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
Twitter: Dereklowe
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May 22, 2009
Posted by Derek
I’ve been getting a lot of objections to my opinion on Arena’s obesity candidate lorcaserin. Specifically, the first level of the dispute seems to be whether or not the recent clinical trial results met the FDA’s criteria for efficacy or not. So, let’s look at the details. Here’s how Arena press-released the results of the trial:
The hierarchically ordered endpoints were the proportion of patients achieving 5% or greater weight loss after 12 months, the difference in mean weight loss compared to placebo after 12 months, and the proportion of patients achieving 10% or greater weight loss after 12 months. Compared to placebo, using an intent-to-treat last observation carried forward (ITT-LOCF) analysis, treatment with lorcaserin was associated with highly statistically significant (p<0.0001) categorical and average weight loss from baseline after 12 months:
-- 47.5% of lorcaserin patients lost greater than or equal to 5% of their
body weight from baseline compared to 20.3% in the placebo group. This
result satisfies the efficacy benchmark in the most recent FDA draft
guidance.
-- Average weight loss of 5.8% of body weight, or 12.7 pounds, was achieved
in the lorcaserin group, compared to 2.2% of body weight, or 4.7 pounds,
in the placebo group. Statistical separation from placebo was observed
by Week 2, the first post-baseline measurement.
-- 22.6% of lorcaserin patients lost greater than or equal to 10% of their
body weight from baseline, compared to 7.7% in the placebo group.
Lorcaserin patients who completed 52 weeks of treatment according to the protocol lost an average of 8.2% of body weight, or 17.9 pounds, compared to 3.4%, or 7.3 pounds, in the placebo group (p<0.0001).
Now let’s go to the FDA’s 2007 draft guidance for weight management therapies. Regarding the primary efficacy endpoint in a Phase III trial of such a new agent, the agency says:
The efficacy of a weight-management product should be assessed by analyses of both mean and categorical changes in body weight.
• Mean: The difference in mean percent loss of baseline body weight in the active-product versus placebo-treated group.
• Categorical: The proportion of subjects who lose at least 5 percent of baseline body weight in the active-product versus placebo-treated group.
And here’s the part that people keep wanting me to highlight:
In general, a product can be considered effective for weight management if after 1 year of treatment either of the following occurs:
• The difference in mean weight loss between the active-product and placebo-treated groups is at least 5 percent and the difference is statistically significant
• The proportion of subjects who lose greater than or equal to 5 percent of baseline body weight in the active-product group is at least 35 percent, is approximately double the proportion in the placebo-treated group, and the difference between groups is statistically significant
So lorcaserin showed 47.5% of patients losing at least 5% of their body weight, versus 20.3 for placebo. And yes, that does appear to meet what the FDA's looking for in terms of categorical efficacy, which is why the company highlighted that result in their press release. And yes (here it comes, Arena fans), the FDA does say ("in general") that an agent can be considered efficacious if a compound meets either the mean or the categorical standards.
But (and you knew that this paragraph was going to start with that word). . .but the FDA does not say "efficacious enough for approval". In general, to use their phrase, the agency does approve things that are efficacious and show safety. But they do that on their own terms, and they are (for better or worse) completely within their rights to turn around and ask for more details - for example, how well a compound like this performs as a combination therapy (which is how many physicians would likely wish to prescribe it).
Then we have the issue of "efficacious to interest a partner". Arena is surely looking to do that, since (as noted the other day) it does not appear that they have the resources to push the product through on their own. Given the potential size of the market for an effective obesity drug, we can be sure that a number of potential partners have been approached, and have taken a meaningful look at the data. So far, no one has taken them up on it. And whatever one thinks about the press coverage that lorcaserin has received (or the reaction from analysts who follow the stock, which has also not been good), it's for sure that these opinions don't count for much when it comes time for two companies to do a deal. Put more directly, if Arena sits down with Merck or Pfizer, what I say on this blog means nothing at all once the door closes. Heck, what they say at JP Morgan means nothing at all, either, because we're all outsiders. Potential partners are getting a chance to look over Arena's prospects, and if the numbers look convincing, someone will bite. If no one bites, we can assume that no one was convinced.
Or perhaps they're waiting for Arena to get even more cash-strapped and desperate. That isn't a very nice way to do business, but isn't unheard of, either, and I can tell you that these aren't very nice times in the drug business. At any rate, for those Arena fans who have been waiting for me to say something about all this, well, here you are. This is as good as you'll get from me - but really, you're wasting your time. You need to be hoping to persuade the people who can initiate nine-figure wire transfers.
Comments (8)
+ TrackBacks (0) | Category: Business and Markets | Clinical Trials | Diabetes and Obesity | Regulatory Affairs
May 18, 2009
Posted by Derek
I wrote in March about lorcaserin, Arena Pharmaceutical's serotonin ligand for obesity. Their clinical data had come out, and things (at least to me) didn't look good. They didn't quite make the minimum threshold for efficacy, and the FDA isn't in a mood to take a flyer on on things that don't quite work.
Well, according to Ruthanne Roussel at Obesity Investor, the company looks like it could be running out of cash. So far, at any rate, no partner is appearing. Obesity has always been a tough area to work in, and this economic environment isn't making it any easier for the smaller companies to survive. Arena's done some interesting work over the years, and I'd hate to see them collapse. But it sure looks like a possible outcome at this point. . .
Update: note that not everyone agrees with my take here. On the other hand, others are even more harsh. . .we'll see what comes out in the end. And as always, since I've said nothing about having a position in Arena's stock, that means that I have none.
Comments (23)
+ TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity
May 13, 2009
Posted by Derek
Now, this is an example of an idea being followed through to its logical conclusion. Here’s where we start: the good effects of exercise are well known, and seem to be beyond argument. Among these are marked improvements in insulin resistance (the hallmark of type II diabetes) and glucose uptake. In fact, exercise, combined with losing adipose weight, is absolutely the best therapy for mild cases of adult-onset diabetes, and can truly reverse the condition, an effect no other treatment can match.
So, what actually causes these exercise effects? There has to be a signal (or set of signals) down at the molecular level that tells your cells what’s happening, and initiates changes in their metabolism. One good candidate is the formation of reactive oxygen species (ROS) in the mitochondria. Exercise most certainly increases a person’s use of oxygen, and increases the work load on the mitochondria (since that’s where all the biochemical energy is coming from, anyway). Increased mitochondrial formation of ROS has been well documented, and they have a lot of physiological effects.
Of course, ROS are also implicated in many theories of aging and cellular damage, which is why cells have several systems to try to soak these things up. That’s exactly why people take antioxidants, vitamin C and vitamin E especially. So. . .what if you take those while you’re exercising?
A new paper in PNAS askes that exact question. About forty healthy young male volunteers took part in the study, which involved four weeks of identical exercise programs. Half of the volunteers were already in athletic training, and half weren’t. Both groups were then split again, and half of each cohort took 1000 mg/day of vitamin C and 400 IU/day vitamin E, while the other half took no antioxidants at all. So, we have the effects of exercise, plus and minus previous training, and plus and minus antioxidants.
And as it turns out, antioxidant supplements appear to cancel out many of the beneficial effects of exercise. Soaking up those transient bursts of reactive oxygen species keeps them from signaling. Looked at the other way, oxidative stress could be a key to preventing type II diabetes. Glucose uptake and insulin sensitivity aren't affected by exercise if you're taking supplementary amounts of vitamins C and E, and this effect is seen all the way down to molecular markers such as the PPAR coactivator proteins PGC1 alpha and beta. In fact, this paper seems to constitute strong evidence that ROS are the key mediators for the effects of exercise, and that this process is mediated through PGC1 and PPAR-gamma. (Note that PPAR-gamma is the target of the glitazone class of drugs for type II diabetes, although signaling in this area is notoriously complex).
Interestingly, exercise also increases the body's endogenous antioxidant systems - superoxide dismutase and so on. These are some of the gene targets of PPAR-gamma, suggesting that these are downstream effects. Taking antioxidant supplements kept these from going up, too. All these effects were slightly more pronounced in the group that hadn't been exercising before, but were still very strong across the board.
This confirms the suspicions raised by a paper from a group in Valencia last year, which showed that vitamin C supplementation seemed to decrease the development of endurance capacity during an exercise program. I think that there's enough evidence to go ahead and say it: exercise and antioxidants work against each other. The whole take-antioxidants-for-better-health idea, which has been taking some hits in recent years, has just taken another big one.
Comments (24)
+ TrackBacks (0) | Category: Aging and Lifespan | Biological News | Cardiovascular Disease | Diabetes and Obesity
March 31, 2009
Posted by Derek
After talking the other week about the problems that Takeda has had with their DPP-IV inhibitor for diabetes, it now appears that AstraZeneca and Bristol-Myers Squibb have made it through the same narrows with their own drug. Saxagliptin has met the FDA's latest guidelines for cardiovascular safety, which (you'd think) will remove the biggest potential barrier to approval. The advisory committee is meeting today, so we'll see how their vote goes.
Comments (10)
+ TrackBacks (0) | Category: Diabetes and Obesity | Regulatory Affairs
Posted by Derek
One of the drug targets for obesity that’s been kicking around for years now is a serotonin-receptor based idea, a 5-HT2c agonist. There are several lines of evidence that make this a plausible way to affect appetite – well, as plausible as any of the appetite-based obesity targets are. I’ve long been wary of these, since we’ve found (over and over) that human feeding behavior is protected by multiple, overlapping redundant pathways. We are the descendants of a long line of creatures that have made eating and reproducing their absolute priorities in life, and neither of those behaviors are going to be altered lightly. The animals that can be convinced to voluntarily eat so little that they actually lose weight, just through modifying a single biochemical pathway, are all dead. Our ancestors were the other guys.
Arena Pharmaceuticals is the latest company to give us more evidence for this point of view. Many drug discovery organizations have taken a crack at 5-HT2c compounds, as a look at the patent literature will make clear. But Arena got theirs, Locaserin, well into the clinic, and yesterday they announced the results. And. . .well, it depends on how you spin it. If you’re a glass-half-full sort of person, you could say that twice as many people in the drug treatment group lost at least the FDA’s target of their body mass, as compared to placebo.
