat), brand-named Alli.
What's ridiculous about all the coverage and hype is that the drug isn't (of course) new. And it frankly wasn't all that successful when Roche sold it by prescription. So it goes OTC and everyone goes crazy for it? No, not for long they won't. From what I can see, this is just pent-up demand for something, anything, that will help people lose weight without having to work too hard.
This is not the drug to do that. And that's putting things gently. It is, as it's been rightly termed, "the Antabuse of fat". It's there to keep you on a low-fat diet, and to make you pay if you stray. If you're taking orlistat but go out and eat a bucket of fried chicken, you're going to regret that excursion for years to come. Generally, people just gradually seem to stop taking the stuff regularly, which makes it less likely to do anything, which in turn provides the perfect reason to stop taking it completely.
So my forecast for Alli is strong sales - for a while. Then it takes a dive, never to scale those heights again, as the word gets out. And the demand continues to grow for a weight-loss drug that works. . .
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+ TrackBacks (0) | Category: Diabetes and Obesity
June 15, 2007
Posted by Derek
Everyone will have heard the news about Wednesday's FDA Advisory Commitee vote on Accomplia / Zimulti (rimonabant). If you'd tried to convince folks a few years ago that this drug wouldn't make it to a vote until summer of 2007, and would be unanimously rejected when it did, you'd have been looked at with pity and concern. No, this drug was going to conquer the world, and now people are talking merger-of-desperation.
Hey, you don't even have to go back a few years. Here's an article from 2006:
"A new anti-obesity pill that market observers say could become the world's biggest-selling drug is close to getting approval from the European Commission. . .
Gbola Amusa, an analyst with research firm Sanford C Bernstein, said that Acomplia could achieve $4.1bn in annual sales by 2010, in part because it has been shown in clinical trials not only to trim fat but to increase levels of good cholesterol and control diabetes.
"In the blue sky scenario, this could become the world's best- selling drug as the indication is so broad," he said. "It has a path to revenues that we rarely ever see from a pharma product."
Oh, the blue sky scenario. I'm no stranger to it myself - I love the blue sky scenario. But how often does it ever descend to earth? It's not going to do it this time. Sanofi-Aventis was reduced to making the suggestion that every potential patient be first screened for depression, which doesn't sound like the sort of iron wrecking ball that usually gets welded to the world's best-selling drugs.
In the wake of this development disaster, here are a few points that may not get the attention they deserve: first, consider the money that S-A has spent on this drug. We're never going to be shown an accurate accounting; no one outside the upper reaches of the company will ever see that. But I seriously doubt if they've ever spent more on any program. There's an excellent chance that most of it will never be recovered, not by rimonabant - it'll have to be recovered by whatever drugs the company can come up with in the future. They'll be priced accordingly.
Second, think about the position of their competitors. All sorts of companies have pursued this wonder blockbuster opportunity. If you run CB-1 antagonists through the databases, all kinds of stuff comes hosing out. Merck and Pfizer are the companies that were most advanced - you don't get much more advanced than Phase III clinical trials - but plenty of others spent time and money on the chase. All of those prospects have taken grievous damage. Odds are that rimonbant's problems are mechanism-related, and proving otherwise will be an expensive job. This is something to consider when you next hear about all those easy, cheap me-too drugs.
And finally, it's worth thinking about what this says about our abilities to prosecute drug development in general. Just as in the case of Pfizer's torcetrapib, we have here a huge, expensive, widely anticipated drug that comes down out of the sky because of something we didn't know about. It's going to happen again, too. Never think it won't. This is a risky, white-knuckle business, and it's going to be that way for a long time to come.
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+ TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | The Central Nervous System | Toxicology
June 11, 2007
Posted by Derek
The FDA briefing documents for Wednesday's discussion of Accomplia / Zimulti (rimonabant) have been posted, and they're an interesting read indeed. As everyone in the industry knows, this drug was once looked on as the next potential record-breaker, and writing the first part of this sentence in that verb form tells you a lot about what's happened since. It's the first antagonist targeting the cannabinoid CB-1 receptor, and at one point it looked like it was going to make people lose their excess weight, shed their addictions, and for all I know refinance their mortgages.
