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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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February 21, 2014

Ces3 (Ces1) Inhibition As a Drug Target

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Posted by Derek

Update: the nomenclature of these enzymes is messy - see the comments.

Here's another activity-based proteomics result that I've been meaning to link to - in this one, the Cravatt group strengthens the case for carboxylesterase 3 as a potential target for metabolic disease. From what I can see, that enzyme was first identified back in about 2004, one of who-knows-how-many others that have similar mechanisms and can hydrolyze who-knows-how-many esters and ester-like substrates. Picking your way through all those things from first principles would be a nightmare - thus the activity-based approach, where you look for interesting phenotypes and work backwards.

In this case, they were measuring adipocyte behavior, specifically differentiation and lipid accumulation. A preliminary screen suggested that there were a lot of serine hydrolase enzymes active in these cells, and a screen with around 150 structurally diverse carbamates gave several showing phenotypic changes. The next step in the process is to figure out what particular enzymes are responsible, which can be done by fluorescence labeling (since the carbamates are making covalent bonds in the enzyme active sites. They found my old friend hormone-sensitive lipase, as well they should, but there was another enzyme that wasn't so easy to identify.
WWL113.png
One particular carbamate, the unlovely but useful WWL113, was reasonably selective for the enzyme of interest, which turned out to be the abovementioned carboxyesterase 3 (Ces3). The urea analog (which should be inactive) did indeed show no cellular readouts, and the carbamate itself was checked for other activities (such as whether it was a PPAR ligand). These established a strong connection between the inhibitor, the enzyme, and the phenotypic effects.

With that in hand, they went on to find a nicer-looking compound with even better selectivity, WWL229. (I have to say, going back to my radio-geek days in the 1970s and early 1980s, that I can't see the letters "WWL" without hearing Dixieland jazz, but that's probably not the effect the authors are looking for). Using an alkyne derivative of this compound as a probe, it appeared to label only the esterase of interest across the entire adipocyte proteome. Interestingly, though, it appears that WWL13 was more active in vivo (perhaps due to pharmacokinetic reasons?)
WWL229.png
And those in vivo studies in mice showed that Ces3 inhibition had a number of beneficial effects on tissue and blood markers of metabolic syndrome - glucose tolerance, lipid profiles, etc. Histologically, the most striking effect was the clearance of adipose deposits from the liver (a beneficial effect indeed, and one that a number of drug companies are interested in). This recapitulates genetic modification studies in rodents targeting this enzyme, and shows that pharmacological inhibition could do the job. And while I'm willing to bet that the authors would rather have discovered a completely new enzyme target, this is solid work all by itself.

Comments (14) + TrackBacks (0) | Category: Biological News | Chemical Biology | Diabetes and Obesity

February 7, 2014

Irisin and Metabolism - A New Target Emerges

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Posted by Derek

Here's something for metabolic disease people to think about: there's a report adding to what we know about the hormone irisin, secreted from muscle tissue, that causes some depots of white adipose tissue to become more like energy-burning brown fat. In the late 1990s, there were efforts all across the drug industry to find beta-3 adrenoceptor agonists to stimulate brown fat for weight loss and dyslipidemia. None of them ever made it through, and thus the arguments about whether they would actually perform as thought were never really settled. One of the points of contention was how much responsive brown adipose tissue adults had available, but I don't recall anything suspecting that it could be induced. In recent years, though, it's become clear that a number of factors can bring on what's been called "beige fat".

Irisin seems to be released in response to exercise, and is just upstream of the important transcriptional regulator PGC-1a. In fact, release of irisin might be the key to a lot of the beneficial effects of exercise, which would be very much worth knowing. In this study, a stabilized version of it, given iv to rodents, had very strong effects on body weight and glucose tolerance, just the sort of thing a lot of people could use.

One of the very interesting features of this area, from a drug discovery standpoint, is that no one has identified the irisin receptor just yet. Look for headlines on that one pretty soon, though - you can bet that a lot of people are chasing it as we speak.

Update: are human missing out on this, compared to mice and other species?

Comments (14) + TrackBacks (0) | Category: Biological News | Diabetes and Obesity

January 13, 2014

Boost Your NAD And Fix It All?

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Posted by Derek

Here's a paper from a few weeks back that I missed during the holidays: work from the Sinclair labs at Harvard showing a new connection between SIRT1 and aging, this time through a mechanism that no one had appreciated. I'll appreciate, in turn, that that opening sentence is likely to divide its readers into those who will read on and those who will see the words "SIRT1" or "Sinclair" and immediate seek their entertainment elsewhere. I feel for you, but this does look like an interesting paper, and it'll be worthwhile to see what comes of it.

Here's the Harvard press release, which is fairly detailed, in case you don't have access to Cell. The mechanism they're proposing is that as NAD+ levels decline with age, this affects SIRT1 function to the point that it no longer constains HIF-1. Higher levels of HIF-1, in turn, disrupt pathways between the nucleus and the mitochondia, leading to lower levels of mitochondria-derived proteins, impaired energy generation, and cellular signs of aging.

Very interestingly, these effects were reversed (on a cellular/biomarker level) by one-week treatment of aging mice with NMN (nicotine mononucleotide edit: fixed typo), a precursor to NAD. That's kind of a brute-force approach to the problem, but a team from Washington U. recently showed extremely similar effects in aging diabetic rodents supplemented with NMN, done for exactly the same NAD-deficiency reasons. I would guess that the NMN is flying off the shelves down at the supplement stores, although personally I'll wait for some more in vivo work before I start taking it with my orange juice in the mornings.

Now, whatever you think of sirtuins (and of Sinclair's work with them), this work is definitely not crazy talk. Mitochondria function has long been a good place to look for cellular-level aging, and HIF-1 is an interesting connection as well. As many readers will know, that acronym stands for "hypoxia inducible factor" - the protein was originally seen to be upregulated when cells were put under low-oxygen stress. It's a key regulatory switch for a number of metabolic pathways under those conditions, but there's no obvious reason for it to be getting more active just because you're getting older. Some readers may have encountered it as an oncology target - there are a number of tumors that show abnormal HIF activity. That makes sense, on two levels - the interiors of solid tumors are notoriously oxygen-poor, so that would at least be understandable, but switching on HIF under normal conditions is also bad news. It promotes glycolysis as a metabolic pathway, and stimulates growth factors for angiogenesis. Both of those are fine responses for a normal cell that needs more oxygen, but they're also the behavior of a cancer cell showing unrestrained growth. (And those cells have their tradeoffs, too, such as a possible switch between metastasis and angiogenesis, which might also have a role for HIF).

There's long been speculation about a tradeoff between aging and cellular prevention of carcinogenicity. In this case, though, we might have a mechanism where our interests on on the same side: overactive HIF (under non-hypoxic conditions) might be a feature of both cancer cells and "normally" aging ones. I put that word in quotes because (as an arrogant upstart human) I'm not yet prepared to grant that the processes of aging that we undergo are the ones that we have to undergo. My guess is that there's been very little selection pressure on lifespan, and that what we've been dealt is the usual evolutionary hand of cards: it's a system that works well enough to perpetuate the species and beyond that who cares?

Well, we care. Biochemistry is a wonderful, heartbreakingly intricate system whose details we've nowhere near unraveled, and we often mess it up when we try to do anything to it, anyway. But part of what makes us human is the desire (and now the ability) to mess around with things like this when we think we can benefit. Not looking at the mechanisms of aging seems to me like not looking at the mechanisms of, say, diabetes, or like letting yourself die of a bacterial infection when you could take an antibiotic. Just how arrogant that attitude is, I'm not sure yet. I think we'll eventually get the chance to find out. All this recent NAD work suggests that we might get that chance sooner than later. Me, I'm 51. Speed the plow.

Comments (17) + TrackBacks (0) | Category: Aging and Lifespan | Biological News | Diabetes and Obesity

December 19, 2013

Bristol-Myers Squibb Exits Diabetes

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Posted by Derek

As the Wall Street Journal reported last night, Bristol-Myers Squibb is getting out of the diabetes business entirely, selling its collaboration with AstraZeneca back to AZ.

As part of the transaction, and subject to local consultation and legislation, Bristol-Myers Squibb and AstraZeneca anticipate that substantially all employees of Bristol-Myers Squibb dedicated to the diabetes business will be transferred to AstraZeneca. A number of R&D and manufacturing employees dedicated to diabetes will remain with Bristol-Myers Squibb to progress the diabetes portfolio and support the transition for these areas. Bristol-Myers Squibb will work closely with AstraZeneca to ensure a smooth transition.

What happens once that diabetes portfolio is "progressed"? I haven't heard details yet, and they may not even be available. Given the recent moves by BMS, though, this announcement shouldn't come as a huge surprise. It does say some interesting things about the positions of the two companies. BMS sees big opportunities in its oncology portfolio, and by comparison, the diabetes business looks slow-moving and too expensive for the return it offers. AstraZeneca, by contrast, needs all the help it can get. Actual drugs that are bringing in actual money, and whose patents are not expiring next Tuesday? Not bad.

Comments (21) + TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity

November 15, 2013

Zafgen's Epoxide Clears A Hurdle

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Posted by Derek

I wrote here about Zafgen and their covalent Met-Ap2 inhibitor beloranib. Word is out today that the compound has passed its first Phase II trial handily, so score one for covalent epoxides as drug candidates.

Zafgen has followed up promising results from early-stage work on its weight drug beloranib with a stellar Phase II study that tracked rapid weight loss among the severely obese, with one group shedding an average of 22 pounds in 12 weeks. CEO Tom Hughes says the mid-stage success clears a path to a Phase IIb trial that can fine tune the dose while taking more time to gauge the longterm impact of its treatment on weight. And the data harvest sets the right tone for ongoing talks with investors about a new financing round for the biotech.

Efficacy, though, doesn't seem to have been in much doubt with this compound. Phase III will be the big one, because the worry here will be some sort of funny longer-term toxicity. No one's quite sure what inhibiting that enzyme will do (other than this pretty impressive weight loss), and a covalent drug (even a relatively benign and selective one like an epoxide) is always going to have questions around it until it's proven itself in human tox. But so far, so good.

One thing that beloranib has going for it is that patients would presumably take for a relatively limited course of therapy and then try to keep the weight off on their own. That's a big distinction, toxicologically. On one end of the spectrum, you've got your one-time-use drugs, like an anesthetic, and then there are the anti-infectives that you might take for two weeks or (at most) a few months. But at the other end, you have the cardiovascular and diabetes drugs that your patient population is going to be taking every morning for the rest of their lives, and the safety profile is clearly going to have to clearer in those cases.

Critics of the industry never fail to mention that we, supposedly, are not looking for cures, but rather for drugs in that latter category so we can reap the big, big profits. They haven't thought this through well enough: for one thing, a cure is worth more money up front. And there is that tiny little factor of patent lifetime. To hear some people talk, you'd think that a drug's discoverers continue to reap the gains forever, but it ain't so. Ask Eli Lilly right now how that's going - most of their revenue is in the process of packing up and leaving for the generics companies. It doesn't matter if a company finds a drug that people need to take for fifty years; they're not going to be selling it that long.