Unfortunately, the glass-half-empty people are probably going to win this one. The FDA wants to see 5% weight loss (versus placebo) with a drug therapy, arguing (correctly, I think) that showing less than that really doesn’t give you much risk/benefit over just plain old diet and exercise. Arena’s compound averages out at 3.6%, and I don’t see how that’s going to cut it, especially with a new central nervous system mechanism. By “new”, I don’t mean “new to science” – as mentioned above, this idea has been around for years. But it would be a new thing to try out in millions of patients if you let a drug through, that’s for sure. I think it’s safe to say that a certain fraction of those are going to react in ways that you didn’t expect. 5-HT2 receptors are involved in a lot of different things, and there's bound to be a lot about any agent in this class that we don't know. Locaserin seems to have been well tolerated in trials, but I personally would be jumpy if I were taking something like this out into the broad population.
That’s not why I think this compound won’t make it, though. The FDA doesn’t even have to talk safety; they can reject it just on the grounds of efficacy. And it’s hard to imagine a lot of insurance plans picking up the tab for something with only those levels of clinical support, too. Arena's CEO says that he's pleased with the results of the trial. No, he isn't. Of course, he also says that he's convinced that the company will get Locaserin approved and find a partner to market it with, too. But then, that's his job.
Comments (30)
+ TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity
March 17, 2009
Posted by Derek
DPP-IV is short for “dipeptidylpeptidase IV”, understandably, and we need a good abbreviation for it. It’s an important enzyme target for diabetes therapy, since under normal conditions it breaks down glucagon-like-peptide 1. Longer-circulating GLP-1 would actually do a lot of diabetics good, and people have actually made such proteins as separate drugs, so inhibiting an enzyme that clears it out looks like a good bet. Of such reasoning are drug targets made.
A lot of companies have bought into this reasoning, for sure. For quite a while, Novartis looked like the leader in the area, with the most advanced clinical candidate and a lot of publications in the literature from their development work. But Merck turned out to be running a big effort of their own, and actually got to market first with Januvia (sitagliptin). Novartis’s drug (Galvus, vildagliptin) looks as if it will never make it at all here in the US.
They had to slow down development due to some troubling side effects, giving Merck the edge. There are several DPP subtypes, and you need to be pretty selective, as it turns out – at least some of the problems stem from that consideration. This wasn’t fully appreciated in the first wave of development in this area – the pioneers had to figure it out the hard and expensive way. But a number of companies have come up behind, trying to get a piece of the market, and they now have a clearer idea of what they need to accomplish.
Or do they? Takeda recently heard from the FDA that their DPP-IV inhibitor alogliptin has been turned down for now. What’s more, the agency wants more cardiovascular safety data from them and from anyone else who comes in with a drug in that category. Cardiovascular problems have always been the weak point for Type II diabetes drugs, to be sure. The patient population tends to be older and overweight, often with elevated blood pressure, so you really don’t have much room to work in when it comes to side effects. That’s led to a lot of attempts to come up with therapies that address the CV side of things at the same time as glucose levels (such as the ill-fated disaster of the PPAR alpha-gamma compounds, all of when went most expensively down in flames). DPP-IV inhibitors wouldn’t be expected to have any direct CV benefits, but they do have to avoid making things any worse.
So Merck looks to have the market to itself for a while longer, but as the only DPP-IV drug on the market, they’re going to be under a good deal of scrutiny. The company has already had its share of post-launch cardiovascular nightmares; you’d think that they’re going to work hard to avoid any more. And now all we have to do is assure ourselves that the actions of the DPP-IV inhibitors are all through making GLP-1 last longer. Because even if you're selective for that one enzyme, it has a lot of other substrates. So the story may well swing back to the biochemical mechanism again before we're through.
Comments (19)
+ TrackBacks (0) | Category: Cardiovascular Disease | Diabetes and Obesity | Regulatory Affairs
February 26, 2009
Posted by Derek
Metformin, now there’s a drug story for you. It’s a startlingly small molecule, the sort of thing that chemists look and and say “That’s a real drug?” It kicked around in the literature and the labs in the 1960s, was marketed in Europe in the 1980s but was shopped around in the US for quite a while, partly because a lot of people had just that reaction. (It didn't help that a couple of other drugs in the same structural class turned out to cause lactic acidosis and had to be pulled from use). Bristol-Myers Squibb finally took metformin up, though, and did extremely well with it in the end under the brand name Glucophage. It’s now generic, and continues to be widely prescribed for Type II diabetes.
But for many years, no one had a clue how it worked. It not only went all the way through clinical trials and FDA approval without a mechanism, it was nearly to the end of its patent lifetime before a plausible mechanism became clear. It’s now generally accepted that metformin is an activator (somehow, maybe through another enzyme called LKB1) of adenosine monophosphate kinase (AMPK), and that many (most?) of its effects are probably driven through that pathway. AMPK’s a central player in a lot of metabolic processes, so this proposal is certainly plausible.
But never think that you completely understand these things (and, as a corollary, never trust anyone who tries to convince you that they do). A new paper in PNAS advances the potentially alarming hypothesis that metformin may actually exacerbate the pathology of Alzheimer’s disease. This hasn’t been proven in humans yet, but the evidence that the authors present makes a strong case that someone should check this out quickly.
There’s a strong connection between insulin, diabetes, and brain function. Actually, there are a lot of strong connections, and we definitely haven’t figured them all out yet. Some of them make immediate sense – the brain pretty much has to run on glucose, as opposed to the rest of the body, which can largely switch to fatty acids as an energy source if need be. So blood sugar regulation is a very large concern up there in the skull. But insulin has many, many more effects than its instant actions on glucose uptake. It’s also tied into powerful growth factor pathways, cell development, lifespan, and other things, so its interactions with brain function are surely rather tangled.
And there’s some sort of connection between diabetes and Alzheimer’s. Type II diabetes is considered to be a risk factor for AD, and there’s some evidence that insulin can improve cognition in patients with the disease. There’s also some evidence that the marketed PPAR-gamma drugs (the thiazolidinediones rosiglitazone and pioglitazone) have some benefit for patients with early-stage Alzheimer’s. (Nothing, as far as I’m aware, is of much benefit for people with late-stage Alzheimer’s). Just in the past month, more work has appeared in this area. The authors of this latest paper wanted to take a look at metformin from this angle, since it’s so widely used in the older diabetic population.
What came out was a surprise. In cell culture, metformin seems to increase the amount of beta-amyloid generated by neurons. If you buy into the beta-amyloid hypothesis of Alzheimer’s, that’s very bad news indeed. (And even people that don’t think that amyloid is the proximate cause of the disease don’t think it’s good for you.) It seems to be doing this by upregulating beta-secretase (BACE), one of the key enzymes involved in producing beta-amyloid from the larger amyloid precursor protein (APP). And that upregulation seems to be driven by AMPK, but independent of glucose and insulin effects.
The paper takes this pretty thoroughly through cell culture models, and at the end all the way to live rats. They showed small but significant increases in beta-secretase activity in rat brain after six days of metformin treatment. And the authors conclude that:
Our finding that metformin increases A-beta generation and secretion raises the concern of potential side-effects, of accelerating AD clinical manifestation in patients with type 2 diabetes, especially in the aged population. This concern needs to be addressed by direct testing of the drug in animal models, in conjunction with learning, memory and behavioral tests.
Unfortunately, I think they’re quite right. Update - in response to questions, it appears that metformin may well cross into the brain, presumably at least partly by some sort of active transport. There's some evidence both ways, but it's certainly possible that relevant levels make it in. With any luck, this will be found not to translate to humans, or not with any real clinical effect, but someone’s going to have to make sure of that. For those of us back in the early stages of drug discovery, the lesson is (once again): never, never think we completely understand what a drug is doing. We don’t.
Comments (19)
+ TrackBacks (0) | Category: Alzheimer's Disease | Diabetes and Obesity | Drug Industry History | Toxicology
November 25, 2008
Posted by Derek
Avandia (rosiglitazone) has been under suspicion for the last couple of years, after data appeared suggesting a higher rate of cardiovascular problems with its use. GlaxoSmithKline has been disputing this association all the way, as well they might, but today there’s yet more information to dispute.
A retrospective study in the Archives of Internal Medicine looked at about 14,000 patients on Medicare (older than 65) who were prescribed Avandia between 2000 and 2005. Now, looking backwards at the data is always a tricky business. For example, comparing these patients to another group that didn’t get the drug could be quite misleading – the obvious mistake there is that if someone has been prescribed Avandia, then they’re likely getting it because they’ve got Type II diabetes (or metabolic syndrome at least). Comparing that cohort to a group that isn’t showing such symptoms would be wildly misleading.
But this study compared the Avandia patients to 14,000 who were getting its direct competitor, Actos (pioglitazone). Now that’s more like it. The two drugs are indicated for the same patient population, for the same reasons. Their mechanism of action is supposed to be the same, too, as much as anyone can tell with the PPAR-gamma compounds. I wrote about that here – the problem with these drugs is that they affect the transcription of hundreds of genes, making their effects very hard to work out. Rosi and pio overlap quite a bit, but there are definitely (PDF) genes that each of them affect alone, and many others that they affect to different levels. Clinically, though, they are in theory doing the exact same thing.
But are they? This study found that the patients who started on Avandia had a fifteen per cent higher deaths-from-all-causes rate than the Actos group. To me, that’s a startlingly high number, and it really calls for an explanation. The Avandia group had a 13 per cent higher rate of heart failure, but no difference in strokes and heart attack, oddly. The authors believe that these latter two causes of death are likely to be undercounted in this population, though – there’s a significant no-cause-reported group in the data.
The authors also claim that the two populations were “surprisingly similar”, strengthening their conclusions. I think that that’s likely to be the case, given the similarities between the two drugs. GlaxoSmithKline, for their part, is saying that these numbers don’t match the safety data they’ve collected, and that a randomized clinical trial is the best way to settle such issues.
Well, yeah: a randomized clinical trial is the best way to settle a lot of medical questions. But neither GSK (nor Takeda and Lilly, makers of Actos) have seen fit to go head-to-head in one, have they? My guess is that both companies felt that the chances of showing a major clinical difference between the two was small, and that the size, length, and expense of such a trial would likely not justify its results. And if we’re talking about the beneficial mechanisms of action here, that’s probably true. You’d have quite a time showing daylight between the two drugs on things like insulin sensitivity, glycosylated hemoglobin, and other measures of diabetes. Individual patients may well show differences, and that's useful in practice - but that's a hard thing to show in a large averaged set of data. But how about nasty side effects? Maybe there's some room there - but in a murky field like PPAR-gamma, you'd have to have a lot of nerve to run a trial hoping to see something bad in your competitor's compound, while still being sure enough of your own. No, it's disingenuous to talk about how these questions need to be answered by a clinical trial, when you haven't done one, haven't planned one, and have (what seemed to be) good reasons not to.