But then the delays hit in the US - long, long ones, delays which made fools of everyone who tried to predict when they would be over. And the drug meanwhile made it to market in Europe, where it has very quietly done not very much.
Now we may be seeing some of the reasons for the FDA'a "approvable" letter over a year ago. It's not efficacy - the FDA's briefing summary states that:
"Rimonabant 20 mg daily vs. placebo was associated with statistically and clinically
significant weight loss. Rimonabant 5 mg daily vs. placebo was associated with
statistically significant but clinically insignificant weight loss. . .rimonabant 20 mg daily vs. placebo was associated with a statistically significant 8% increase in HDL-C and a statistically significant 12% decrease in TG levels. There were no significant improvements in levels of total or LDL-C in the rimonabant 20 mg daily vs. placebo group. . .rimonabant 20 mg compared with placebo was associated with a statistically significant 0.7% reduction in HbA1c in overweight and obese subjects with type 2 diabetes taking either metformin or a sulfonylurea."
Not bad - just the sort of thing you'd want to go after the whole obesity/diabetes/cardiovascular area, you'd think. But the problem is in the side effects, and one in particular:
"The incidence of suicidality – specifically suicidal ideation – was higher for 20 mg
rimonabant compared to placebo. Similarly, the incidence of psychiatric adverse events,
neurological adverse events and seizures were consistently higher for 20 mg rimonabant compared to placebo. . ."
They're also concerned about other neurological side effects, and seizures as well. The seizure data don't look nearly as worrisome, except in the obese diabetic patients, for whom everything seems to be amplified. And all of this happens at the 20-mg dose, not at the 5 (which doesn't do much for weight, either, as noted above). And for those who are wondering, yes, on my first pass through the data, I find these statistics much more convincing than I did the ones on the Avandia (rosiglitazone) association with cardiac events.
I had my worries about rimonabant a long time ago, but not for any specific reason. It's just that I used to work on central nervous system drugs, and you have to be ready for anything. Any new CNS mechanism, I figured, might well set off some things that no one was expecting, given how little we understand about that area.
But isn't it good to finally hear what the arguing is about? Sanofi-Aventis has been relentlessly tight-lipped about everything to do with the drug. I can see why, after looking at the FDA documents, but this isn't a problem that's going to go away by not talking about it. The advisory committee meeting is Wednesday. Expect fireworks.
Comments (9)
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | The Central Nervous System | Toxicology
May 31, 2007
Posted by Derek
GlaxoSmithKline is breaking out the data to respond to the Nissen and Wolski NEJM paper on the possible cardiovascular risks of Avandia (rosiglitazone). In a letter published by The Lancet (PDF), the company's chief medical officer, Ronald Krall, defends the drug (and the company):
"GlaxoSmithKline did similar meta-analyses in 2005 and 2006 and found hazard ratios in the same direction as Nissen and Wolski. However, all these results are highly dependent on the methods used and the studies included, given the small number of events reported. For example, the actual number of myocardial infarctions in the Nissen and Wolski meta-analysis yields a very low frequency of events (0·6%), and the absolute difference in rates of myocardial infarctions between rosiglitazone and controls is less than 0·1%.
These observations support a view expressed by Nissen and Wolski them-selves: “a meta-analysis is always considered less convincing than a large prospective trial designed to assess the outcome of interest.”
He then goes back over the data in the three large trials that bear on the question. Reanalyzed data from the ADOPT study still do not show a statistically meaningful cardiovascular risk for rosiglitazone versus the other two diabetes drugs in the trial (metformin and glibenclamide). (There's no placebo group - this is one of those head-to-head comparisons of a drug versus its strongest competitors, a type of study that some people believe never takes place). The second completed study, DREAM, looked at co-administration of rosiglitazone and the ACE inhibitor ramapril. There were four groups - placebo only, rosi and placebo, ramapril and placebo, and rosi plus ramapril. The first three showed no difference in cardiovascular events, but the last one did, for unknown reasons.