Back to Zafgen, though. They've got an interesting program going here, and I'm very curious to see how it works out. Going after obesity from the metabolic end is something that a lot of people have tried, through various mechanisms, but it's still probably a better bet than trying to affect appetite. And I'll be glad to see an epoxide-based drug prove itself in the clinic, because I think that evidence suggests that they're better drug candidates than we give them credit for (see the link in the first line of this post for more on that). We medicinal chemists need all the options we can get. From the way things look, I'd bet on beloranib going fine through the rest of Phase II - and then begins the finger-crossing and rabbit's-footing.

Comments (16) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity

November 8, 2013

Exiting Two Therapeutic Areas

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Posted by Derek

So Bristol-Myers Squibb did indeed re-org itself yesterday, with the loss of about 75 jobs (and the shifting around of 300 more, which will probably result in some job losses as well, since not everyone is going to be able to do that). And they announced that they're getting out of two therapeutic areas, diabetes and neuroscience.

Those would be for very different reasons. Neuro is famously difficult and specialized. There are huge opportunities there, but they're opportunities because no one's been able to do much with them, for a lot of good reasons. Some of the biggest tar pits of drug discovery are to be found there (Alzheimer's, chronic pain), and even the diseases for which we have some treatments are near-total black boxes, mechanistically (schizophrenia, epilepsy and seizures). The animal models are mysterious and often misleading, and the clinical trials for the biggest diseases in this area are well-known to be expensive and tricky to run. You've got your work cut out for you over here.

Meanwhile, the field of diabetes and metabolic disorders is better served. For type I diabetes, the main thing you can do, short of finding ever more precise ways of dosing insulin, is to figure out how to restore islet function and cure it, and that's where all the effort seems to be going. For type II diabetes, which is unfortunately a large market and getting larger all the time, there are a number of therapeutic options. And while there's probably room for still more, the field is getting undeniably a bit crowded. Add that to the very stringent cardiovascular safety requirements, and you're looking at a therapeutic that's not as attractive for new drug development as it was ten or fifteen years ago.

So I can see why a company would get out of these two areas, although it's also easy to think that it's a shame for this to happen. Neuroscience is in a particularly tough spot. The combination of uncertainly and big opportunities would tend to draw a lot of risk-taking startups to the area, but the massive clinical trials needed make it nearly impossible for a small company to get serious traction. So what we've been seeing are startups that, even more than other areas, are focused on getting to the point that a larger company will step in to pay the bills. That's not an abnormal business model, but it has its hazards, chief among them the temptation to run what trials you can with a primary goal of getting shiny numbers (and shiny funding) rather than finding out whether the drug has a more solid chance of working. Semi-delusional Phase II trials are a problem throughout the industry, but more so here.

Comments (58) + TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity | Drug Development | The Central Nervous System

August 15, 2013

Mannkind's Latest Data

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Posted by Derek

I haven't written much about Mannkind recently. This has been a long, long, expensive saga to develop an inhaled-insulin delivery system (Afrezza), which is an idea that all by itself has seems to have swallowed several billion dollars and never given anything back yet. (That link above will send you to some of the story, and this one will tell you something about the disastrous failure of the only inhaled insulin to reach the market so far).

In 2011, Mannkind looked as if they were circling the drain. But (as has been the case many times before), more money was heaved into what might still turn out to be an incinerator, and they kept going. Just in the last few days, they've released another batch of Phase III data, which looked positive. You can see from the year-to-date stock chart that people have been anticipating this, which might account for the way that MNKD hasn't exactly taken off on the news. The stocked jumped at the open yesterday, then spent the rest of the day wandering down, and opened today right back where it was before the news came out.

People might be worried about possible effects on lung function, which show up in the data (FEV1 as well as a side effect of coughing). But there are potentially even bigger concerns in the number for HbA1c and fasting glucose. A closer look at the data shows that Mannkind's product may not have clearly established itself versus the injected-insulin competition. As that FiercePharma story says, this might not keep the product from being approved, but it could give it a rough time in the marketplace (and give Mannkind a rough time finding a big partner).

I wonder if there are any investors - other than Al Mann - who have stuck with this company all the way? If so, I wonder what effect that's had on their well-being? It has been a long, bizarre ride, and no one knows how many more curves and washed-out bridges might still be out there.

Comments (27) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity

July 11, 2013

The Last PPAR Compound?

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Posted by Derek

Roche has announced that they're halting trials of aleglitazar, a long-running investigational drug in their diabetes portfolio. I'm noting this because I think that this might be the absolute last of the PPAR ligands to fail in the clinic. And boy howdy, has it been a long list. Merck, Lilly, Kyorin, Bristol-Myers Squibb, Novo Nordisk, GlaxoSmithKline, and Bayer are just the companies I know right off the top of my head that have had clinical failures in this area, and I'm sure that there are plenty more. Some of those companies (GSK, for sure) have had multiple clinical candidates go down, so the damage is even worse than it appears.

That why I nominated this class in the Clinical Futility Awards earlier this summer. Three PPAR compounds actually made it to market, but the record has not been happy there, either. Troglitazone was pulled early, Avandia (rosiglitazone) has (after a strong start) been famously troubled, and Actos (pioglitazone) has its problems, too.

The thing is, no one knows about all this, unless they follow biomedical research in some detail. Uncounted billions have been washed through the grates; years and years of work involving thousands of people has come to nothing. The opportunity costs, in retrospect, are staggering. So much time, effort, and money could have been spent on something else, but there was no way to know that without spending it all. There never really is.

I return to this theme around here every so often, because I think it's an important one. The general public hears about the drugs that we get approved, because we make a big deal out of them. But the failures, for the most part, are no louder than the leaves falling from the trees. They pass unnoticed. Most people never knew about them at all, and the people who did know would rather move on to something else. But if you don't realize how many of these failures there are, and how much they cost, you can get a completely mistaken view of drug discovery. Sure, look at the fruit on the branches, on those rare occasions when some appears. But spare a glance at that expensive layer of leaves on the ground.

Comments (31) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | Drug Development

June 6, 2013

Today's Avandia Hearing at the FDA

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Posted by Derek

If you want to follow the blow-by-blow of today's FDA hearing on the marketing restrictions on Avandia (rosiglitazone), I can send you to Matthew Herper's Twitter feed. He has the goods.

Comments (3) + TrackBacks (0) | Category: Diabetes and Obesity | Regulatory Affairs

March 22, 2013

Trouble for a Whole Class of Diabetes Drugs?

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Posted by Derek

The FDA has been turning its attention to some potential problems with therapies that target the incretin pathways. That includes the DPP-IV inhibitors, such as Januvia (sitagliptin) and GLP-1 peptide drugs like Byetta and Victoza.

There had been reports (and FDA mentions) of elevated risks with GLP-1 drugs, but this latest concern is prompted by a recent paper in JAMA Internal Medicine that uses insurance company data to nail down the effect. Interestingly, the Endocrine Society has come out with a not-so-fast press release of its own, expressing doubts about the statistics of the new paper. I'm not quite sure why they're taking that side of the issue, but there it is.

For what it's worth, this looks to me like one of those low-but-real incidence effects, with consequences that are serious enough to make physicians (and patients) think twice. At the very least, you'd expect diabetic patients on these drugs to stay very alert to early signs of pancreatitis (which is really one of the last things you need to experience, and in fact, may be one of the last things you experience should the case arise). And this just points out how hard the diabetes field really is - there are already major cardiovascular concerns that have to be checked out with any new drug, and now we have pancreatitis cropping up with one of the large mechanistic classes. In general, diabetic patients can have a great deal wrong with their metabolic functions, and they have to take your drugs forever. While that last part might sound appealing from a business point of view, you're also giving every kind of trouble all the time it needs to appear. Worth thinking about. . .

Comments (8) + TrackBacks (0) | Category: Diabetes and Obesity | Toxicology

February 20, 2013

A New Old Diabetes and Obesity Drug Candidate

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Posted by Derek

Obesity is a therapeutic area that has broken a lot of hearts (and wallets) over the years. A scroll back through this category will show some of the wreckage, and there's plenty more out there. But hope does that springing-eternal thing that it does, and there's an intriguing new possibility for a target in this area. Alan Saltiel of Michigan (whose group has had a long presence in this sort of research), along with a number of other well-known collaborators, report work on the inflammation connection between diabetes and obesity:

Although the molecular events underlying the relationship between obesity and insulin resistance remain uncertain, numerous studies have implicated an inflammatory link. Obesity produces a state of chronic, low-grade inflammation in liver and fat accompanied by the local secretion of cytokines and chemokines that attenuate insulin action. Knockout or pharmacological inhibition of inflammatory pathways can disrupt the link between genetic- or diet-induced obesity and insulin resistance, suggesting that local inflammation is a key step in the generation of cellular resistance to important hormones that regulate metabolism.

Saltiel's lab had already implicated IKK-epsilon as a kinase involved in this pathway in obese mouse models, and they've been searching for small-molecule inhibitors of it. As it turns out, a known compound (amlexanox) with an uncertain mechanism of action is such an inhibitor. It's best-known, if it's known at all, as a topical canker sore treatment, and has been around since at least the early 1990s.

Administration of this selective TBK1 and IKK-ε inhibitor to obese mice produces reversible weight loss and improved insulin sensitivity, reduced inflammation and attenuated hepatic steatosis without affecting food intake. These data suggest that IKK-ε and TBK1 are part of a counterinflammatory process that sustains energy storage in the context of insulin resistance. Disruption of this process by amlexanox thus increases adaptive energy expenditure and restores insulin sensitivity. Because of the apparent safety of this drug in patients, we propose that it undergo study for the treatment of obesity, type 2 diabetes and nonalcoholic fatty liver disease in patients.

I don't see why not. The compound does seem to be absorbed after oral dosing (most of the topical paste ends up going down into the stomach and intestines), and about 17% is excreted unchanged in the urine. You'd think some sort of oral formulation could be worked out, given those numbers. It looks like a low-micromolar inhibitor, and is selective against a kinase panel, which is good news. And treatment of mice on a high fat diet prevented weight gain, while not altering food intake. Their insulin sensitivity improved, as did the amount of fat in the liver tissue. Giving the compound to already-obese mice (either through diet or genetically predisposed (ob/ob) animals) caused the same effect. Metabolic cage studies showed that increased energy expenditure seemed to be the mechanism (as you'd think - thermodynamics will only give you so many ways of losing weight while eating the same amount of food, and the obvious alternative mechanism might not be very popular).

Just how the compound does all this is somewhat mysterious:

The precise mechanisms by which amlexanox produces these beneficial effects in obese rodents have not yet been completely elucidated. Although amlexanox is known to be a mast cell stabilizer of unknown mechanism20, and depletion of mast cells may have beneficial metabolic effects59, most of the in vivo and in vitro evidence points to a role for the drug in increasing expenditure of energy while reducing its storage in adipocytes and hepatocytes. Furthermore, the lack of a phenotype in wild-type mice reconstituted with Ikbke knockout bone marrow indicates that the role of IKK-ε in bone marrow-derived cells such as mast cells and macrophages is less important than its role in other cell types such as adipocytes and hepatocytes. Although IKK-ε and TBK1 expression is elevated as part of the inflammatory program downstream of NF-κB, the kinase targets of the drug do not seem to be direct participants in the increased inflammatory program. In fact, the reduced inflammation observed in vivo with amlexanox treatment may be an indirect effect of improved metabolic disease or, perhaps, of elimination of a feedback pathway that maintains inflammation at low levels such that inflammation is permitted to resolve. Moreover, despite the fact that administration of amlexanox to obese mice restores insulin sensitivity, these compounds are not direct insulin sensitizers in vitro.