This kind of study is the best rosi-to-pio comparison we're likely to get. And it does not look good for Avandia. GSK is going to have to live with that - and in fact, they already are.
Comments (4)
+ TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | Toxicology
November 6, 2008
Posted by Derek
The painful saga of Acomplia (rimonabant) has finally come to an end. Sanofi-Aventis has announced that they're completely giving up on the drug. There was really no other option - the compound was never approved in the US, and was never going to be, and late in October the EU ordered it to be withdrawn from Europe. The psychiatric side effects which sank the drug's chances here were showing up in real-world use, and the risk/benefit ratio could no longer be seen as anything but negative.
And Pfizer has just announced that they're giving up work on their own Phase III compound in the area, CP-945,598. They're not citing safety concerns - and as Jim Edwards over at Bnet notes, that puts them in the odd position of saying that they have a safe, effective drug for a huge market that they're not going to do anything with. My guess is that the company is worried that the drug would indeed show an unfavorable safety profile, especially under the sort of scrutiny that any drug in this class would have by now, and that they decided to stop before things got to that point. Otherwise, you'd think that a big, safe, effective first-in-class obesity therapy would be just what Pfizer needs - wouldn't you?
So, goodbye to the CB-1 antagonists. I don't see much work going on in this area for some time to come, unless the pharmacology gets untangled to the point that someone can see a safe way through. There may well not be one.
And before we all try to forget that this all happened, let's spare a thought for the huge amounts of time, effort, brainpower and money that went into this area over the last eight or ten years. Three of the biggest research organizations in the industry have now flamed out trying to develop these drugs, and plenty of smaller players were trying, too, as a glance at the patent literature will make clear. The end result is that we have paid a gigantic amount of money to learn that the biology is more complicated than we thought, and it needed no ghost come from the grave to tell us this. If you think that drug development is a sure road to riches - if anyone still thinks that - then come survey this wreckage and think again.
And to finish, let's hop in the time machine and go back. . .well, not all that far. Just to mid-2006. There we find a world in which rimonabant was poised to become one of the biggest selling drugs in all the world, part of a wave of drugs which would transform the industry and spew profits in all directions. Billions of dollars in revenues are mentioned. Oh, dear.
Comments (11)
+ TrackBacks (0) | Category: Diabetes and Obesity | Drug Development
October 31, 2008
Posted by Derek
Let’s talk sugar, and how you know if you’ve eaten enough of it. Just in time for Halloween! This is a field I’ve done drug discovery for in the past, and it’s a tricky business. But some of the signals are being worked out.
Blood glucose, as the usual circulating energy source in the body, is a good measure of whether you’ve eaten recently. If you skip a meal (or two), your body will start mobilizing fatty acids from your stored supplies, and circulate them for food. But there’s one organ that runs almost entirely on sugar, no matter what the conditions: the brain. Even if you’re fasting, your liver will make sugar from scratch for your brain to use.
And as you’d expect, brain glucose levels are one mechanism the body uses to decide whether to keep eating or not. A cascade of enzyme signals has been worked out over the years, and the current consensus seems to be that high glucose in the brain inactivates AMP kinase (AMPK). (That’s a key enzyme for monitoring the energy balance in the brain – it senses differences in concentration between ATP, the energy currency inside every cell, and its product and precursor, AMP). Losing that AMPK enzyme activity then removes the brakes on the activity of another enzyme, acetyl CoA-carboxylase (ACC). (That one’s a key regulator of fatty acid synthesis – all this stuff is hooked together wonderfully). ACC produces malonyl-CoA, and that seems to be a signal to the hypothalamus of the brain that you’re full (several signaling proteins are released at that point to spread the news).
You can observe this sort of thing in lab rats – if you infuse extra glucose into their brains, they stop eating, even under conditions when they otherwise would keep going. A few years ago, an odd result was found when this experiment was tried with fructose: instead of lowering food intake, infusing fructose into the central nervous system made the animals actually eat more. That’s not what you’d expect, since in the end, fructose ends up metabolized to the same thing as glucose does (pyruvate), and used to make ATP. So why the difference in feeding signals?
A paper in PNAS (open access PDF) from a team at Johns Hopkins and Ibaraki University in Japan now has a possible explanation. Glucose metabolism is very tightly regulated, as you’d expect for the main fuel source of virtually every living cell. But fructose is a different matter. It bypasses the rate-limiting step of the glucose pathway, and is metabolized much more quickly than glucose is. It appears that this fast (and comparatively unregulated) process actually uses up ATP in the hypothalamus – you’re basically revving up the enzyme machinery early in the pathway (ketohexokinase in particular) so much that you’re burning off the local ATP supply to run it.
Glucose, on the other hand, causes ATP levels in the brain to rise – which turns down AMPK, which turns up ACC, which allows malonyl-CoA to rise, and turns off appetite. But when ATP levels fall, AMPK is getting the message that energy supplies are low: eat, eat! Both the glucose and fructose effects on brain ATP can be seen at the ten-minute mark and are quite pronounced at twenty minutes. The paper went on to look at the activities of AMPK and ACC, the resulting levels of malonyl CoA, and everything was reversed for fructose (as opposed to glucose) right down the line. Even expression of the signaling peptides at the end of the process looks different.
The implications for human metabolism are clear: many have suspected that fructose could in fact be doing us some harm. (This New York Times piece from 2006 is a good look at the field: it's important to remember that this is very much an open question). But metabolic signaling could be altered by using fructose as an energy source over glucose. The large amount of high-fructose corn syrup produced and used in the US and other industrialized countries makes this an issue with very large political, economic, and public health implications.
This paper is compelling story – so, what are its weak points? Well, for one thing, you’d want to make sure that those fructose-metabolizing enzymes are indeed present in the key cells in the hypothalamus. And an even more important point is that fructose has to get into the brain. These studies were dropping it in directly through the skull, but that’s not how most people drink sodas. For this whole appetite-signaling hypothesis to work in the real world, fructose taken in orally would have to find its way to the hypothalamus. There’s some evidence that this is the case, but that fructose would have to find its way past the liver first.
On the other hand, it could be that this ATP-lowering effect could also be taking place in liver cells, and causing some sort of metabolic disruption there. AMPK and ACC are tremendously important enzymes, with a wide range of effects on metabolism, so there's a lot of room for things to happen. I should note, though, that activation of AMPK out in the peripheral tissues is thought to be beneficial for diabetics and others - this may be one route by which Glucophage (metformin) works. (Now some people are saying that there may be more than one ACC isoform out there, bypassing the AMPK signaling entirely, so this clearly is a tangled question).
I’m sure that a great deal of effort is now going into working out these things, so stay tuned. It's going to take a while to make sure, but if things continue along this path, there could be reasons for a large change in the industrialized human diet. There are a lot of downstream issues - how much fructose people actually consume, for one, and the problem of portion size and total caloric intake, no matter what form it's in, for another. So I'm not prepared to offer odds on a big change, but the implications are large enough to warrant a thorough check.
Update: so far, no one has been able to demonstrate endocrine or satiety differences in humans consuming high-fructose corn syrup vs. the equivalent amount of sucrose. See here, here, and here.
Comments (21)
+ TrackBacks (0) | Category: Biological News | Diabetes and Obesity | The Central Nervous System
October 2, 2008
Posted by Derek
Merck has taken a step that many people have been expecting, and announced that they are no longer developing taranabant, their cannabinoid antagonist (or is it an inverse agonist?)
I'd expressed grave doubts about the drug earlier this year, which turned out to be well-founded. That latter post included the line "I don't see how they can get this compound through the FDA", and now Merck seems to have come to the same conclusion. Further clinical data seem to have shown far too many psychiatric side effects (anxiety, depression, and so on), which increased along with the dose of the drug.
The cannabinoid antagonist field has already experienced a crisis of confidence after Sanofi-Aventis's rimonabant failed to gain approval in the US. This latest news should ensure that no company tries to develop one of these drugs until we've learned a great deal more about their pharmacology. Given how little we know about the mechanisms of these mental processes, though, that could take a long, long time. We can pull the curtain over this area, I think.
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+ TrackBacks (0) | Category: Diabetes and Obesity | Drug Development | The Central Nervous System | Toxicology
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. . .
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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. . .
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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. . .
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+ 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.
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+ 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.
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+ 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.
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+ 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.
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+ 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”.
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+ 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.
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+ 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.
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+ 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.
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+ 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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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.
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+ 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.
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+ 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 from plenty of other sources, either, which is why people like me are perhaps too touchy on the subject.
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+ TrackBacks (0) | Category: Cardiovascular Disease | Diabetes and Obesity | Press Coverage | Why Everyone Loves Us
May 24, 2007
Posted by Derek
Steve Nissen has (once again) made waves with an analysis of cardiovascular risk. This time the subject is Avandia (rosiglitazone), a therapy for diabetes that's the oldest PPAR-gamma drug on the market. A meta-analysis of 42 reported clinical trials of the drug led to the conclusion that rosiglitazone is associated with a statistically significant risk of cardiac events.
The similarities to the Vioxx situation are what have made headlines (and what sent GlaxoSmithKline's stock down about 8% on the day the paper was released). But there are some important differences. Merck's ran into the Vioxx numbers in their own clinical data - the arguing has been whether they recognized the effects earlier (or should have), but it was a specific trial of theirs that led to the statistics that sank the drug. A meta-analysis is a much different beast, since you're trying to fit a large number of different trials, run in different ways for different reasons, into the same framework. Not everyone trusts them, even when the analysis is performed by someone as competent as Nissen, who does mention the limitations of the approach in the paper:
"Our study has important limitations. We pooled the results of a group of trials that were not originally intended to explore cardiovascular outcomes. Most trials did not centrally adjudicate cardiovascular outcomes, and the definitions of myocardial infarction were not available. Many of these trials were small and short-term, resulting in few adverse cardiovascular events or deaths. Accordingly, the confidence intervals for the odds ratios for myocardial infarction and death from cardiovascular causes are wide, resulting in considerable uncertainty about the magnitude of the observed hazard. Furthermore, we did not have access to original source data for any of these trials. Thus, we based the analysis on available data from publicly disclosed summaries of events. The lack of availability of source data did not allow the use of more statistically powerful time-to-event analysis. A meta-analysis is always considered less convincing than a large prospective trial designed to assess the outcome of interest."
And that's what's happening here. A number of people at large diabetes treatment centers aren't ready to buy into a cardiovascular risk for Avandia yet, because they're wary of the statistics. There's a large cardiovascular outcome trial of the drug going on now, which won't wrap up until 2009, but several people seem to want to wait for that as a more definitive answer.