These two studies are in the Nissen/Wolski meta-analysis, of course, but as I noted originally, it was the sum of the smaller studies that gave them their cardiovascular warning. But when the statistically less powerful trials show one thing that isn't borne out by the larger ones, the issue is (at the very least) still in doubt. The letter also points out that the company's database mining of managed-care patients taking rosi has shown no increase in cardiovascular risks.
Other controlled studies are ongoing, the (now highly awaited) RECORD and another one called ACCORD. Both are designed from the start to address cardiovascular outcomes (which are a major complication in diabetic patients). Krall's letter lifts the veil a tiny bit on RECORD, saying that the independent review board has now completed an interim analysis of its cardiovascular data and concluded that the trial should continue. This would not be the case, you'd have to presume, were the numbers to clearly show increased CV deaths in the treatment group.
My take on this is that the company has a pretty strong case so far, certainly strong enough to wait for the ongoing trials to settle the issue. What never fails to disappoint me, though, is the way that stories like this are jammed into ready-made templates. Depending on the editorial writer, the appearance of the NEJM paper became "FDA Corrupt, Broken: Snores While Dangerous Drugs Kill Thousands", or "Giant Drug Company Sells Heart Attack Poison, Doesn't Give Hoot". Or maybe just "Drug Approval System Completely Broken - Again".
Now, Steve Nissen does sound the alarm a lot, but I have no doubt that his intentions are honorable. His paper, to me, was the equivalent of saying "Hey, you people may have a problem here. Did you know that?" GSK's response, then is "Yeah, we've looked at that, too, but we don't see it. Are you sure your numbers are good?" Meanwhile, the studies which should answer the question for good are already years into their runs. If this is our standard for a broken drug approval system, we've certainly become mighty fastidious over the years. For what it's worth, The Lancet agrees.
Comments (11)
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | Press Coverage
May 25, 2007
Posted by Derek
Insider, author of the Pharmagossip site, sent along this link to an article on Avandia at the Health Care Renewal site, flagged as "essential reading". After looking it over, I don't think I agree, and I thought it might be worthwhile to explain why.
The HCR piece quotes extensively from this New York Times article, headlined "Years Ago, Agency Was Warned of a Drug's Risks". Its focus is a letter that Dr. John Buse of UNC (now president-elect of the American Diabetes Association) sent to the FDA in 2000 on the possible cardiovascular risks of Avandia. Reading HCR's summary is a somewhat different experience than reading the original article, though - for one thing, you miss out on the part about how even now Dr. Buse isn't calling for Avandia to be be taken off the market. Rather than finding the Nissen New England Journal of Medicine paper to be the smoking gun he's been waiting for, he advocates waiting for the GSK cardiovascular risk study to be completed before making any decisions.
The HCR article has some good points in it, but to my ear they're phrased oddly. For example, it advocates a skeptical attitude toward the marketing claims made by drug companies, which is very good advice. But that's very good advice for evaluating the marketing claims of companies in every other industry, too. They're trying to sell you something. They will present their product in the most favorable light possible, whether that product is a car, a diabetes drug, or a burrito.
And that's the part that drives some people crazy, because it seems wrong to have potential life-saving drugs handled the same way as pickup trucks and enchiladas. They're not, though: the reason we can argue about drug company marketing is that drugs already have something that almost no other product has, which is a body of statistically valid comparison data. No data exist as to the long-term advantages and disadvantages of consuming a given brand of burrito versus its competition or versus an alternative meal. Cars are somewhat more data-rich, thanks to government and insurance company testing, and frequency-of-repair databases like those kept by Consumer Reports. But that's about the highest standard for comparison data outside of the drug industry, and you'll look in vain for P values and other tests of statistical significance, because there aren't any. In short, marketing claims in virtually every other industry can go relatively unchallenged, because there's little to measure them against.
So, that's why one of the things that I dislike about the Health Care Renewal piece is the hand-rubbing now-we've-got-'em tone that I detect in it. You don't have to go far to find it fr |