This level of unworkedoutness will surely interest some companies in taking a look at this, and if proof-of-concept can be found with amlexanox itself, a more potent inhibitor would also be something to search for. I have just one worry, though (he said, in his Peter Falk voice).

We were just talking around here about how mouse models of inflammation are probably useless, were we not? So it would be good news if, as speculated above, the inflammation component of this mechanism were to be an effect, not a cause. A direct attack on metabolic syndrome inflammation in mouse models is something that I'd be quite wary of, given the recent reports. But this might well escape the curse. Worth keeping an eye on!

Comments (12) + TrackBacks (0) | Category: Diabetes and Obesity

February 1, 2013

So How Does One Grow Beta-Cells?

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Posted by Derek

The short answer is "by looking for compounds that grow beta cells". That's the subject of this paper, a collaboration between Peter Schulz's group, the Novartis GNF. Schultz's group has already published on cell-based phenotypic screens in this area, where they're looking for compounds that could be useful in restoring islet function in patient with Type I diabetes.

These studies have used a rat beta-cell line (R7T1) that can be cultured, and they do good ol' phenotypic screening to look for compounds that induce proliferation (while not inducing it across the board in other cell types, of course). I'm a big fan of such approaches, but this is a good time to mention their limitations. You'll notice a couple of key words in that first sentence, namely "rat" and "cultured". Rat cells are not human cells, and cell lines that can be grown in vitro are not like primary cells from a living organism, either. If you base your entire approach this way, you run the risk of finding compounds that will, well, only work on rat cells in a dish. The key is to shift to the real thing as quickly as possible, to validate the whole idea.

That's what this paper does. The team has also developed an assay with primary human beta cells (which must be rather difficult to obtain), which are dispersed and plated. The tricky part seems to be keeping the plates from filling up with fibroblast cells, which are rather like the weeds of the cell culture world. In this case, their new lead compound (a rather leggy beast called WS-6) induced proliferation of both rat and human cells.

They took it on to an even more real-world system, mice that had been engineered to have a switchable defect in their own beta cells. Turning these animals diabetic, followed by treatment with the identified molecule (5 mpk, every other day), showed that it significantly lowered glucose levels compared to controls. And biopsies showed significantly increases beta-cell mass in the treated animals - all together, about as stringent a test as you can come up with in Type I studies.

So how does WS6 accomplish this? The paper goes further into affinity experiments with a biotinylated version of the molecule, which pulled down both the kinase IKK-epsilon and another target, Erb3 binding protein-1 (EBP1). An IKK inhibitor had no effect in the cell assay, interestingly, while siRNA experiments for EBP1 showed that knocking it down could induce proliferation. Doing both at the same time, though, had the most robust effect of all. The connection looks pretty solid.

Now, is WS6 a drug? Not at all - here's the conclusion of the paper:

In summary, we have identified a novel small molecule capable of inducing proliferation of pancreatic β cells. WS6 is among a few agents reported to cause proliferation of β cells in vitro or in vivo. While the extensive medicinal chemistry that would be required to improve the selectivity, efficacy, and tolerability of WS6 is beyond the scope of this work, further optimization of WS6 may lead to an agent capable of promoting β cell regeneration that could ultimately be a key component of combinatorial therapy for this complex disease.

Exactly so. This is excellent, high-quality academic research, and just the sort of thing I love to see. It tells us useful, actionable things that we didn't know about an important disease area, and it opens the door for a real drug discovery effort. You can't ask for more than that.

Comments (18) + TrackBacks (0) | Category: Chemical Biology | Diabetes and Obesity | Drug Assays

January 17, 2013

More on Metformin and Cancer (and Alzheimer's)

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Posted by Derek

Metformin: what a weird compound it is. Very small, very polar, the sort of thing you'd probably cross off your list of screening hits. But it's been taken by untold millions of diabetics (and made untold billions of dollars in the process), because it really does reduce glucose levels. It does so though mechanisms that are still the subject of vigorous debate and which (I might add) were completely unknown when the drug was approved. (I keep running into people who think that mechanism-of-action is some sort of FDA requirement, but it most certainly is not. Not saying that it wouldn't help, but what the regulatory agencies want are efficacy and safety. As they should).

And evidence has been piling up that the compound does many other things besides. The situation is murky. There was a report in 2009 that suggested that it might exacerbate the pathology of Alzheimer's. But last summer there was a rodent study that showed (in obese mice) that the compound seemed to improve neurogenerative effects seen in the hippocampus. (Whether this operates in animals, or humans, who are not metabolically impaired is an open question, although metformin is right in the middle of the whole "Type III diabetes" debate about Alzheimer's, which I'm going to cover in another post at some point soon). Meanwhile, human studies (in the large populations taking the drug) are not saying one way or another just yet. This British analysis suggested that there might be an association, but it's not for sure.

Then there's oncology. In 2010 I wrote about the evidence linking metformin use with lower incidence of some types of cancer, and one proposal for the mechanism. Now another paper is out suggesting that the compound works in this regard through modifying the inflammatory cascade. (Note that James Watson also highlighted this lab's previous work in his recent paper, blogged about here). The summary:

. . .Taken together, our observations suggest that metformin inhibits the inflammatory pathway necessary for transformation and CSC formation. To link our results with previous work on metformin in the diabetic context, we speculate that metformin may block a metabolic stress response that stimulates the inflammatory pathway associated with a wide variety of cancers. . .

. . .We suspect that this glucose- and metabolism-mediated pathway operates in many different cell types, and hence might explain why metformin reduces incidence of different human cancers and why the combination of metformin and chemotherapy is effective on many cell types in the xenograft context. While this pathway is hypothetical and has not been described in molecular terms, our results suggest that components in this pathway might be potential targets for cancer therapy.

The pathway referred to is through Src and IkappaB (of the NF-kB pathway), among others; the paper goes into more detail for those who are interested. There's a lot of stuff going on in the clinic with metformin added to different chemotherapy regimes, and I very much look forward to seeing the results. On the molecular level, I'd agree with the statement above - there's a lot to dig into here. The whole intersection of metabolism and cancer is a very large, very complex (and very tricky) area, but you'd have to think that there's a lot of really useful stuff to be found in it.

Comments (17) + TrackBacks (0) | Category: Cancer | Diabetes and Obesity

January 15, 2013

Is Obesity An Infectious Disease?

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Posted by Derek

Like many people, I have a weakness for "We've had it all wrong!" explanations. Here's another one, or part of one: is obesity an infectious disease?

During our clinical studies, we found that Enterobacter, a genus of opportunistic, endotoxin-producing pathogens, made up 35% of the gut bacteria in a morbidly obese volunteer (weight 174.8 kg, body mass index 58.8 kg m−2) suffering from diabetes, hypertension and other serious metabolic deteriorations. . .

. . .After 9 weeks on (a special diet), this Enterobacter population in the volunteer's gut reduced to 1.8%, and became undetectable by the end of the 23-week trial, as shown in the clone library analysis. The serum–endotoxin load, measured as LPS-binding protein, dropped markedly during weight loss, along with substantial improvement of inflammation, decreased level of interleukin-6 and increased adiponectin. Metagenomic sequencing of the volunteer's fecal samples at 0, 9 and 23 weeks on the WTP diet confirmed that during weight loss, the Enterobacteriaceae family was the most significantly reduced population. . .

They went on to do the full Koch workup, by taking an isolated Enterobacter strain from the human patient and introducing it into gnotobiotic (germ-free) mice. These mice are usually somewhat resistant to becoming obese on a high-fat diet, but after being inoculated with the bacterial sample, they put on substantial weight, became insulin resistant, and showed numerous (consistent) alterations in their lipid and glucose handling pathways. Interestingly, the germ-free mice that were inoculated with bacteria and fed normal chow did not show these effects.

The hypothesis is that the endotoxin-producing bacteria are causing a low-grade chronic inflammation in the gut, which is exacerbated to a more systemic form by the handling of excess lipids and fatty acids. The endotoxin itself may be swept up in the chylomicrons and translocated through the gut wall. The summary:

. . .This work suggests that the overgrowth of an endotoxin-producing gut bacterium is a contributing factor to, rather than a consequence of, the metabolic deteriorations in its human host. In fact, this strain B29 is probably not the only contributor to human obesity in vivo, and its relative contribution needs to be assessed. Nevertheless, by following the protocol established in this study, we hope to identify more such obesity-inducing bacteria from various human populations, gain a better understanding of the molecular mechanisms of their interactions with other members of the gut microbiota, diet and host for obesity, and develop new strategies for reducing the devastating epidemic of metabolic diseases.

Considering the bacterial origin of ulcers, I think this is a theory that needs to be taken seriously, and I'm glad to see it getting checked out. We've been hearing a lot the last few years about the interaction between human physiology and our associated bacterial population, but the attention is deserved. The problem is, we're only beginning to understand what these ecosystems are like, how they can be disordered, and what the consequences are. Anyone telling you that they have it figured out at this point is probably trying to sell you something. It's worth the time to figure out, though. . .

Comments (32) + TrackBacks (0) | Category: Biological News | Diabetes and Obesity | Infectious Diseases

October 23, 2012

Huge But Effective

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Posted by Derek

Of the physical properties that make up the "Rule of Five" (and similar schemes), the one that I think is easiest to breach is molecular weight. I'm not saying that it's a good idea to breeze past 500 daltons with a song on your lips - you should always realize that you're probably asking for trouble up there. But trouble seems to follow a bit less often than it does with, say, a high logP. For a high-value target, I think it's certainly worth pursuing if that's really where you have to go.

Here's a whopper of a molecule, for example, an inhibitor of PTP-MEG2 (also known as PTPN9). That's an unusual phosphatase involved in hepatic insulin signaling, and it's already been shown that knocking it down seems to be beneficial in diabetic rodent models. But, like another longtime diabetes target in this space (PTP1B), it's not easy to get a decent inhibitor. Phosphatases are tricky. Their active sites are very polar (as you'd imagine, having to work with phosphate anions all day), and there aren't all that many phosphatase subtypes as you'd expect, given the amount of such work there is to do. That leads to worries about selectivity, even should you find a molecule that seems to work.
Compound%207.png
So if you can't find a decent inhibitor, how about an indecent one? That's the first reaction on seeing the structure at left. You can certainly see its resin-bound peptidomimetic library roots. I only wish the authors had found a way to incorporate a chlorine atom somewhere; it would have been one of the rare compounds that runs the table on the halogens. As it is, this floating island weighs 1084, well beyond what anyone could consider reasonable for a drug candidate.

It's selective, naturally. Something this size is making so many interactions that its chances of fitting in a lot of different places is quite small. (There's a crystal structure, which doesn't appear to be showing up in the PDB as yet). It's got a Ki of 34 nanomolar against its target, and about 600 for PTP-TC and PTP1B. All the other protein tyrosine phosphatases are dead, and I'd be very surprised if it hits something from another class. But selectivity isn't the hurdle for these leviathans - it's pharmacokinetics. And here we have a surprise.