If Nissen's data hold up - and statistically, I'm definitely not up to the task of evaluating his approach - then we might be looking at a Vioxx-like risk level. Out of some 14,000 patients on the drug in the various studies, there were 86 heart attacks in the treatment groups, and 72 in the controls. That comes out to be statistically significant, but (as you can see) the problem is that Type II diabetics have a high background rate of CV problems. Looking at Nissen's Table IV, it also seems clear that most of the significance he's found comes from the pooling of the smaller studies. The larger trials are nowhere near as clear-cut, which makes you wonder if this effect is real or an artifact.
I'm certainly not prepared to say one way or another, and I just hope that the ongoing trial settles the question. It's certainly not unreasonable to imagine a PPAR gamma drug having this side effect, but if this were a strong mechanism-based phenomenon the numbers would surely be stronger. If a risk is confirmed, though, we'll then be faced with a risk-benefit question. Does the glycemic control that Avandia provides lead to enough good outcomes to offset any cardiovascular risk over a large population? If you think getting the current numbers is a tough job, wait until you try to work that one out.
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+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | Toxicology
April 11, 2007
Posted by Derek
Looks like my doubts about the potential of Pfizer's inhaled insulin Exubera were well-founded. Pfizer's having some trouble making headway, and have announced a re-launch of the product. Needless to say, you don't re-launch products that are performing up to expectation.
When I wrote about the product a year or so ago, various dissenting comments on that post used phrases like "grand slam", "smash hit", and the ever-popular "blockbuster". It hasn't happened, though, and odds are lengthening that it ever will.
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March 30, 2007
Posted by Derek
Remember back when Sanofi-Aventis submitted Acomplia (rimonabant) to the FDA? Remember when the FDA told them that they needed more data before it would be approved? That's been over a year ago now - time flies - and now they're saying that another hearing with the agency is scheduled for June 13.
There was an excellent summary of the whole situation by Jeanne Whalen in the Wall Street Journal the other day, which subscribers will already have seen. Here's the article for free access in the Arizona Republic for everyone else. This will take you through the whole story, from the hype of 2004 to the. . .well, uncertainly today.
What's worth thinking about are the (in retrospect, rash) statement of Sanofi's people back then about the huge blockbuster potential of the drug, and the (in retrospect, clueless) statements of various analysts back a year ago. "A brief delay" was one phrase that turned up several times, along with predictions of approval by the middle of 2006. . .make the the end of the year. . .OK, first quarter of 2007. . .fine, fine, by the end of '07.
And what's continued to amaze me is the ability of the S-A management to give no details about what's going on with the drug. A year ago, I thought they'd be forced to talk shortly by investor pressure, but I'm clearly a bit clueless myself. . .
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November 1, 2006
Posted by Derek
The German government has handed down some interesting pharmaceutical decisions recently. Although Sanofi-Aventis's Accomplia (rimonabant) is available there (in fact, that's probably the largest market it's shown up in so far), the German regulators have decided that state health care plans are not going to reimburse for it. They've put it in the "lifestyle" drug category, which they don't cover. This appears to be a cost-cutting move, and there's a 60-day window in which it can be changed.
S-A had better hope that HMOs here don't follow suit. Of course, for this to be an issue, the drug would actually have to be approved by the FDA here, and the company still has no details to offer about when they might expect that. Their quarterly report states that they've answered the FDA's concerns, which isn't much of an update, but goes no further, as far as I can see.
Meanwhile, Pfizer's inhaled insulin Exubera has also been denied reimbursement in Germany, which follows on a similar British decision earlier. I expressed doubts about the product here a while ago (I wasn't alone), and now the doubters are getting louder. Exubera hasn't been launched in the US, either, despite being approved early this year, which isn't helping sooth Pfizer's hardy investors, either. . .
Presumably both these products will debut here in 2007, and we can all see how they do in the most lucrative pharmaceutical market in the world. If anyone is thinking of making a big upside investment decision based on these compounds, though, I think they'd be well advised to sit on their money for a while.
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+ TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity
October 17, 2006
Posted by Derek
Merck had their DPP-IV inhibitor for diabetes approved by the FDA today, which is good news for them and for many diabetic patients. I'll defer discussion of the mechanism and the compound for now, though, because what I wanted to mention is how this illustrates Merck's business style.
The first compound of this type that most medicinal chemists heard about was from Novartis. They popped up as early as 1999 with the first of many publications on their compound class, and a lot of corresponding patent activity. Merck, for their part, stayed out of the spotlight. You had to watch the patent databases closely to get an idea of what they were up to, and they didn't really publish anything until 2004. Novartis, naturally, had plenty of motivation to keep up with the news and knew that Merck was in the hunt, but they were still surprised earlier this year when Merck filed for regulatory approval months before anyone thought that they were ready.
In some cases, you can get a reading on what Merck is up to when they break from their usual stealth mode. For example, some years ago they appeared with a big splash in Science, touting a small molecule that could actually affect the autophosphorylation of the insulin receptor. An oral competitor to insulin? The dawn of a new era? Nah - just an interesting failed project. The compound was going nowhere, and the only thing it was good for was to make a big noise in Science. The contrast with academic publication habits is noteworthy.
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+ TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity
October 5, 2006
Posted by Derek
Since I was asking the same musical question just the other day, I wanted to refer people to this article by Matthew Herper over at Forbes, who also wants to know: where is Acomplia/rimonabant, anyway?
It's amazed me for months now that Sanofi-Aventis can get away with saying nothing at all about the prospects for their potential biggest-selling drug ever. Back when the first FDA action came, I predicted, with miserable inaccuracy, that the company would have something to say within days. It's been months, and no one knows anything more than we did back in February.
As the Forbes piece makes clear, analysts and institutional investors seem to be losing patience. I'm not sure what it is about the Sanofi corporate culture that makes this strategy seem like a good idea, but they might want to reexamine it. What might appear like calm and steadfast behavior from their perspective is starting to look, from the outside, like the actions of a company with something to hide. This is America, guys. We talk about things over here; you can't shut us up. Join the party.
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October 3, 2006
Posted by Derek
A lot of people had given up on neuropeptide Y antagonists as potential obesity therapies, but Merck kept the faith. They were enrolling patients in a combination trial with one of their compounds (MK-0557, a Y5 ligand which I believe is this guy) as recently as three years ago, although I believe that all clinical work stopped on the drug sometime in 2005. (See the note on this site from New Zealand; a search within the page for "0557" will turn it up).
Now the post-mortem for the drug has appeared in Cell Metabolism. Nature's news site has a good summary of the story, although they treat it as more of a fresh news bulletin than it really is. In short, the compound can cause statistically significant (but very modest and clinically useless) weight loss.
It joins a large and varied junk heap of obesity compounds (this category has comments on some of them). I'm surprised that Merck was still cranking away on this particular mechanism, but they have a reputation for tenacity. And they also have several other compounds in the clinic, including another CB-1 antagonist as competition for rimonabant. Speaking of which, where is rimonabant? And will it avoid being the largest compound on the same heap?
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+ TrackBacks (0) | Category: Diabetes and Obesity
September 6, 2006
Posted by Derek
When I tell people that I work for a drug company, they often want to know what disease I'm working on. I've been able to give all kinds of answers over the years, and most of them go over well. Everyone's glad to hear that you're doing research on diabetes, cancer, Alzheimer's or other widespread high-profile problems. Of the areas I've spent time in, cancer probably has the most cachet on this scale, since almost everyone knows of someone who's had serious trouble with one form or another.
The antithesis of cancer's situation is probably obesity. No matter how many headlines come out on its epidemic nature, huge public health consequences, and so on, it still doesn't get you the respect that other indications do. There are several reasons for this, the first of which is the seriousness of the disease, as defined by life expectancy. For better or worse, obesity patients are going to survive for much longer periods than cancer patients.
Scientifically, this actually makes the field more difficult to work in. Frankly, with most of the current cancer therapies, all we can offer is a few more months or (in some cases) years of life for most patients, so until recently long-term side effect issues haven't been a big concern. (Note, though, that this is changing). But obesity therapies are going to be used for longer periods of time. Obesity is associated with a shorter lifespan, true, but the level of obesity that some people are wanting to treat doesn't have that great an effect on mortality, and the survival rate with even morbid obesity is one heck of a lot better than with most kinds of cancer.
Getting back to the seriousness problem, another issue is that for many people, it's hard to shake the image of obesity as something that could be better treated by just eating less food and getting off the couch. I realize that that's not always a fair judgement, and my heart does indeed go out to people who put on weight more easily than the average person. But that said, there can be little doubt that eating fewer calories and doing a bit more exercise would take off untold numbers of pounds nationwide. The question is, as physicians will tell you, is whether anyone is going to do those things. If they can be more motivated by taking an obesity drug along with changing their diet and doing some exercise, then perhaps the drugs will have partially proved their worth. Of course, you could argue that similar effects at that level might be obtained by pills filled with, say, oat bran, billed as wonderful new obesity therapies: Placebatrim, anyone?
No, we're not going to be able to get away with that one. That's a market for the "nutritional supplement" people. An obesity drug from a real pharmaceutical company is going to have to really do something to get past the FDA, and it's going to have to be extremely safe in order to stay on the market. (Thus the current state of the obesity drug market). Anything that meets these criteria will make a huge amount of money. But respect? Fair or not, that might be asking too much. . .
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June 29, 2006
Posted by Derek
Well, although Sanofi-Aventis still hasn't been very forthcoming on their FDA problems, their CB-1 antagonist Accomplia (rimonabant) has now been approved in Europe, and is already on sale in the UK. (S-A still say that they expect it to make it through in the US by the end of the year).
This article from Bloomberg is an excellent summary of the situation. No new obesity drugs have been approved for almost ten years, and potential sales of a safe and effective one are almost impossible to estimate. But there's room to argue about how effective rimonabant is, and (as with any drug) there's always room to argue about safety. And that's particularly true in what some people are already calling the post-Vioxx era.
The article makes some of the same points that I've made here before: new therapies and new mechanisms have risks, and there is no way that we (the drug industry and the regulatory authorities) can get rid of them. We can test for the big ones and read the signs for the smaller ones, but if a new drug is going to taken by millions of people for long periods, things will happen that no one ever saw during the clinical trials.
I hope, for Sanofi's sake and everyone else's, that there's nothing weird lurking down in the statistical weeds this time. But you can be absolutely sure that the company is holding its breath. We all do. It doesn't help.
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February 24, 2006
Posted by Derek
Well, Sanofi-Aventis has held their meeting with analysts and taken questions, and there's still not much to say about the Acomplia (rimonabant) situation. They still say that they plan to launch the drug later this year, and that they plan to talk with the FDA in March. A Bloomberg story says that they hope to resolve the issues "within months", which they'd better do if they're planning on 2006.
As far as I can determine, they still haven't come out and said just what the FDA's concerns are. And that, to me, has to be a bad sign. If the problems were inarguably small, the company would surely be motivated to tell everyone about them. But it looks more like: "We think we can launch this year. But if we told about you all the FDA's concerns, you might not think so yourselves. So we're not going to tell you."
If more details come out, I'll revise my opinion. But failing that, can anyone think of a reason why this isn't the right way to interpret this?
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February 20, 2006
Posted by Derek
Sanofi-Aventis basically has their future riding on their obesity therapy Acomplia (rimonabant), which was (until a day or two ago) expected to be approved before the middle of this year. But the FDA gave them one of those "Approvable, But. . ." letters which sow fear and confusion whenever they arrive.
The fear is self-explanatory, and the confusion comes because the letters don't have to be made public. No one knows what the FDA's concerns are, because Sanofi-Aventis doesn't have to say - yet. But in the case of a drug that was expected to be this big, and one that S-A's management was telling everyone just the other day was in fine, fine shape, they're going to have to come out with something soon or risk a complete loss of confidence and credibility.
There are quite a few possibilities, as this post at Pharmagossip lays out. I have to say, rimonabant has always made me a bit nervous, and that's not just hindsight talking. Back in 2004 I wrote about some possible bad side effects of the drug, and last year I worried in general about the problems of taking such a drug (huge buildup, huge market, totally new mechanism of action) to market.
You see, the problem is, I did the first half of my career in CNS drug discovery. Drugs that act on central nervous system receptors can do all kinds of odd stuff, and we most definitely do not know enough about brain chemistry to predict what those interesting surprises might be. The endocannabinoid receptor that rimonabant targets is very much an evolving story - it's even less worked out than the other brain targets. The thought of a CNS drug whose target is relatively less well understood than the others should be enough to make anyone gaze thoughtfully out the window for a bit.
The field has other brisk and tangy qualities. For example, the patient population tends to have an alarmingly heterogeneous response to CNS drugs, as a look at the antipsychotic and antidepressant markets will show you. Drugs that work fine for one person do nothing for another, and we don't yet know why. I can see no reason why rimonabant should be any different.
This FDA action may have borne out some of these fears, or it may be that Sanofi is just involved in an argument about a too-aggressive labeling proposal. Here's betting that they fill in some details real soon now. The longer they wait, the worse it'll be for them. By. . .Wednesday, I'd say?
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February 15, 2006
Posted by Derek
I haven't mentioned Pfizer's inhaled insulin project in a while, but a few weeks ago they got the stuff approved, at (very) long last. The development of Exubera, which is certainly a cheerful brand name, has been anything but uplifting, though Here's a piece I did three years ago, when the story already seemed to have been going on for a long time.
Insulin, of course, is the very definition of a well-established drug, but that's only if you inject it. Slowing things down have been problems which are unique to inhaled powders: the effect on lung function over time, the changes in dosage under suboptimal conditions (allergy, flu, etc.), and the reproducibility of the dose. These are particularly worrisome for insulin, which is a tough situation: it's vital to its users, and it has a lower margin for error (both under- and over-dosing) than most other drugs. As I put it in that 2003 post, if you take twice as much aspirin as you should, it'll be rough on your stomach. If you take twice as much insulin, you're going to end up on the floor (and there had better be someone around with a candy bar).
You can see this troubled history in the drug's labeling, which Frederick Cohen at Crownstone has been going over. To pick one interesting detail, patients will be required to have a baseline pulmonary function test before starting the drug, with monitoring thereafter. And this brings up the current worry: how much will Exubera (and its baggage) cost, and who's going to pay for it? The product won't be launched until mid-year, and no one knows quite what its price will be. Pfizer's just saying that it will be "competitive", an answer which is synonymous with "Go away", but you can find estimates of up to four times the cost of injectable insulin (my guess is 2.5x). Call it a convenience premium. Will it fly?
Well, here's a piece in Business Week that's enough to make you wonder. It's written by a pair of consultants from the Bruckner Group, an outfit that's very big on outcome-based medicine, and from that perspective they think Exubera's in trouble even before it launches:
". . . Based on our analyses and interviews with major managed-care decision-makers, we expect that payers will either dramatically limit Exubera's availability to patients, impose very high co-payments, or reject coverage of it outright. . .For Exubera to achieve widespread preferential formulary status, payers will need to see a credible and compelling value proposition rather than an argument centered on patient convenience. The crux of the issue is whether an inhaled therapy will improve compliance and lead to significant improvements in patient health."
As they point out, the data on other inhaled therapies isn't too reassuring. Studies have indicated that asthma inhalers, for example, are often misused, both quantitatively and qualitatively. The Flumist inhaled flu vaccine has also been a disappointment compared to its injectable competition.
Pfizer may be counting on its (justly) famous marketing powers to put Exubera over. If the landscape, though, really is changing to more rigorous cost/benefit calculations, that might not do the trick. I realize that the BW authors have an interest in promoting this viewpoint, but I hope that they're on to something. I'd rather see more of the competition between drug companies taking place over medical evidence and financial benefit, rather than the size of the sales forces. Salesmanship alone can't put over a lousy drug. But it can take away from the issues that really should be decisive.
Tomorrow we'll take a look at how this applies to oncology, where things are getting really interesting. . .
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November 29, 2005
Posted by Derek
There's a peptide hormone called ghrelin that a lot of pharmaceutical companies have worked on in the last few years. It's a good target for obesity (and perhaps diabetes, too), since it's involved in appetite signaling between the stomach and the central nervous system. It's also involved in growth hormone signaling, too, though, so the situation is complicated.
And it just got more so. It turns out, according to a paper in the November 11 issue of Science. A group at Stanford has discovered that the same percursor protein that's carved up to produce ghrelin is also used to produce another peptide hormone that they've called obestatin. That one has its own receptor, and its own signaling network, and it appears to do the exact oppositeof what ghrelin does. Injections of ghrelin stimulate feeding in mice, and injections of obestatin inhibit it, for example. Similarly, ghrelin increases gastric emptying, and obestatin slows it down. (One place where the two peptides don't match up is their effects on growth hormone secretion - obestatin doesn't seem to do anything to the growth hormone axis at all).
So now we know more about the regulation of appetite than we used to, although researchers in that field probably thought it was complicated enough already, thanks very much. What I find particularly interesting about this discovery is how these two opposing hormones are cut from the same larger protein. That means that they both come from the same gene, you know. Which shows you just how far a pure genome-driven approach to drug discovery will get you: not far enough. You'd never know about ghrelin from just reading off human genes, because it's produced after the orginal protein is transcribed. And you'd never know that the same protein is the source for another hormone that negates ghrelin, either. All that complexity is downstream of the DNA. (Update: see the comments for some dissenting voices on this issue).
We already knew that general principle, of course. As soon as the estimates of the total number of human genes starting coming in, it was clear that they were way too low to explain the number of different proteins that we already knew about. But examples like this one just rub it in. . .
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October 28, 2005
Posted by Derek
I missed last night's announcement from Bristol-Meyers Squibb until this morning. It looks like the situation with Pargluva (muraglitazar) is even worse than people had thought.
The FDA had granted "conditional approval" for the drug, but that doesn't mean all that much. The conditions for approval weren't made public, by either the agency or the companies involved - all we knew was that they wanted to address cardiovascular risk factors. Now BMS says that the ongoing trials won't be able to answer the FDA's concerns, and that new trials would be needed, which they say might take up to five years. That could scuttle the drug entirely.
I'm not sure what to make of this. It's entirely possible that BMS and Merck don't have anything currently powered to address cardiovascular risk in the way the the FDA would like. People complained that the Cleveland Clinic article in JAMA was based on incomplete data, but if there were good cardiovascular numbers on this drug, they would have been in that data set. But five years seems like a long time, even if the FDA is really lowering the boom on them and requiring long-term data in a large number of people. Even then, even factoring in recruitment and data workup, that's a whopper of a trial.
Still, I think the companies are clearly looking at more time and money than they probably want to spend, on a drug that frankly was a bit disappointing in its clinical data. Pargluva lowers blood glucose, but so do the existing PPAR-gamma agents. They already do about as much as can be done through that mechanism. And the additional PPAR-alpha activity does seem to help HDL cholesterol and other blood lipid parameters, but the cardiovascular risk that seems to be there more than offsets those numbers.
Merck and BMS run the risk of spending a very large amount of money just in order to definitively prove that their drug should not be sold. Even if they were able to make their case, it's unlikely that they'd be able to make a strong case in the market: "Pargluva! Not As Bad As You Thought!" And the market would have changed by the time they staggered on to approval, anyway. They may just give this one a pass.
It'll be interesting to see how this plays in the press. It'll be easy to fit this into a template of "FDA messes up, independent review by Cleveland Clinic saves the day again." But that's not quite true, I think. The FDA advisory committee didn't distinguish itself, and the Cleveland team was quick to pick up on that, but the agency itself requested the additional data before the JAMA article came out. I don't know what might have gone on behind the scenes, but on the face of it, this was one of the cases that proves (as the fine print says) that the FDA doesn't have to abide by the decisions of its advisory committees.
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October 20, 2005
Posted by Derek
I wrote a brief wrap-up on the FDA's concerns about the new Bristol-Meyers Squibb / Merck diabetes drug Pargluva (muraglitazar). It's officially "approvable", but the FDA wants more cardiovascular safety data before it can be sold. But just this morning the JAMA web site has rushed out an article from a team at the Cleveland Clinic on the drug's clinical trial data. (Accompanying editorial here). It's very disturbing, in more ways than one.
At the time, I said that "By my reading, the cardiovascular event profile of the drug subjects looks slightly but noticeably worse than that of the placebo group. There are plenty of possible extenuating factors, and the number of patients involved is small, but I think that this is going to be a problem for the companies during the FDA hearing. Here's the list of questions the FDA has proposed for discussion (PDF again), and you can see that edema and cardiovascular safety loom large. . ." That's fine, as far as it goes, but I didn't dig far enough into the data, and I wonder if the advisory panel did, either.