First off, the compound shows good activity in mouse heptatocytes, and in other insulin-sensitive cell lines. That's quite interesting, since PTP-MEG2 is surely intracellular - so what part of the cell membrane is letting Godzilla through the turnstiles? The authors moved on to i.p. injection in mice, and found that at at 20 mpk level the compound hit a Cmax of 4.5 micromolar (pretty respectable, considering that molecular weight), and had a half-life of 1.8 hours. That's short, but not as short as one might have feared. Multiday treatment of mice showed just the sorts of on-target effects that one might have predicted: inhibition of hepatic gluconeogenesis, enhanced glucose clearance and insulin sensitivity. That's just the sort of profile you'd want for a Type II diabetes drug, and with a bit of work on the half-life, you might have one here as an injectable. I don't hold out much hope for oral activity with a molecule like this, but it's impressive that it gets this far, and it provides some real proof-of-concept for PTP-MEG2 as a drug target.

So in case anyone's wondering whether I can say anything kind about tool compounds, or about academic drug discovery (this paper's from Indiana U), well, here's your evidence. I don't know whether the authors were brave or just foolhardy to consider these structures, but they've latched onto something worthwhile.

Comments (21) + TrackBacks (0) | Category: Diabetes and Obesity

October 17, 2012

Zafgen's Epoxide Adventure

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Posted by Derek

Zafgen is a startup in the Boston area that's working on a novel weight-loss drug called beloranib. Their initial idea was that they were inhibiting angiogenesis in adipose tissue, through inhibition of methionine aminopeptidase-2. But closer study showed that while the compound was indeed causing significant weight loss in animal models, it wasn't through that mechanism. Blood vessel formation wasn't affected, but the current thinking is that Met-AP2 inhibition is affecting fatty acid synthesis and causing more usage of lipid stores.

But when they say "novel", they do mean it. Behold one of the more unlikely-looking drugs to make it through Phase I:
Beloranib.png
Natural-product experts in the audience might experience a flash of recognition. That's a derivative of fumagillin, a compound from Aspergillus that's been kicking around for many years now. And its structure brings up a larger point about reactive groups in drug molecules, the kind that form covalent bonds with their targets.

I wrote about covalent drugs here a few years ago, and the entire concept has been making a comeback. (If anyone was unsure about that, Celgene's purchase of Avila was the convincer). Those links address the usual pros and cons of the idea: on the plus side, slow off rates are often beneficial in drug mechanisms, and you don't get much slower than covalency. On the minus side, you have to worry about selectivity even more, since you really don't want to go labeling across the living proteome. You have the mechanisms of the off-target proteins to worry about once you shut them down, and you also have the ever-present fear of setting off an immune response if the tagged protein ends up looking sufficiently alien.

I'm not aware of any published mechanistic studies of beloranib, but it is surely another one of this class, with those epoxides. (Looks like it's thought to go after a histidine residue, by analogy to fumagillin's activity against the same enzyme). But here's another thing to take in: epoxides are not as bad as most people think they are. We organic chemists see them and think that they're just vibrating with reactivity, but as electrophiles, they're not as hot as they look.

That's been demonstrated by several papers from the Cravatt labs at Scripps. (He still is at Scripps, right? You need a scorecard these days). In this work, they showed that some simple epoxides, when exposed to entire proteomes, really didn't label many targets at all compared to the other electrophiles on their list. And here, in an earlier paper, they looked at fumagillin-inspired spiroexpoxide probes specifically, and found an inhibitor of phosphoglycerate mutase 1. But a follow-up SAR study of that structure showed that it was very picky indeed - you had to have everything lined up right for the epoxide to react, and very close analogs had no effect. Taken together, the strong implication is that epoxides can be quite selective, and thus can be drugs. You still want to be careful, because the toxicology literature is still rather vocal on the subject, but if you're in the less reactive/more structurally complex/more selective part of that compound space, you might be OK. We'll see if Zafgen is.

Comments (21) + TrackBacks (0) | Category: Chemical Biology | Diabetes and Obesity | Drug Development

October 5, 2012

The Return of CB1

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Posted by Derek

CB1 ligands were all the rage a few years ago, headlined by Sanofi's rimonabant. These looked like the best shot at the obesity market in a long time, if you were of an optimistic frame of mind. But the entire class came crashing down with the regulatory rejection of rimonabant itself, followed by the failure of Merck's taranabant in the same area. (Pfizer publicly dropped out of the area, and number of other CB1 programs never even upped periscope, after watching the chaos up there on the surface).

Now there might be another shot. CNS side effects doomed the original ligands, but many people thought that the brain was the site of action. How about a compound that's selective for the periphery? Work has been going on over the last few years to just that end, It turns out that these actually do seem to show effects in rodent models, so the chase might be on again. You'd think that anything that avoids the brain, with its ever-present potential for "Wow, who knew that would happen?" effects, would have a better shot. Given the size of the obesity market, I think we'll be given the chance to find out. . .

Comments (10) + TrackBacks (0) | Category: Diabetes and Obesity

August 29, 2012

Caloric Restriction Flops?

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Posted by Derek

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

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

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

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

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

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

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

May 24, 2012

An Oral Insulin Pill?

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Posted by Derek

Bloomberg has an article on Novo Nordisk and their huge ongoing effort to come up with an orally available form of insulin. That's been a dream for a long time now, but it's always been thought to be very close to impossible. The reasons for this are well known: your gut will treat a big protein like insulin pretty much like it treats a hamburger. It'll get digested, chopped into its constituent amino acids, and absorbed as non-medicinally-active bits which are used as raw material once inside the body. That's what digestion is. The gut wall specifically guards against letting large biomolecules through intact.

So you're up against a lot of defenses when you try to make something like oral insulin. Modifying the protein itself to make it more permeable and stable will be a big part of it, and formulating the pill to escape the worst of the gut environments will be another. Even then, you have to wonder about patient-to-patient variability in digestion, intestinal flora, and so on. The dosing is probably going to have to be pretty strict with respect to meals (and the content of those meals).

But insulin dosing is always going to be strict, because there's a narrow window to work in. That's one of the factors that's helped to sink so many other alternative-dosing schemes for it, most famously Pfizer's Exubera. The body's response to insulin in brittle in the extreme. If you take twice as much antihistamine as you should, you may feel funny. If you take twice as much insulin as you should, you're going to be on the floor, and you may stay there.

So I salute Novo Nordisk for trying this. The rewards will be huge if they get it to work, but it's a long way from working just yet.

Comments (32) + TrackBacks (0) | Category: Diabetes and Obesity | Drug Development | Pharmacokinetics

May 18, 2012

Strangely Good Results in Diabetes and Cardiovascular Disease

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Posted by Derek

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

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

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

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

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

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

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

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

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

May 10, 2012

Arena and Lorcaserin, Back at the FDA

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Posted by Derek

For those of you following Arena Pharmaceuticals and their long-running efforts to get lorcaserin approved by the FDA, there's a committee hearing on that matter today. Adam Feuerstein is live-blogging the event here. The big issues, now with fresh data: tumors in rat models, and possible heart-valve damage, versus efficacy. The FDA has until June 27 to make a decision.

Comments (10) + TrackBacks (0) | Category: Diabetes and Obesity

January 19, 2012

Dapagliflozin Goes Down (For the Last Time?)

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Posted by Derek

To no one's surprise, the FDA has rejected dapagliflozin, an SGLT2 inhibitor for diabetes. The advisory panel voted it down back during the summer, and the agency has asked AstraZeneca and Bristol-Myers Squibb to provide more safety data. As it stands, the increased risk of bladder and breast cancer (small but significant) that was seen in the clinic just outweighs the drug's benefits.

That's the sodium-glucose cotransporter 2, and what it does normally is reabsorb glucose in the kidney to keep it from going on into the urine and being lost. It's been the subject of quite a bit of drug development over the last few years, with the thought being that spilling glucose out of the bloodstream, as an adjunct to other diabetes therapy, might be more of a feature than a bug.

Not with that safety profile, though. And since this compound has been through nearly a dozen different advanced trials in the clinic, I really don't see how anyone's going to be able to provide any safety data at this point to change anyone's mind about it. Type II diabetes is an area with a lot of treatment options, and while all of them have their advantages and disadvantages, taken together, there's quite a bit than can be done. So if you're going to enter a crowded field like this, a new mechanism is a good idea (thus SGLT2). But you're also up against a lot of things that have proven themselves in the real world, some of them for a long time now, so your safety profile has to be above reproach.

Canagliflozin, from J&J, is still out there in the clinic, and you can bet that the folks there will be digging through the data from every direction. Are dapagliflozin's problems mechanism-related, or not? Would you care to spend nine figures to find out? That's how we do it around here. . .

Comments (10) + TrackBacks (0) | Category: Diabetes and Obesity | Toxicology

December 22, 2011

More From Hua - A Change of Business Plans?

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Posted by Derek

You may remember the mention of Hua Pharmaceuticals here back in August, and the follow-up with details from the company. They're trying to in-license drugs from other companies and get them approved as quickly as possible in China. The original C&E News article made them sound wildly ambitious, while the company's own information just made them sound very ambitious.

Now we have some more information: Roche has licensed their glucokinase activator program (for diabetes) to Hua (that's a development effort I wrote about here). And that's an interesting development, because the Hua folks told me that:

"Hua Medicine intends to in-license patented drugs from the US and EU, and get them on the market and commercialized in the 4 year timeframe in China. This is about the average time it takes imported drugs (drugs that are approved and marketed in the US or EU but are coming newly into the Chinese market) to get approved by the SFDA in China."

And that's fine, but Roche's glucokinase activators haven't been approved or marketed anywhere yet. In fact, I'm not at all sure of the lead compound ever even made it to Phase III, so there's a lot of expensive work to be done yet, and on a groundbreaking mechanism, too. The only thing I can say is that approval in the US for diabetes drugs has gotten a lot harder over the years - the market is pretty well-served, for one thing, and the safety requirements (particularly cardiovascular) have gotten much more stringent. Perhaps these concerns are not so pressing in China, leading to an easier development path?

Easier or not, these compounds have a lot of time and money left to be put into them, which is not the sort of program that Hua seemed to be targeting before. One wonders if there just weren't any safer bets available. At any rate, good luck to them, and to their financial backers. Some will be needed; it always is.

Comments (8) + TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity | Drug Development

November 22, 2011

Regeneron Finally Makes It to the Market

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Posted by Derek

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

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

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

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

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

August 23, 2011

SRT1720: Good (And Confusing) News for Obese Mice

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Posted by Derek

Readers of this blog will be fairly familiar with the long, interesting story of sirtuin activators. Today we will speak of SRT1720, of which we have spoken before. This molecule was described in 2007 as an activator of Sirt1 with beneficial effects in rodent models of diabetes. But both of those statements were called into question by a series of papers which found difficulties with both the in vitro and the in vivo results (summarized here). The GSK/Sirtris team fired back, but that paper also served as a white flag on the in vitro assay questions: there were indeed artifacts due to the fluorescent peptides used. (Another paper has since confirmed these problems and proposed an off-target mechanism).

But that GSK response didn't address the in vivo assay questions at all - we still had a situation where one group said that these compounds (SRT1720 in particular) were beneficial, and another said that it showed no benefit and was toxic at higher doses. Adding to the controversy, another paper appeared late last year that went back to nematodes, and found the SRT1720 did not extend their lives, either. The state of this field can be fairly described, then, as "extremely confused".