What the authors of this new paper have noticed is the number of patients taking a low dose of muraglitazar - lower than the companies ended up seeking approval for. They didn't show enough beneficial effects for that dose to be worthwhile, but since muraglitazar's cardiovascular problems appear to be strongly correlated with dose, these patients also had no cardiovascular events at all. The problem is that these patients were included in the risk calculations, and that makes the drug look safer than it would be under real-world conditions.
The Cleveland group's recalculations now put the risk of cardiovascular events with clinically relevant doses of muraglitazar at 20% higher than the placebo group, and at 67% higher than the combined placebo-standard of care group. (That includes patients treated with pioglitazone, a PPAR-gamma compound that's been approved for some years now). Put that way, this sounds like a huge increase, but it's important to remember that both of these figures, though real, are pretty small. The placebo group had about 34 events per 1000 patient years, and the drug treatment group, in the new analysis, had around 40 events. So, back-of-the-envelope, for every thousand patients on muraglitazar, you might expect an extra 6 cardiovascular incidents per year. The similarities to the Vioxx data are not hard to spot, and in fact the authors of this paper have been very much involved in that controversy as well.
But I'm not going to push that comparison. This is a different case than Vioxx, a drug that (for many patients) really does seem to do more than existing compounds can. The problem here is that muraglitazar (and all the PPAR alpha-gamma compounds that have gone into development) was supposed to be better for cardiovascular outcomes than the plain PPAR-gamma compounds that are already out there. Needless to say, it was also supposed to be better than a damned placebo, which it isn't. The entire dual-PPAR-agonist idea is in trouble. The whole point of adding PPAR-alpha activity was to improve blood lipid profiles, and pretty much the whole point of doing that is to improve cardiovascular health. The first part is working, but the second part, the important part, just doesn't seem to be happening. Looking at the data, I find it hard to imagine why anyone would take muraglitazar over the exisiting therapies, when there's no evidence for what is supposed to be its main advantage.
As if that weren't bad enough, there's also a background worry about cancer rates with PPAR compounds. The muraglitazar data aren't totally reassuring on this front, either. Other compounds in this class died because of carcinogenicity in long-term rodent studies, and muraglitazar is the first compound to actually make it past such studies. But the data submitted to the FDA show that rats given the compound at high doses do indeed show bladder cancer - it just seems to be less of a problem than it was for the earlier compounds from Merck, Kyorin, Novo, Dr. Reddy's, et al. For a marginal compound, though, this is a real issue.
I don't necessarily think that the people at BMS (and Merck, a latecomer to this compound) were sitting around wondering about just how to snow the FDA. But it would certainly cheer me up if I could rule that out, wouldn't it, now? At the very least, the companies weren't being as critical of themselves as scientists have to be, and they've committed a mistake that would flunk a PhD candidate or get a paper tossed back from a well-refereed journal. Something has gone seriously wrong here. We're supposed to be better than this.
What on Earth were they thinking, submitting data in a way that makes it look like they were trying to pull a fast one with the cardiovascular risk factors? Now, of all times? Who knows, maybe people at BMS had just convinced themselves that things were fine, somehow - the capacity for human self-deception is limitless. But didn't anyone at Merck turn pale and have to sit down when they saw these numbers? I didn't realize how bad the situation was back in September, but even then I wondered about this, saying: "I can't predict which way this one is going to go, and neither can anyone else. But post-COX-2 is a bad time to be coming to the FDA with possible low-level cardiac risks in your clinical data. . ." Now that the risks look even worse, I'm baffled. You people want the sky to come down on your heads?
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+ TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | The Dark Side
October 18, 2005
Posted by Derek
Well, that title above doesn't sound like something you'll see on a Broadway marquee, does it? As predicted here, although it didn't exactly take psychic powers, the FDA has asked for more cardiovascular data for the new PPAR alpha-gamma drug Pargluva.
Merck and Bristol-Meyers Squibb are quoted as saying that they're "eager to talk" to the agency to find out what's required, and I'll bet they are. Analysts have pushed the likely launch date of the drug back to late next year.
I'm starting to wonder if the PPAR drugs are ever going to able to live up to the expectation that many people had for them. The whole point of an alpha-gamma combination was to reduce blood sugar and improve cardiovascular health at the same time, which makes the emergence of cardiovascular risk with Pargluva particularly annoying.
That whole nuclear receptor field is still a wonderful area for basic research, but turning things into useful drugs has been harder than anticipated. For a while there, it looked as if we'd be able to take all sorts of combination of the three subtypes and turn out drugs for all sorts of indications - diabetes, high blood lipids, various cancers, wound healing, what have you. And perhaps we still can, after another ten or twenty years of hard labor.
(Some of my personal history with these compounds will be illustrated within the next month or so in Bioorganic and Medicinal Chemistry Letters, for those who are interested.)
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September 8, 2005
Posted by Derek
There's a lot of metabolic disease news this week from the FDA. We'll get to the inhaled insulin decision next week, but I thought I'd try to catch the next one before it happens. On Friday they're reviewing the first PPAR alpha-gamma ligand to make it to the regulatory approval stage, Bristol-Meyers Squibb's unmelodious "Pargluva" (muraglitazar), which sounds more like a disease than a drug. This is a therapeutic class that everyone had great hopes for a few years ago, with most of the big players competing at full speed. In theory, this combination should help with insulin sensitivity, cholesterol, and triglycerides all at the same time, which you'd think would be just what an overweight type II diabetic patient (and there are many) might need.
But development of these compounds has been a nightmare, with bad and unexpected toxicity cropping up deep in the late-phase work. BMS (and their late-arriving partner Merck) managed to get past those rapids and through clinical trials. But their drug shows a side effect that all PPAR-gamma drug programs have had to worry about, namely edema.
They also seem to have some (perhaps related) worries about cardiovascular events, which are broken out into completely separate categories in the FDA briefing document (big PDF). That document, whopper thought it is, is worth a look if you want to see what it's like to decide whether to approve a new drug or not. I wouldn't like to have to explain it all to a lay jury, that's for sure. No doubt a few whoops and hollers, along with the occasional choked tearful expression, would help.
By my reading, the cardiovascular event profile of the drug subjects looks slightly but noticeably worse than that of the placebo group. There are plenty of possible extenuating factors, and the number of patients involved is small, but I think that this is going to be a problem for the companies during the FDA hearing. Here's the list of questions the FDA has proposed for discussion (PDF again), and you can see that edema and cardiovascular safety loom large. I can't predict which way this one is going to go, and neither can anyone else. But post-COX-2 is a bad time to be coming to the FDA with possible low-level cardiac risks in your clinical data. . .
By the way, with thousands of people involved in the clinical studies, there are bound to be some. . .unplanned adverse events. I quote without comment from the briefing document linked to above, just in case you thought (for some odd reason) that running clinical trials was easy. . .
"Subject CV168021-29-21 was a 44-year old white maile with a 3-year history of diabetes and history of overweight, hypercholesterolemia and impotence. On study day 29 the subject died as the result of a gun shot wound.
Subject CV-168006-5-3 was a 62-year old white female with a history of hypertension, smoking, and alcohol use. On study day 112 she died in a motor vehicle accident. Her car was stopped at a light when struck by a truck. The investigator considered the event not likely related to study drug."
Yes, one would, on the whole, conclude that it wasn't . . .
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August 23, 2005
Posted by Derek
I'll tell you a company that's been watching what's happened to Merck and thinking hard about it: Sanofi. Well, OK, everyone in the industry has been looking at Merck's situation and shuddering, but I suspect the people at Sanofi(-Aventis) are especially jumpy. Why? Rimonabant.
Rimonabant, which will come to the market next year (most likely) under the name Acomplia, is one everyone's short list of potential multibillion dollar drugs. It'll be the first new drug treatment for obesity in years, and it's the first one ever with its mechanism of action (antagonism of the CB(1) receptor). It has potential for many sorts of addiction therapy as well. Although there's room to argue about just how effective it is compared to existing therapies, and there's some concern about how many HMOs will pay for it, there's little doubt that it's going to sell like crazy.
And there's the worry. There is absolutely no way that large enough clinical trials could be run on a drug like this to predict everything that might happen when millions of people start taking it. Can't be done. You can get down to a margin of safety that will get you past the FDA, but that isn't enough, now is it? No, if one person out of a hundred thousand has a nasty side effect, that's enough to bring the sky down on your head. And we can't test down to the level of one-per-hundred-thousand effects.
A fine situation, isn't it? This same argument applies to every new drug, naturally, but especially to a groundbreaking compound like rimonabant. That's just what we needed, an incentive not to be first in class with a new drug. What, exactly, are we doing to ourselves?
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March 17, 2005
Posted by Derek
I wanted to take a moment to congratulate Amylin on the FDA approval of their diabetes therapy Symlin. I've known a couple of people out there over the years. Actually, a lot of people have had a chance to know someone at Amylin, because the company has had more than one near-death experience, during which they've had to fire big swaths of their staff. A couple of years later, they'd start hiring again, until the next safe landed on top of them. I'd like to know just how many employees have been with them for more than ten years - you could probably count them on one hand.
As this look back at the Motley Fool mentions, the drug has been through six Phase III trials over the years. That's a level of perseverance that borders on the pathological. You could only get away with this with a biological product, where the barrier to going generic is so high. A small molecule would have about ten minutes left on its patent by now, and its value would be much lower (which gets back to that Forbes column about patent extensions, actually.)
Here's a multiyear chart of Amylin's stock, so you can vicariously experience the thrills yourself.
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July 20, 2004
Posted by Derek
Continuing on the theme of unexpected toxicity landmines, I wanted to take a look at a highly anticipated obesity drug from Sanofi. Rimonabant is a small molecule antagonist of the CB-1 receptor, and it's been getting a lot of press - both for its impressive efficacy and for its mechanism of action. The "CB" in the receptor name stands for "cannabinoid", and the drug blocks the same receptor whose stimulation causes the well-known food cravings brought on by marijuana.
Interestingly, blockade of this receptor not only seems to affect appetite, but also seems to help with cravings for nicotine. As you can imagine, the market potential for the drug could be immense (and as you can imagine, other drug companies are chasing the same biological target, too.)
But what else does an antagonist do? The receptor has, no doubt, several functions in the brain (all the CNS receptors do multiple duty), and it's scattered around in the nerves and other tissues as well. There have been a couple of reports that bear watching. A team of researchers (German/Italian/US) reported earlier this year that the CB-1 receptor seems to be involved in inflammation of the colon. Mice with the receptor knocked out show great susceptibility to chemical irritants in the gut, and (more disturbingly) the same effect was seen in normal mice treated with a CB-1 antagonist. The authors suggest that CB-1 may be involved in diseases like Crohn's and irritable bowel syndrome, but antagonists would, if anything, make the problem worse.
That's bad enough, but there's a potential disaster that just showed up last month. The authors report that a patient of theirs suddenly came down with multiple sclerosis after having been a subject in a rimonabant trial. Now, there's no way to prove causation, as they freely admit, but there's some evidence that CB-1 has a neuroprotective effect under normal conditions. So blocking its actions might conceivably expose neurons to damage, and when you combine that with the above potential role in inflammation, you have something that you should keep an eye on.
No one can say how this will play out. The most likely outcome is the best one - that the drug isn't associated with MS or Crohn's. After all, it's been through some extensive trials, and Sanofi still seems confident - which, believe me, they wouldn't be if a good fraction of the participants had come down with irritable bowel syndrome, much less multiple sclerosis. But there's another possibility, that the trouble will only show up in some patients under some conditions, and it might be rare enough that you won't see it until it gets out into the general population. There's just no way to run a clinical trial to nail down the statistics on, say, a one in 50,000 side effect. You'll never see it coming.
That MS report in particular must have the Sanofi people a bit worried, and I'm sure it has the attention of the other players in the area, who will be glad to let Sanofi go out and be the lightning rod in case anything bad happens. Odds are that it won't, but there are no sure things, not with this drug or any other. Honestly, it's years before you can relax in this business, if you ever do. Good luck, guys.
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+ TrackBacks (0) | Category: Diabetes and Obesity | Drug Development | Toxicology
July 19, 2004
Posted by Derek
The PPAR family (known in the US as alpha, gamma, and delta, for obscure historical reasons) is one of those biological jungles that keep us all employed. They're nuclear receptors, and thus they're involved in up- and down-regulation of hundreds of genes. Like most of the other nuclear receptors, they do that by responding to small molecules, which makes the whole class a unique opportunity for medicinal chemists.
Normally, we can't do much about gene regulation, because it's all handled by huge multicomponent protein complexes, terrible and unlikely candidates for intervention with our drug molecules. But when the whole thing is set off by binding of a small ligand, well, that's all the invitation we need. To pick a well-known class of small ligands, the best-known members of the NR superfamily are the steroid receptors, which should give you some idea of how powerful these things can be.
For their part, the PPARs are all major players in cellular energy balance and fuel use, the handling of fatty acids and other lipids, the generation and remodeling of adipose tissue, and similar things. That lands them squarely in some very important therapeutic areas such as diabetes, obesity, and cardiovascular disease. But more recently, it's become clear that they're also involved in things like inflammation and carcinogenesis, which brings in another huge swath of the drug industry. Every large drug company is working on them, for one indication or another. Heck, you could run an entire drug company on nothing but PPAR-related targets, that is, if you weren't terrified by the insane risk that you were taking.
Problem is, the biology of nuclear receptors is powerfully complex and murky. We know a lot more about them than we did five or ten years ago, but it's obvious to everyone in the field that we still have very little idea of what we're doing. Take a look at the three PPARs: there are two diabetes drugs on the market that target PPAR gamma (Avandia and Actos, aka rosiglitazone and pioglitazone), but no one has been able to get anything significantly better or safer than either of those. PPAR alpha is supposed to be the way an old class of lipid lowering drugs (the fibrates) work, but no one's really sure that they believe that. Several companies have been working on PPAR alpha drugs for a long time now, and nothing's made it deep into the clinic yet, which isn't a good sign. And no one really knows what PPAR delta does - it seems to have something to do with lipid levels, and something to do with wound healing, and something to do with colon cancer. The clues are rather widely scattered.
I've mentioned that several companies have been working on combination diabetes drugs that would hit both PPAR gamma and alpha. The idea is that they'd do all the glucose lowering of a gamma-targeted drug, and lower lipid levels at the same time - a worthy goal for the typical overweight Type II diabetic patient. But Novo Nordisk, racing along with a compound they licensed from India's Dr. Reddy's (the evocatively named ragaglitazar) hit the banana peel when long-term rodent testing showed that the compound was associated with bladder cancer. Then Merck, which had a compound from Japan's Kyorin in advanced trials, pulled it when another rare cancer showed up in long-term rodent studies. Screeching halt, all over the industry.
Now the FDA has jumped in, with a requirement that any new PPAR drugs go through two-year rodent toxicity testing. That's an unusual requirement, but (as the two examples above show) it's something that companies were already doing on their own initiative. Bristol-Meyers Squibb and AstraZeneca have already done theirs, for example, and are plowing on.
The feeling has been: no one really knows what to expect from new PPAR compounds, so you'd better test the waters extensively. The thought of putting a compound on the market that turns out - years later - to be linked to increased risk of something like bladder cancer is enough to give everyone nightmares. I should mention that nothing bad has been seen from the two marketed PPAR gamma compounds I mentioned. But everyone remembers that there was another one, troglitazone, the first to market and the first to be pulled. It showed liver toxicity, but that seems to have been compound-related rather than mechanism-related.
Here's an article from Forbes on the subject, one of the few outlets that covered this story in any detail. It's pretty good, although it glosses over a lot of things. For example, the article quotes Ralph DeFronzo of UT-San Antonio saying that the fibrate drugs have been targeting PPAR-alpha for years, so why is the FDA worried about that subtype? What that ignores is that the fibrates are actually very weak drugs at alpha, which is why I mentioned the doubts people have about the whole mechanism. The drugs being developed now are thousands of times more potent. And look at the alpha-gamma combinations: why did all the trouble start only when alpha was added to the mix?
Well, we've got plenty of work to do. Unraveling the biological effects of the PPARs is going to take many, many years. And we're going to have to do it in rodents, in dogs, and in humans, at the very least - all the major species that are tested for toxicity. We already know about some significant differences between the species in the way that these nuclear receptors work. Will these cancer problems be another one? Are humans going to be just fine? Or will we react in even worse ways, given enough time? We just don't know. Everyone's holding their breath, waiting to see what comes next. . .
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+ TrackBacks (0) | Category: Cancer | Diabetes and Obesity | Drug Development | Toxicology
May 10, 2004
Posted by Derek
I've written before about method-of-treatment patents, and now the subject makes today's front page of the Wall Street Journal. They've picked a pure example of the breed. Hans-Ulrich Demuth at the University of Halle in Germany filed for a patent in 1996 on the use of inhibitors of dipeptidyl peptidase IV in the treatment of diabetes. The patent was granted in the U.S. in late 2001 (as US6303661, and no, for those outside the field, that's not an odd delay at all, for better or worse.)
Like many peptidases, DPP-IV is a wrecking ball of an enzyme. It breaks down (among other things) an important signaling protein called GLP-1 (that stands for glucagon-like-peptide 1, which shows you how fuzzy a lot of biochemical nomenclature can be.) And GLP-1 is important in maintaining glycemic control - type II diabetic patients could sure use more of it than they have. If you could find a GLP-1 mimic, you'd have a very interesting drug. That's an unlikely hope for a small molecule, though, so other bounce-shot approaches have been tried. GLP-1 itself has been tweaked in attempts to make it more stable, and people have tried various smaller proteins as well.
There are more. People have tried to cause more GLP-1 to be secreted, without tremendous amounts of success, and then there's the DPP-IV inhibitor approach, which would cause it not to be broken down so quickly. Whatever works! Several companies have taken a whack at this route, because the inhibition of protease enzymes, while still nowhere near a sure thing, has a reasonably good track record in drug development. Novartis is the company in the lead, with a compound well into clinical trials.
Demuth, naturally enough, wants a piece of the action. His first patent claim is for: "A method for lowering elevated blood glucose levels in mammals resulting from food intake comprising administering at least one oral administration of a therapeutically effective amount of at least one inhibitor of Dipeptidyl Peptidase IV (DP IV) or of DP IV-like enzyme activity."
Well, that covers the bases, you'd think. But there's a Prof. Jens Holst in the picture as well, from the University of Copenhagen. His group published a paper a few months before Delmuth's patent was filed, in which they showed the effect of a DPP-IV inhibitor in vitro, and suggested it as an adjunct therapy for diabetes. That's a complication, because if anyone spells out your idea in print, you can't get a patent on it later. (This applies to your own statements, too, which is another reason why we in the drug industry only publish on projects that either well along in the clinic or already dead.)
But Delmuth's patent issued, Holst or no Holst, and he cited the prior work in it. That makes breaking his patent harder, because (presumably) the patent examiner took Holst's work into account and decided to allow the claim anyway. Anyone who wants to say that the earlier publication is invalidating prior art is going to have to prove that the examiner blew it - which certainly isn't unheard of, but is still a harder path to take.
Merck and J&J have already either paid Delmuth or indicated that they're going to. BMS isn't saying what they'll do. Novartis, on the other hand, has so far flatly refused to pay anything. A spokesman told the Journal that they're considering doing some sort of deal, though. You can bet that it's going to be based strictly on the numbers: on one side, figure out how much the drug is likely to make, and find out what sort of cut Delmuth wants. Then factor in how likely it is that you'll actually get to the market. On the other side, how much would it cost in time and legal fees to break his patent? Factor in how likely you think you'll be to win, and you've got the whole equation.
Now, I haven't studied this closely, but that's not going to stop me from having an opinion. (When, since the dawn of time, has that every stopped anyone?) Holst's paper looks like a reasonable candidate for prior art to me, frankly. (He seems to think so, too - he and Delmuth have had some testy exchanges in print.) You'd want to look over the prosecution history of Delmuth's patent, to see if there was any back-and-forthing about it during the examination period. It seems clear to me that the higher the expectations Novartis has for their inhibitor, the less likely they'll be to settle.
But all this suggests the next question, coming up for discussion here within the next few days: should such patents even be granted? Highly paid people are prepared to argue either side of the issue! Heck, I'm even prepared to take one side of it myself.
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+ TrackBacks (0) | Category: Diabetes and Obesity | Patents and IP
November 19, 2002
Posted by Derek
The Advertising column in today's Wall St. Journal has an interesting note on some recent Merck ads for their COX-2 inhibitor, Vioxx. What they've done is break their TV ads up into pieces. Why would you do that? Well, the FDA rules are that if you mention a drug and what it's good for in the same ad, you also have to list the possible bad side effects - the sort of thing that's in the package insert. And since every drug has side effects, that's a real problem for an advertising agency - finding something to do on screen while the voice-over announcer drones on quickly about flatulence, night sweats, and other appealing topics.