Now we have a new paper whose title gets right down to it: "SRT1720 improves survival and healthspan of obese mice". First time I've seen "healthspan" as a word, I might add, and another interesting sidelight is that this appears in Nature Scientific Reports, the publishing group's open-access experiment. But now to the data:

What this (large) team did was place one-year-old male mice on a high-fat diet in the presence of two different doses of SRT1720 in the chow, corresponding to 30 mg/kilo and 100mg/kilo. The effects on lifespan were notable: standard-diet animals had a median lifespan of 125 weeks, and that was shortened to 94 weeks on the high fat diet. But on that diet plus the lower dose of SRT1720, the median lifespan was 103 weeks, and on the higher dose it was 115 weeks. It's interesting, though, that this took place while the animals ate the same number of calories and gained the same amount of (extra) weight as the control group.

Blood work and histopathology revealed many more differences. The high-fat animals (with no SRT1720) showed the expected problems that you see in such studies - fat accumulation in the liver, increased numbers of beta-cells in the pancreas, higher insulin levels, and so on. But the SRT1720-dosed animals showed a good deal of reversal of all these effects. DIgging down to the molecular level, inflammatory markers, indicators of apoptosis and DNA fragmentation were increased in the high-fat animals, and these were also mitigated by SRT1720.

There are many other effects mentioned in the paper, but I'm not going to go into all the details - hey, it's open-access, so if you're really into this stuff you can find it all. Suffice it to say that a long list of deleterious effects of a high-fat diet on rodents seem to be partially to fully reversed on treatment with SRT1720, particularly at the higher dose, without significant evidence of toxicity. But how do we reconcile that with the report that the compound showed no benefit, and toxic effects to boot? I'll let the authors tackle that one:

Our results continue to support the beneficial pharmacological effect of SRT1720 in models of metabolic disease despite a recent report by Pacholec and colleagues to the contrary14 where the authors report 100 mg/kg SRT1720 is not tolerable and increases mortality in mice and that the compound does not elicit beneficial effects in the Lep ob/ob mouse model of diabetes. This conclusion is inconsistent with not only our findings but also several additional studies where SRT1720 has been reported to exert positive effects in multiple models of metabolic disease including Lep ob/ob mice, diet-induced obese mice, MSG-induced hypothalamic obese mice15 and Zucker fa/fa rats. Pacholec and colleagues did report that fasting insulin levels are reduced by SRT1720 administration, which is in agreement with our findings (Fig. 2) and with data reported previously in diet-induced obese mice. The putative toxicity of SRT1720 administered at a 100 mg/kg oral dose to 8 mice over 18 days is inconsistent with a study where the compound exhibited no toxicity at a 5-fold higher dose for 15 weeks12 nor is it consistent with our long-term feeding study involving over 100 mice consuming an equivalent daily dose. In fact, our mice showed increased survival and improvement in multiple physiological parameters in response to SRT1720 treatment and did not display overt signs of toxicity even after more than 80 weeks of treatment.

So yes, there's pretty much a flat contradiction here, and I have no idea of how to resolve it. This paper doesn't reference the failure of SRT1720 to show effects in nematodes, but that's another piece of the puzzle that can't be ignored, either. One possibility is that the doses of the compound need to be rather heroic. Believe me, by the usual pharmacological standards, extended dosing at 100 mpk is pretty heavy-duty (and, I might add, basically unattainable in humans under normal conditions, especially humans on a high-fat diet).

So for now, I have to throw up my hands. This latest paper seems very thorough, and represents a really significant effort on the part of a long list of highly competent people. But there can be no doubt that the SRT1720 story (and the story of sirtuin activators in general) is still very complex and hard to evaluate, because the various problems and complications that have been found can't be dismissed, either. There's something here, all right, and it could well be very important. But what are we looking at?

Side note: this work was the subject of a writeup by Nicholas Wade in the New York Times the other day. It reveals that there's another arm of this study - normal mice, on normal chow, also treated with SRT1720. Those results, out next year, will be very interesting indeed, although I can only think that they're just going to keep the fires burning. I'd also like to note (as one comment on this blog did) the tone of most of the online comments on the Times story. They can, I think, be summed up as "Great, the big evil drug companies have found something so people can just stay big and fat and not die early, and they're going to sell it to us for a zillion dollars while their corporate masters stay thin and healthy and laugh at us all". Read through a few of them and see if I haven't captured their general spirit - and think for a bit about what that tells us, both about the public perception of drug research and (perhaps) about the sort of people who leave comments over at the Times.

Comments (39) + TrackBacks (0) | Category: Aging and Lifespan | Diabetes and Obesity

August 15, 2011

mINDY Mice - No Obesity, No Diabetes?

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Posted by Derek

Caloric restriction increases healthy lifespan. That's true in a range of organisms, and probably in humans. But it's never going to be popular - and what's more, it's not going to be feasible, either, given how clearly people like to eat. So the search has been on for just how it exerts its effects, with a number of interesting clues turning up.

And now there's another one. There's a longevity gene in fruit flies known as INDY (short for, I fear, "I'm Not Dead Yet", and if you don't get that reference, you should probably turn in your geek license. This would be a good time to note, as required by law, that the fruit fly people are a longstanding and apparently endless fountain of weird nomenclature). Reducing INDY expression definitely lengthens lifespan in flies and in the nematode C. elegan.

A recent paper in Cell Metabolism, from a large-multicontinent team involving the Shulman group at Yale and many others, explores the effects of the mammalian homolog, mINDY, in mice. The knockout mice are smaller, although they take in the same number of calories. They are much leaner, though, with remarkable less fat. Their metabolism seems to be ramped up, as you might figure from that situation, and they're especially good at fat oxidation in the liver. Very interestingly, they maintain this phenotype as they age, while normal mice tend to put on more fat. They have lower basal glucose and insulin levels, and are better at clearing glucose, apparently through better uptake in skeletal muscle. They also seem resistant to the bad effects of a high-fat-chow diet, show a much reduced tendency to putting on weight and developing insulin resistance. All in all, this is what you'd call a desirable metabolic phenotype, and it fits in very well with what has been worked out in the fruit flies.

So what does this gene code for? Turns out that it's a citrate transporter, which might not be the most obvious thing at first, but it makes sense. Citrate is converted to acetylCoA, which is the building block for fatty acid synthesis. Cutting down its availability basically starves the liver tissue, which depends on fatty acids for a good part of its energy needs, and causes it to efficiently burn off whatever fatty acids it can acquire. And this effect might just be one of the things that produce the benefits of caloric restriction - in other words, you might not have to deprive your whole body of calories, just the key parts of it. To show that I'm not overinterpreting here, I'll let the authors say it:

These data suggest that mIndy may be a key mediator of the beneficial effects of dietary energy restriction. Since prolonged caloric restriction is very difficult to achieve in humans, our observations raise the tantalizing possibility that modulating the levels or function of mIndy could lead to some of the health-promoting effects of calorie restriction, without requiring severe caloric restriction.

And as they go on to suggest, this makes for a very interesting target for obesity, diabetes, and fatty liver disease. What about extending lifespan? Well, I've dug through the paper several time, and can find no mention of mice older than 8 months, and no numbers on their longevity. I assume that this will be the subject of another paper as the rodents get older - it's too big an issue to ignore, and this paper seems determined not to say a word about it.

Comments (26) + TrackBacks (0) | Category: Aging and Lifespan | Diabetes and Obesity

May 4, 2011

GSK and Alli. Not Quite Working Out

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Posted by Derek

Jim Edwards at Bnet has a report that GlaxoSmithKline doesn't seem to be doing quite as well selling Alli (orlistat) as they'd planned. This notwithstanding that their CEO, Andrew Witty, has said that they've had some interest from outside buyers for the franchise.

No, if you run the numbers, it's hard to see how GSK is making any money at all from the drug, especially if sales figures went down last year they way they'd gone down the year before. But then, it's not that the company is telling us those numbers, which might tell you something right there. How could anyone have predicted such a thing?

Comments (12) + TrackBacks (0) | Category: Diabetes and Obesity

March 2, 2011

MannKind: It's Not Looking Good

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Posted by Derek

Back in August, I noted that Mannkind - who have been developing an inhaled insulin product for many years now - had done a stock-swap deal with Seaside 88. That, I thought, was not a good sign. They're an investment group that I profiled (unfavorably) here, in reference to their dealings with Generex (another spray-insulin company, allegedly working on an oral delivery route).

Adam Feuerstein's the guy who put me on to Generex. (Last I heard, was getting sued by them for his comments, although his opinions seemed to me to be well justified. No updates on that, as far as I know). He's also recently updated the Mannkind situation, and it's not looking good. Last month the company fired about 40% of its workforce, and apparently has about enough cash on its books to make it to the end of the year. Its founder, Al Mann, has plowed a lot of his own money into the company, but on a recent conference call, he declined to say if he's going to put in any more. Mann is a real believer, and has given this his best shot. But it may not be enough.

The class-action suits are already fluttering through the air. And the bubbling tar pit that is spray-delivered insulin continues to churn.

Comments (4) + TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity

October 25, 2010

Lorcaserin's Complete Response

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Posted by Derek

Arena released their complete response from the FDA over the weekend, regarding the non-approval of their weight loss drug Lorcaserin. And the arguing has already started about just how bad the news is. There are several levels that this process could be tracking on, and we just don't know which one it's on yet.

And the varied regulatory paths that result give you answers to "When will the drug be approved" ranging from "Maybe in six months" through "Maybe in a year" on out to "Maybe in a few years", which at that point shades into "Never". One of the main sticking points is the carcinogenicity data from the animal studies - the FDA is worried, and they want Arena to round up some outside experts to go over the data to address their concerns. Problem is, we don't quite know what that means. It could be anything from "Have some people assure that FDA that everything's actually fine" (the Arena bull position) to "Go run a bunch more long clinical trials" (which is one of the bear positions). I think it's unlikely that the FDA will let the company go through without at least running more rodent studies; I just can't see an outside review of the data doing enough to calm them down. The agency, I believe, is in more of a "Get some people to help you design some good studies" mode.

Matthew Herper's take seems reasonable to me. As he points out, even when companies have gotten a drug through after one of these Complete Response Letters, it's taken at least seven months when the issues didn't involve the clinic. He seems to be taking flak from Arena investors who have loarcaserin penciled in for somewhere around Valentine's Day. But I don't see how that's going to happen, either. Try April Fool's - of some other year.

Comments (4) + TrackBacks (0) | Category: Diabetes and Obesity | Regulatory Affairs

September 24, 2010

Avandia Goes Down: A Research Rant

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Posted by Derek

So now Avandia (rosiglitazone) looks to be withdrawn from the market in Europe, and heavily restricted here in the US. This isn't much of a surprise, given all the cardiovascular worries about it in recent years, but hindsight. Oh, hindsight: all that time and effort put into PPAR ligands, back when rosi- and pioglitazone were still in development or in their first few years on the market. Everyone who worked on metabolic diseases took a swing at this area, it seems - I spent a few years on it myself.

And to what end? Only a few drugs in this class have ever made it to market, and all of them were developed before we even knew they they hit the PPAR receptors at all. The only two that are left are Actos (pioglitazone) and fenofibrate, which is a PPAR-alpha compound for lack of any other place to put it. Everything else: a sunk cost.

Allow me to rant for a bit, because I saw yet another argument the other day that the big drug companies don't do any research, no, it's all done at universities with public funds, at which point Big Pharma just swoops in and makes off with the swag. You know the stuff. Well, I would absolutely love to have the people who hold that view explain the PPAR story to me. I really would. The drug industry poured a huge amount of time and money into both basic and applied research in that area, and they did it for years. No one has to take my word for it - ask any of the academic leaders in the field if GSK or Merck, to name just two companies, managed to make any contributions.

We did it, naturally, because we expected to make a profit out of it in the end. The whole PPAR story looked like a great way to affect metabolic disorders and plenty of other diseases as well: cancer, inflammation, cardiovascular. That is, if we could just manage to understand what was going on. But we didn't. Once we all figured out that nuclear receptors were involved and got busy on drug discovery on that basis, we didn't help anyone with any diseases, and we didn't make any profits. Big piles of money actually disappeared during the process, never to be seen again. You could ask Merck about that, or GSK (post-rosiglitazone), or Lilly, or BMS, or Bayer, and plenty of other players large and small.

No one hears about these things. We're understandably reluctant to go on about our failures in this industry, but the side effect is that people who aren't paying attention end up thinking that we don't have any. Nothing could be more mistaken. And they aren't failures to come up with a catchy slogan or to find a good color scheme for the packaging - they're failures back at the actual science, where reality meets our ideas about it, and likely as not beats them down to the floor.

Honestly, I don't understand where these they-don't-do-any-research folks get off. Look at the patent filings. Look at the open literature. Where on earth do you think all those molecules come from, all those research programs to fill up all those servers? There are whole scientific journals that wouldn't exist if it weren't for a steady stream of failed research projects. Where's it all coming from?

Note: previous posts about PPAR drug discovery can be found here, here, and here. Previous posts (and rants) about research in the drug industry (and academia, and the price of it all) can be found here, here, here, here, here, here, here, here, and here.

Comments (49) + TrackBacks (0) | Category: Diabetes and Obesity | Drug Industry History | Regulatory Affairs | Why Everyone Loves Us

September 16, 2010

Live-Blogging Arena's FDA Committee Hearing

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Posted by Derek

San Diego newspaper blogger Keith Darce is doing it here. The meeting should start up again about 1 PM Eastern. So far, the company and the FDA staff have been presenting reviews of the Lorcaserin data. The committee member questions don't look particularly encouraging. . .

Update: the committee votes "No", 9-5. We'll see what the agency itself does. I expect the same outcome.

Comments (7) + TrackBacks (0) | Category: Diabetes and Obesity | Regulatory Affairs

September 14, 2010

Lorcaserin in Trouble

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Posted by Derek

The FDA committee that will be looking over Arena's lorcaserin for weight loss has released its briefing information, and there were some nasty surprises therein. A memo states that the drug did not satisfy the mean efficacy requirements that the FDA has laid down for obesity therapies, and satisfied the categorical efficacy one "by a slim margin".

Well, that was known. I said as much back in May of last year, and didn't the Arena fans ever give me an earful about it. What wasn't apparent was the two-year rodent tox. The briefing document raises questions about the number of malignancies that showed up in these rats, and that's not good. The safety profile of any drug in this area has to be very clean, especially if the efficacy is borderline.

As for the big worry about any serotinergic compound in this area, 5-HT2b heart valve trouble, the briefing document isn't too reassuring there, either. The FDA staffers note that the company didn't run a positive control in the animal models, and didn't look at proliferative markers during the human clinical trials. They conclude that "the FDA has not definitively concluded that lorcaserin is devoid of valvulopathy-related cardiac effects in animals".

Frankly, I think that the tox/efficacy combination is likely to sink the drug's approval chances. There are other problems, but this is the big one. The market seems to be agreeing - Arena's stock is getting hammered today. I look forward to hearing from the various people who were after my hide about this.

Comments (39) + TrackBacks (0) | Category: Diabetes and Obesity | Regulatory Affairs

August 12, 2010

MannKind and Seaside 88?

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Posted by Derek

Readers may remember Generex, the company that's developing a buccal insulin spray. I'm not sold on their technology or their prospects, to put it mildly. In this post I took a look at the investment outfit that did a stock transaction with the company, and found them not to my taste, either.

Well. . .now to MannKind. They've been developing an inhaled insulin formulation (not a buccal spray, I hasten to add) for a long time now. Everyone who's ever worked in the area has had to be in it for the long haul, as the Pfizer/Exubera story will show. It has been long, and it has been expensive, and there have been worries that MannKind might not have enough money to stay the course. They've been seeking a partner for some time now.

Back in March the company got a response from the FDA about the prospects for the drug, which had been delayed. The agency has recently accepted the company's NDA resubmission, with a decision due by the end of the year.

But now comes news that the company is doing a stock-swap deal involving Seaside 88. Given how Seaside 88 looks on close inspection (see that link in the first paragraph), I find it hard to imagine that they'd be anyone's first choice for financing. I have no stock or option position in MannKind - long or short. But if I were long the company, this news would not be making me happy.

Comments (6) + TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity

July 28, 2010

PPAR: A Veil Is Lifted, At Last

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Posted by Derek

I used to work on compounds targeting the PPAR family (and nuclear receptors in general). I knew nothing about the field when I started, which is the traditional situation a medicinal chemist is in, but I picked it up. And picked it up. . .and picked up still more information, on and on, as it dawned on me that the whole field was quite possibly beyond our ability to deal with in an organized fashion.

Not that people didn't try, famously Glaxo. They cranked up a huge effort to go after these targets with the full toolbox - structure, pharmacology, med-chem, animal models, the lot. Merck and others did the same, but Glaxo's team were out there front and center at every conference, presenting data and mentioning in asides that they had X dozen crystal structures of that receptor, and this-many compounds heading into development, and so on. Very little has emerged out on the money-making end from all this work, by all the companies who've tried it. Avandia (rosiglitazone) and Actos (pioglitazone) are still the only PPAR-targeting drugs on the market, with Avandia in serious trouble, and they were both developed before anyone knew what their target was.

But there's absolutely no doubt that PPAR subtypes are major metabolic players; it's just that we don't quite know how to untangle the huge number of effects they have. Now a paper from one of the longtime leaders in the field, Bruce Spiegelman, might restore some order. And it does so in an unexpected way.

Upstream of all the hideously complex transcriptional effects, subtly modulated by ligand, by cell type, by time of day and who know what else, Spiegelman's groups has found that it's the phosphorylation of PPAR-gamma by the kinase CDK5 that might be the key. That doesn't alter the broad strokes of transcription, but it does alter specific genes that are associated with obesity and the metabolic syndrome. (It's known that the PPARs associate with a host of other protein cofactors, and this phosphorylation probably affects some protein-potein binding surface).

High-fat diets in rodents crank up CDK5 activity, and a whole list of effective PPAR compounds, it turns out, keep the receptor from being phosphorylated by it. Moreover, insulin sensitivity correlates quite well with the degree of phosphorylation. It really does look as if the code has been cracked - we may finally know what the primary PPAR-linked event is that affects type II diabetes. So, forget all those other assays: just measure the amount of serine-273 phosphorylation and you've done what you need to do?

This work has doubtless caused plenty of people in the metabolic disease field to drop whatever they were holding and start thinking things all over again. There are a lot of questions to answer: what happens if you dose a CDK5 inhibitor? In what other tissues does a high-fat diet alter CDK5 activity? Could you get all the insulin-sensitization effects of a glitazone drug without the side effects, by targeting a drug development program differently? Does CDK5 have anything to do with the cardiac side effects that everyone's so worried about with Avandia? And so on. It's a great result, one of those papers where you really come away knowing something crucial that you didn't before.

Comments (12) + TrackBacks (0) | Category: Diabetes and Obesity

July 23, 2010

Vivus, Qnexa, Arena, Lorcaserin and the FDA

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Posted by Derek

One big story from the last week was the FDA advisory panel's "No" decision on Qnexa, the drug-combo obesity therapy developed by Vivus. This is the one that's a combination of phentermine and topiramate, both of which have been around for a long time. And clinical trials showed that patients could indeed lose weight on the drug (with the required diet and exercise) - but also raised a lot of questions about safety.

And it's safety that's going to always be a worry with any obesity drug, even once you get past the (rather large) hurdle of showing efficacy. That's what took the Fen-Phen combination off the market, and what torpedoed Acomplia (rimonabant) and the other CB-1 compounds before they'd even been property launched. The FDA panel basically agreed that Qnexa helps with weight loss, but couldn't decide how bad the side effects might be in a wider patient population, and whether they'd be worth it:

But the drug has side effects, both known and theoretical. It may cause birth defects, it may increase suicide risk, it can cause a condition called metabolic acidosis that speeds bone loss, it increases risk of kidney stones, and may have other serious effects.

"It is difficult if not impossible to weigh these issues as the clinical trials went on only for a year, and patients will use this drug for lifetime," (panel chair Kenneth) Burman said. "It is impossible to extrapolate the trial data to the wider population."

That's a problem, all right, and it's not just Vivus that has to worry about it. When the potential number of patients is so large, well, any nasty side effects that are out there will show up eventually. How do you balance all these factors? Is it possible at all? As that WebMD article correctly points out, a new obesity drug will come on the market with all kinds of labeling about how it's only for people over some nasty BMI number, the morbidly obese, people with other life-threatening complications, and so on. But that's not how it's going to be prescribed. Not after a little while. Not with all the pent-up demand for an obesity drug.

Although that's probably the worst situation, this problem isn't confined to obesity therapies - any other drug that requires long-term dosing has this hanging over it (think diabetes, for one prominent example). That brings up the question that anyone looking over clinical trial data inevitably has to face: how much are the trials telling us about the real world? After all, the only way to be sure about how a drug will perform in millions of people for ten years is to dose millions of people for ten years. No one's going to want to pay for any drugs that have been through that sort of testing, I can tell you, so that puts us right where we are today, making judgment calls based on the best numbers we can get.

The FDA itself still has that call to make on Qnexa, and they could still approve it with all kinds of restrictive labeling and follow-up requirements. What about the other obesity compound coming along, then? A lot of people are watching Arena's lorcaserin (which I wrote about negatively here and followed up on here). Arena's stock seems to have climbed on the bad news for Vivus, but I have to say that I think that's fairly stupid. Lorcaserin may well show a friendlier side-effect profile than Qnexa, but if the FDA is going to play this tight, they could just let no one through at all - or send everyone back to the clinic for bankrupting.

As the first 5-HT2C compound to make it through, lorcaserin still worries me. A lot of people have tried that area out and failed, for one thing. And being first-to-market with a new CNS mechanism, in an area where huge masses of people are waiting to try out your drug. . .well, I don't see how you can not be nervous. I said the same thing about rimonabant, for the same reasons, and I haven't changed my opinion.

Since I got a lot of mail the last time I wrote about Arena, I should mention again that I have no position in the stock - or in any of the other companies in this space. But I could change my mind about that. If Arena runs up in advance of their FDA advisory panel in the absence of any new information, I'd consider going short (with money I could afford to lose). If I do that, I'll say so immediately.

Comments (24) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | Regulatory Affairs | The Central Nervous System | Toxicology

July 13, 2010

Avandia: Was the Evidence Buried?