Roche tried this about a year ago (see below,) and Merck seems to be using nearly the same strategy. One ad shows Dorothy Hamill skating, while she talks about how sometimes she has arthritis pain in the morning - followed by an announcer saying that you should ask about new medicines that could help, and giving a phone number for Merck. The other ad has Dorothy Hamill skating, and mentions a medicine from Merck called Vioxx - with another Merck phone number to call. The drug and its intended therapeutic use never get mentioned in the same ad.
Roche got into trouble with this little innovation. They were advertising Xenical (orlistat,) which in my book is a pretty tough sell under the best of circumstances. In case you don't know the mechanism, that drug inhibits pancreatic lipase, the enzyme that's secreted into the gut to break down fat. It would inhibit most any other lipase it got ahold of, for that matter, but it doesn't make it out of the gut, so pancreatic lipase it is. No triglyceride breakdown, not much fatty acid absorption into the body, not much fat from the diet. What could be easier?
Well, that fat has to go somewhere. And in the GI tract, if it's not absorbed, there's only one place for it to go, and the consequences can be most unpleasant. Believe me, taking a pancreatic lipase inhibitor and then pigging out on a bucket of fried chicken will bring on a really unforgettable experience. I will go into no more details, in the interest of maintaining this blog's dignified facade, but will refer you to this page of side effects. Note that none of these are terms that you'd want to mention in your TV commercials if you could posibly help it, especially not ones that run during the dinner hour.
So Roche broke up their ads. One ad mentioned the word "Xenical" and the other ad mentioned weight loss. Otherwise, the two ads were extremely similar - same images, same announcer, colors, fonts. And Roche arranged to have them shown back-to-back (or nearly so) in case anyone missed the point. The FDA sure didn't, and prevailed on them to stop. Merck, on the other hand, seems to be making sure that their ads don't get run back-to-back. The FDA is apparently thinking about whether these are really separate ads, or just an attempt to get around the advertising rules.
I can save them the trouble: of course this is an attempt to get around the rules. Whether these rules should exist in their current form (or exist at all) can be debated; I get e-mail from people who say "ban 'em all" and I get some that say "let 'em all loose." But they exist right now, and there's no arguing about that. And if the FDA lets these through, they should prepare for this to become the standard advertising method for the whole industry.
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+ TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity
October 24, 2002
Posted by Derek
If you want a good example of how something that seems completely sensible can backfire in drug development, look no further than the story of leptin. I remember when this peptide hormone was discovered in rodents in 1995: the news really made a splash among groups working on obesity and metabolic therapies.
If you raised antibodies to leptin and treated mice with then, taking the protein out of circulation, the animals ate like mad. And on the other hand, injecting extra leptin made them turn up their noses at food, even when they should be eating (which for mice and rats is at night - or whenever their dark phase is in the animal rooms.) It turned out that two well-known mutant mice strains (ob/ob and db/db) were actually mutants of leptin function. The first has bollixed-up leptin protein, the second has a problem with its leptin receptors. Both animals eat heavily and put on serious weight (they're rather odd-looking.) It all fell together.
So you can see how everyone got revved up. Here (after many false starts) was the real eating hormone! Under our noses all along! Some companies took at whack at finding small molecules to affect the leptin receptor, but that didn't pan out well. Trying to find a small-molecule drug to tackle a receptor built for a large peptide is usually a losing proposition (which is why people, these many years later, still have to inject themselves with insulin.)
But Amgen was out in the lead with the protein itself. It wasn't going to be an oral medication, but a real wonder-drug for the terminally obese would be worth injecting, right? While they developed it, the research went on, furiously - and some oddities began to emerge. You'd think, from the rodent data, that really obese humans would be leptin deficient, too. Wrong - not only did they have leptin, they usually had well over the normal amounts. Ahem.
That was disturbing. You're clearly not going to accomplish much by giving more of the stuff to someone who has plenty of it already. The picture that began to form was similar to the role of insulin in Type II diabetes (the adult-onset kind.) Type IIs have plenty of insulin, at least in the first phases of their disease. In fact, they have more than normal. The problem is, their tissues have become resistant to its effects, so the pancreas compensates by pumping out more and more of it. (This can go on for years, until the beta-cells finally start to break down under the strain of constant pedal-to-the-floor insulin secretion - and at that point, your diabetic troubles really start to catch up with you.)
Obese humans are resistant to leptin. No one's sure how that happens, or why (no one's really sure how people get resistant to insulin, either, although there's sure no shortage of theories.) Amgen soldiered on into the clinic, and (despite pulling out all the stops) failed to find any real effects. The craze was over.
These days, everyone in the drug industry who studies metabolism knows about leptin, respects its central role in feeding behavior - and sighs at bit at what might have been.
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July 10, 2002
Posted by Derek
A point I made in yesterday's post is worth expanding on - my scepticism about the advent of the Magic Pizza Pill. It's not just hard to develop an obesity drug. It's hard to fight almost any of the biological pathways, even when they're doing harm. Evolution has whittled some of them down to lean, mean, biochemical machines, and the ones that haven't had that treatment are often shaggy, baroque palaces of backup redundant redundancy.
Obesity (and feeding behavior in general) is a good example of the latter. Every year or two, another feeding/satiety signaling pathway is elucidated, and everyone gets excited that this might be the key. The peptide ghrelin is the current example. I hope it works, but the previous star players (leptin, neuropeptide Y, galanin, and so on and so on) have all fallen on their faces. It's often for the same reason: too many backup systems, too strong a thumb on the homeostatic scale. The body really resists delicate tinkering with something as important as eating.
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April 15, 2002
Posted by Derek
There was quite a wave of publicity about a possible "exercise pill" recently. The folks over at Godless Capitalist asked me to take a crack at explaining what all the noise is about. As you might imagine, though, the original research that set this off is a bit less sensational: "Regulation of Mitochondrial Biogenesis in Skeletal Muscle by CaMK" is the catchy title, from a joint effort of teams at Duke and Southwestern/Dallas.
For a long time, it's been known that the key to a muscle's capacity is the number of mitochondria in its cells. Those, of course, are the organelle responsible for energy production. The more you have, the longer you can go without fatigue (which is really just a buildup of toxic waste products formed when the mitochondria can't keep up with demand, and the cell has to switch to other, less efficient pathways.)
It's also been known for decades that exercise causes more mitochondria to be produced inside muscle cells (along with plenty of other changes,) but the genes that are turned on and off to do that are still pretty obscure. One of the things that happens with exercise is elevated calcium levels in the cells, which sets off the activity of several enzymes. These researchers engineered a form of one particular enzyme, CaMK-IV, so that it would be activated even without raised calcium levels. They also took out the section of the protein that would normally keep it inactive under baseline conditions, so the enzyme was set to be set to full activity the entire time.
The transgenic mice made with this mutation are interesting animals. Their pattern of gene expression (and the corresponding levels of various proteins) make their muscles look very similar to normal muscle after extended physical training. Thus the "exercise pill" hype - the mice seem to have developed with pre-exercised muscle tissue.
And, sure enough, microscopic examination showed that the mutant mice had about 50% more mitrochondria in their muscle cells. The teams also identified raised amounts of a protein (PGC-1) that's known to be very important in metabolic balance in fat and muscle tissue. The best guess is that the engineered activity of the CaMK-IV enzyme set off production of more PGC-1, which led to more mitochondria. No one had made that enzyme-PGC connection before - it'll be useful to know that, because PGC-1 has key roles to play in obesity and diabetes, as well as in exercise.
So, now we have a better idea of how muscles figure out how to respond to exercise. Do we have an exercise pill? Nowhere near. Keep in mind that these mice had to be genetically altered to get the activated enzyme. Getting that effect with a drug won't be easy.
One problem is that it's more or less impossible to get an enzyme to do what it does better or more quickly. They're built for speed already. What you can do is find some other system that's naturally slowing it down, and try to gum that pathway up instead, freeing the enzyme of interest to do its thing. (A general motif of medicinal chemistry is that we're a lot better at throwing wrenches into the works than we are at tuning them up to work better; millions of years of evolution are hard to outdo.) There's no guarantee that we'd be able to do this trick with CaMK-IV.
And if we did, there's no telling what might happen (although I'm sure that someone's going to give it a try, and more power to them.) Genetically altered mice, who've had their entire embryonic development to deal with some mutation, can behave very differently from normal adult mice that get suddenly thrown into the same state. A number of these gain-of-function enzyme experiments, for example, have yielded results that don't seem to apply well to the real world (although this one, admittedly, makes a lot of sense.) Don't cash in the health club membership just yet.
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April 1, 2002
Posted by Derek
>A post of mine from February 26 mentioned in passing the side effects of the anti-HIV protease inhibitor drugs. There's nothing inherent in their mechanism that should cause lipid profile changes and insulin resistance, so the hunt has been on for what other target is responsible.
Now a team at Washington University in St. Louis seems to have picked up the scent. They've found that one of the drugs, Crixivan (indinavir) shuts down the action of a protein called Glut4. Metabolism and endocrinology folks will find that connection pretty believable: Glut4 is one of a family of glucose transporter proteins, whose lot in life it is to take glucose out of the blood stream and pump it into cells. They're found everywhere, with different levels of activity, but Glut4 is key one that responds to insulin stimulation - its action is the primary reason why a shot of insulin lowers blood sugar.
Inhibiting it, then, causes some of the most important actions of insulin to be less effective, which is a back-door route into a state much like Type II diabetes. Lipids and glucose are tied together physiologically, since they're the two main circulating fuels available. You can't mess around with one system without the other responding.
I'm not aware of any other molecules that selectively inhibit Glut4 - as you can imagine, doing that hasn't been a priority for anyone. There's not much of a market for a compound that pushes you toward diabetes. Now, if you knew a way to activatethe transporter, or to keep it working longer, then the metabolic-disease researchers would be ringing your phone pretty quickly. No one's been able to do those things, and many of the steps in Glut4 activation aren't well worked out.
And as far as I can tell, the mechanism by which this new inhibition takes place isn't worked out yet, either. The drugs that cause the side effects are structurally rather different, so the best guess is that they're all hitting some other enzyme that's necessary for Glut4 function. It would just be bad luck that this enzyme, whatever it is, looks enough like HIV protease at the molecular level for drugs to shut down both of them.
If we can find the culprit, then we can try to come up with compounds that are more selective, or find some other treatment to compensate. At the same time, figuring out that problem could shed light on some longstanding problems in diabetes research, too. Stay tuned.
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