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Posted by Derek

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

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

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

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

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

Comments (30) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | The Dark Side | Toxicology

May 12, 2010

Insulin Degrading Enzyme's Turn in the Spotlight

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Posted by Derek

Well, you have to go back to the early days of this blog to find it, but I wrote here about insulin degrading enzyme. The name tells you some of what you need to know about it, for sure - it degrades insulin, so if you could stop that, insulin would probably hang around longer in the bloodstream. There's more to it - it's also been thought to be a way that insulin might be broken up inside cells as well, for one thing - but that's the elevator pitch for it.

And it has indeed been a diabetes target through the years. No one's come up with any really good inhibitors of it, although in vitro studies have been done with things like bacitracin and thioesters. Now a large multicenter academic team, led by the Mayo people from Florida, report some compounds that seem quite potent. (It's worth noting that these inhibitors are somewhat old news if you follow the patent literature).

The structures are not lovely, but there are a lot worse compounds in the protease inhibitor world. One thing that every experienced medicinal chemist will quickly notice about these is that they're hydroxamic acids. Those are compounds with a very spotty past in the business (although there is vorinostat (SAHA) out there on the market). Hydroxamates can be very potent inhibitors of metalloenzymes, and every time you target one they're always out there as a temptation, but the ugly clinical failures in that structural class tend to give people pause. Or was it just the targets (chiefly matrix metalloproteases) that the hydroxamates were aimed it? Have they been unfairly maligned? The arguments continue, and these compounds are unlikely to settle them.

Unless, of course, they go to the clinic and make a big success. I wonder if that's going to happen, though - the "go to the clinic" part, that is. This new paper is an interesting piece of work, and has a lot to say about the strange workings of IDE (which go a ways to explaining why there hasn't been much success targeting it - I was once involved briefly in the area myself). But it has nothing to say about whether these compounds have any exposure in any sort of animal, and that's the beginning of the really tricky part. These new compounds, in addition to be hydroxamic acids, are retro-inverso peptides. That's an old trick in the protease inhibitor world where you flip a natural sequence around and use the unnatural (D) amino acids to build it as well. Off the top of my head, I don't know of any retro-inverso compounds that have actually made it to market, although I'd be glad to be corrected on this.

The other complication will be IDE itself. One reason that no company has made a massive push on the target is that the enzyme is known to be multifunctional, as in "doing totally unrelated things all over the darn place", which makes one nervous about an inhibitor. Foremost among the off-target effects would be the beta-amyloid story (which is what led me to write about the enzyme back in 2003). IDE looks as if it could be one clearance mechanism for beta-amyloid (and perhaps for other easily-aggregating peptides), which has prompted people to think of actually trying to enhance its activity as an Alzheimer's therapy. One group that's tried this is, in fact, the same team that's now reporting the inhibitors (see this paper from 2009).

So I think these compounds will prove useful to figure out what IDE is doing, and that's a worthwhile goal. But I don't see them as drugs, no matter what the press release might say.

Comments (9) + TrackBacks (0) | Category: Diabetes and Obesity | Drug Industry History

May 5, 2010

Steve Nissen vs. GlaxoSmithKline

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Posted by Derek

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

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

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

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

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

Nissen's reply is considerably more detailed:

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

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

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

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

April 29, 2010

Treatment INDs - For Any Generex Fans Out There

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Posted by Derek

Adam Feuerstein schools the Generex folks on what a "Treatment IND" really means, quoting chapter and verse from the FDA. The company's fans have made much of that designation for its flagship buccal insulin product. As has the company's CEO - but that link shows her making statements at investor conferences which are, on the face of them, in flat contradiction to the FDA's own understanding of such matters.

The article's worth reading even if you don't give two hoots about Generex, since it'll give you an understanding of what it means (and doesn't mean) when a company has a product designated for "compassionate use". It can also give you an understanding of what it means when a company misrepresents that status, but I think a lot of people here already know what that must mean. . .

Comments (3) + TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity | Regulatory Affairs

April 16, 2010

Generex: Who Buys This Stuff, Anyway?

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Posted by Derek

I've been meaning to do another post on Generex, the company that says it's developing an oral spray form of insulin as an alternative to the injected forms. This is the outfit that's suing Adam Feuerstein of TheStreet.com over his dismissive comments on their business, and here I stated that after looking the operation over a bit, that I agreed with him. In short, I have doubts about the real-world efficacy of buccal insulin delivery, doubts about the acceptance of it in the diabetes patient (and physician) population, and doubts that spring from Generex's own statements about the drug's development. A handful of patients in Ecuador does not make for a convincing reason to move into Phase III - not to me - and you don't press-release your Phase III results when you've only enrolled 10% of your targeted number of patients. And so on. . .but who am I to question the buccal spray delivery technology, when (as Generex states on their web site) it's also being used to develop an "energy spray" called Ba-Boom? (Be sure to turn up your speakers so you can hear the theme music; it's going to play when you click that link. And yes, that is Generex - look at the bottom of the page).

It's been a very busy week around here, but what I do have time to do is take a look at the recent infusion of capital the company has experienced. An investment group called Seaside 88 has announced their intention to buy a large amount of Generex stock. Among the Generex investors calling for my head (and other parts of my anatomy), opinion seems divided about Seaside 88 and my relationship to them (which, let me state right up front, is completely nonexistent - I'd never heard of the outfit until this stuff came up). Some of the hardy GNBT folks point to this deal as evidence that I'm a fool, because here's this big investment outfit pouring money into this wonderful company and its promising product. Others seem to think that I'm being paid off by said big investment outfit, that I'm a black-hatted stock-basher out to secure Seaside 88 a better deal as it scoops up this wonderful stock on the cheap.

Which exciting story to believe? Not for the first time, I'm reminded that too many people who invest in small "story" stocks have worldviews that resemble the story lines of profession wrestling. I'd call it Manichean, but that's a bit too elevated. No, it's all Good Guys and Bad Guys, and there's no room for someone like me, a person with no money in the game who finds the whole thing bizarre and amusing. The smaller the stock prices involved, by the way, the crazier the investors seem to be.

So, Seaside 88. If you go do an EDGAR search on them, you find that they've done similar stock-purchase deals with a number of small companies (and other deals show up as you Google for press releases). Flywheel energy storage companies, obscure fuel-cell makers - it's quite a collection. My personal favorite is Ensurge, Inc., and if you'd like to know what business they're in, you'll just have to read the language in their 10-K. If you're not snorting in derision by the time you get to the South-American-gold-mining stuff, then you're a born penny-stock investor. You'd have to use threats of bodily harm to make these things a centerpiece of my own investment strategy - but hey, that's why I'm going to finish up eating off-label cat food in a trailer while the Generex shareholders are sailing their yachts through the Greek islands. These things have a way of evening out.

So, who are these Seaside 88 people, anyway? Well, as is often the case, there's a whole little constellation of related companies. There's your Seaside Analytics, your Seaside Capital Management, your Seaside Capital II, and so on. One person who figures prominently in all of them is William Ritger, who's been in the investment business for some years now. Here's a biography of him from one of the companies he's helped to found.

In fact, he's been in the business long enough for this article from the the New York Times to turn up. It refers to a former venture of his, Research Works, which seems to have issued favorable reports on obscure stocks - causing their prices to jump - but without making much of the fact that he was being paid by the companies involved to write those reports. One hopes that he is no longer in the business of promoting small stocks in this manner.

Another name that shows up when you search the Seaside family of investment partnerships is Denis O'Donnell. Looking over the EDGAR filings featuring his name, you find his ongoing relationship with a company called American Bio Medica, which I note has also been listed as one of the house favorites of a micro-cap "pump and dump" junk-fax operation. He's also been involved with Columbia Laboratories - now of New Jersey, but formerly of Hollywood, Florida, where (interestingly enough) they were mentioned in that same New York Times article as the subject of one of those paid-for investment reports back in the 1990s. One hopes that he is keeping better company now.

So, Generex investors, enjoy your stock, and enjoy the company of the others who have seen fit to invest in it. I will not be putting any of my own money into it, and they won't let a person short companies that trade at 60 cents a share. Which is too bad, in a way, because the great majority of such companies go to zero.

Comments (43) + TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity | The Dark Side

April 9, 2010

The Crowd Goes Wild

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Posted by Derek

Boy, do the Generex fans love me over at Seeking Alpha, where some of my articles are reposted. I am apparently in the pay of The Hidden Interests (although there are contradictory opinions as to who They may be), and there are calls to have the SEC, the IRS, and all those other fun agencies come and sort me out.

That increases my interest in the company even more, now that I see what high-caliber fans it has. Look for an article on Generex here next week. From what I've been able to find already, I should have something the company's cheering section will enjoy.

Comments (23) + TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity

April 8, 2010

ACC2: Great Metabolic Target, Or Total Bust?

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Posted by Derek

For people who've done work on metabolic disease, this paper in PNAS may come as a surprise, although there was a similar warning in January of this year. Acetyl CoA-carboxylase 2 (ACC2) has been seen for some years as a target in that area. It produces malonyl CoA, which is a very important intermediate and signaling molecule in fatty acid metabolism (and other places as well). A number of drug companies have taken a crack at getting good chemical matter (I'm no stranger to it myself, actually). A lot of the interest was sparked by reports of the gene knockout mice, which seem to have healthy appetites but put on no weight. The underlying reason was thought to be that fatty acid oxidation had been turned up in their muscle and adipose tissue - and a new way to burn off excess lipids sounded like something that a lot of people with excess weight and/or dyslipidemia might be able to use. What's more, the ACC2 knockout mice also seemed to be protected from developing insulin resistance, the key metabolic problem in type II diabetes. An ACC2 inhibitor sounds like just the thing.

Well, this latest paper sows confusion all over that hypothesis. The authors report having made some selective ACC2 knockout mouse strains of their own. If the gene is inactivated only in muscle tissue, the animals show no differences at all in body weight, composition, or food intake compared to control mice. What's more, when they went back and inactivated ACC2 in the whole animal, they found the same no-effect result, whether the animals were fed on standard chow or a high-fat diet. The muscle tissue in both cases showed no sign of elevated fatty acid oxidation. The authors state drily that "The limited impact of Acc2 deletion on energy balance raises the possibility that selective pharmacological inhibition of Acc2 for the treatment of obesity may be ineffective."

Yes, yes, it does. There's always the possibility that some sort of compensating mechanism kicked in as the knockout animals developed, something that might not be available if you just stepped into an adult animal with an inhibiting drug. That's always the nagging doubt when you see no effect in a knockout mouse. But considering that those numerous earlier reports of knockout mice showed all kinds of interesting effects, you have to wonder just what the heck is going on here.

Well, the authors of the present paper are wondering the same thing, as are, no doubt, the authors of that January Cell Metabolism work. They saw no differences in their knockout animals, either, which started the rethinking of this whole area. (To add to the confusion, those authors reported seeing real differences in fatty acid oxidation in the muscle tissue of their animals, even though the big phenotypic changes couldn't be replicated). Phrases like "In stark contrast to previously published data. . ." make their appearance in this latest paper.

The authors do suggest one possible graceful way out. The original ACC2 knockout mice were produced somewhat differently, using a method that could have left production of a mutated ACC2 protein intact (without its catalytic domain). They suggest that this could possibly have some sort of dominant-negative effect. If there's some important protein-protein interaction that was wiped out in the latest work, but left intact in the original report, that might explain things - and if that's the case, then there still might be room for a small molecule inhibitor to work. But it's a long shot.

The earlier results originated from the lab of Salih Wakil at Baylor (who filed a patent on the animals), and he's still very much active in the area. One co-author, Gerry Shulman at Yale, actually spans both reports of ACC2 knockout mice - he was in on one of the Wakil papers, and on this one, too. His lab is very well known in diabetes and metabolic research, and while I'd very much like to hear his take on this whole affair, I doubt if we're going to see that in public.

Comments (14) + TrackBacks (0) | Category: Biological News | Diabetes and Obesity

April 7, 2010

Generex and Their Insulin Spray: Just Hype?

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Posted by Derek

I haven't written anything about Generex, a company developing an oral insulin spray for Type I diabetes, although they have come up in the comments here once or twice. I'm now regretting my lack of coverage, since if I'd said something uncomplimentary about them (an even bet), I might have had my chance to get sued by them as well. That's what's happening to Adam Feuerstein of TheStreet.com.

Feuerstein wrote two recent columns about the company. The first one was quite skeptical of the company's prospects, saying that he thought the company's Oral-lyn was "a total bust". Said Feuerstein:

"Common sense should tell you that an insulin spray like Oral-lyn is more fiction than science. If Oral-lyn was real, Big Pharma would have snatched up the technology a long time ago. Instead, Pfizer lost millions with an insulin bong, and Al Mann, billionaire healthcare entrepreneur and MannKind's founder, is spending hundreds of millions of dollars of his own money to build another inhalable insulin device. For that kind of money, Mann could have bought Generex several times over. He didn't."

There were also some unkind comments about the way the company touts its regulatory approvals in Ecuador, India, Lebanon and Algeria. (You'll notice that India is by far the most serious regulatory and financial market in that list - read on!) He also had things to say about the size of the company's potential market, given the effectiveness of insulin injections for Type I patients. But his second column (written in response to a flood of e-mail and a hostile legal letter from the company about the first one) was even more blunt:

"The more I dig into Generex Biotechnology(GNBT) and its insulin spray for diabetics, the more preposterous the story becomes. . .it becomes apparent almost immediately that the company is using science and the quest to develop an alternative insulin delivery method not to actually help diabetics but as a ruse to perpetuate a 15 year-long stock promotion scheme. In the process, investors are getting fleeced while Generex management earns millions of dollars in compensation."

Read the rest of his article to get the story on the clinical data, which include things like a ten-day trial in two dozen patients in Ecuador. Actually, that's the centerpiece of the clinical story, come to think of it. The company recently press-released "Successful Phase III Data", although they only had data on 60 patients out of the targeted 750. And so on. No, something seems odd about all this.

If you ask me, Feuerstein's likely in the right here. I, too, have trouble believing that an oral insulin spray can reliably treat the type I diabetes population, for whom careful insulin dosing is crucial. And I think that if there were a realistic chance of that happening, that the likes of Novo Nordisk and Eli Lilly would probably have at least looked into the possibility. And even if they'd missed out, if Generex were the company to discover a real opportunity here, I don't see how they wouldn't be able to raise more money (or do a co-development deal) with more convincing clinical data, if they had any. Why treat a handful of people in Ecuador and let your stock value sit at 60 cents a share, if you have the chance to raise the serious money needed to get a real diabetes therapy through some convincing Phase III trials instead? That's not how this business tends to work.

Generex, though, decided after the second Feuerstein column that they'd had enough, and has sued. For two hundred and fifty million dollars, yet. The company has some very vocal defenders, and I believe that they're completely sincere, but this lawsuit makes me think even less of Generex than I did after reading about their product. Why are they wasting time and money on this sort of thing? These kinds of lawsuits have virtually no chance of going anywhere - the only reason I can see for filing one (if indeed they have) is to get more publicity (and look noble and beleaguered).

The same day the lawsuit was announced, Feuerstein dropped another article into the mix, returning to that regulatory-approval-in-India issue. As it happens, the Indian government revoked the approval a year ago, only three months after the product was offered for sale. You can search (and Feuerstein does, gleefully) through all of Generex's press releases, conference call transcripts, and regulatory filings for any mention at all of this material event. There's nothing. Now, the original approval in India was covered extensively by the company, as you'd imagine, but the withdrawal seems to have passed in total silence - with even a denial last fall that there were any delays or problems in India at all. According to Feuerstein, Generex has completed several financing deals without apparently getting around to mentioning this little detail.

Wagering may now commence as to whether either the lawsuit or the oral insulin spray are going anywhere. If the company really has failed to disclose a material event, though, they may be going somewhere themselves.

Comments (32) + TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity | Press Coverage

March 23, 2010

Rats and High-Fructose Corn Syrup

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Posted by Derek

OK, enough politics around here for a while. It's time to talk about fat rats. When I last wrote about fructose around here, it was to highlight a paper that suggested that it had effects on satiety signaling in the brain. The hypothesis was that fructose could lead to an abnormal drop in ATP levels in the hypothalamus, leading to an inappropriate hunger signal. This is partially borne out by the results of infusing various sugars directly into the brains of rats: if you do that trick with glucose, the rats stop eating - their cells have detected abundant glucose, which is a signal that they've been fed recently. On the other hand, if you use fructose, the rodents actually eat more.

Some of the big questions, though, have been whether fructose does this under normal conditions in rats (that is, without the power-drill route of administration into the brain), and whether that result carries over to humans. There's a new paper from a group at Princeton that's sure to add fuel to the debate. They studied the effects on rats of access to high-fructose corn syrup (8% in water) versus 10% sucrose, with unlimited access to normal rat chow, and looked at whether it made a difference if you allowed access for half the day versus the whole 24 hours.

Over an 8-week period, the groups diverged significantly. The half-day corn syrup rats put on significantly more weight than the half-day sucrose rats did, even though (most interestingly) the corn syrup group turned out to be ingesting fewer calories from the added corn syrup than the sucrose rats were getting from their sugar water. That is, the difference in caloric intake (and thus the excess weight) was all coming from eating more chow.

When the study was extended to six months, it turned out that it didn't matter much if the rats had 12-hour or 24-hour access to the high-fructose corn syrup - by week 3, the weights of both groups had diverged from the controls. (Looking at the graphs, it appears that the 24-hour group may have done somewhat worse, but I don't think they reached statistical significance versus the 12-hours). But that result is in male rats. The females showed what seems to be a much less dramatic effect. Only the 24-hour-HFCS group showed a significant weight difference from the controls.

Looking at the fat deposits the rats had laid down during this time shows another gender difference, although it doesn't help clear things up any. The males show a tendency for more fat pad mass, although the only measurement that reached significance was the abdominal fat for the 12-hour-a-day group. The females, although they didn't show nearly as wide a difference in weight gain, had much more significant differences in their fat mass (but only for the 24-hour-a-day HFCS group). Finally, in blood chemistry, none of the groups showed differences in insulin levels. But the both the male HFCS groups had elevated triglycerides, as did the 24-hour-HFCS females.

Taken together, it appears that rats (especially males) are able to adjust their caloric intake when given access to small amounts of sucrose, but not so much when given equivalent amounts of HFCS. Earlier work has shown that access to higher levels of sucrose or other sugars, though, will indeed cause rats to gain weight. But not everyone, it seems, even sees these effects. A study from last December looked at a variety of sweetened waters, given to rats 12 hours/day for ten weeks, but only three days out of each week. No differences in weight were seen, although it should be noted that in head-to-head tests, the rats preferred HFCS to agave or Stevia sweeteners. (I wish this group had run sucrose in this experiment, too).

So does this effect even apply across the board in rodents? And if it does, is it operating in humans as well? Short term, no one has been able to find any short-term differences in satiety or blood chemistry when comparing HFCS with sucrose in humans. That alone (as mentioned in the earlier post here linked in the first paragraph) makes you wonder if that fructose/brain hypothesis can hold up in people. But what about long-term effects, which may or may not have anything to do with that CNS-based mechanism?

As far as I can tell, we have no controlled data for that, which isn't surprising, considering the sort of experiment you'd have to run. Most people aren't in a position to have their food and liquid intake completely monitored for two or three months. But short of that, I'm not sure how we're ever going to straighten all this out.

Comments (42) + TrackBacks (0) | Category: Diabetes and Obesity

March 15, 2010

Tricor's Troubles

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Posted by Derek

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

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

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

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

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

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

March 5, 2010

Your Own Personal Bacteria

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Posted by Derek

There's a report in Nature on the bacteria found in the human gut that's getting a lot of press today (especially for a paper about, well, bacteria in the human gut). A team at the Beijing Genomics Institute, with many collaborators, has done a large shotgun sequencing effort on gut flora and identified perhaps one thousand different species.

I can well believe it. The book I recommended the other day on bacteria field marks has something to say about that, pointing out that if you're just counting cells, that the cells of our body are far outnumbered by the bacteria we're carrying with us. Of course, the bacteria have an advantage, being a thousand times smaller (or more) than our eukaryotic cells, but there's no doubt that we're never alone. In case you're wondering, the average European subject of the study probably carries between 150 and 200 different types of bacteria, so there's quite a bit of person-to-person variability. Still, a few species (mostly Bacteroides varieties) were common to all 124 patients in the study, while the poster child for gut bacteria (E. coli) is only about halfway down the list of the 75 most common organisms. We have some Archaea, too, but they're outnumbered about 100 to 1.

What's getting all the press is that idea that particular mixtures of intestinal bacteria might be contributing to obesity, cancer, Crohn's disease and other conditions. This isn't a new idea, although the new study does provide more data to shore it up (which was its whole purpose, I should add). It's very plausible, too: we already know of an association between Helicobacter and stomach cancer, and it would be surprising indeed if gut bacteria weren't involved with conditions like irritable bowel syndrome or Crohn's. This paper confirms earlier work that such patients do indeed have distinctive microbiota, although it certainly doesn't solve the cause-or-effect tangle that such results always generate.

The connection with obesity is perhaps more of a stretch. You can't argue with thermodynamics. Clearly, people are obese because they're taking in a lot more calories than they're using up, and doing that over a long period. So what do bacteria have to do with that? The only thing I can think of is perhaps setting off inappropriate food cravings. We're going to have to be careful with that cause and effect question here, too.

One problem I have with this work, though, is the attitude of the lead author on the paper, Wang Jun. In an interview with Reuters, he makes a very common mistake for an academic: assuming that drug discovery and treatment is the easy part. After all, the tough work of discovery has been done, right?

"If you just tackle these bacteria, it is easier than treating the human body itself. If you find that a certain bug is responsible for a certain disease and you kill it, then you kill the disease," Wang said

For someone who's just helped sequence a thousand of them, Wang doesn't have much respect for bacteria. But those of us who've tried to discover drugs against them know better. Where are these antibiotics that kill single species of bacteria? No such thing exists, to my knowledge. To be sure, we mostly haven't looked, since the need is for various broader-spectrum agents, but it's hard to imagine finding a compound that would kill off one Clostridium species out of a bunch. And anyway, bacteria are tough. Even killing them off wholesale in a human patient can be very difficult.

Even if we magically could do such things, there's the other problem that we have no idea of which bacterial strains we'd want to adjust up or down. The Nature paper itself is pretty good on this topic, emphasizing that we really don't know what a lot of these bacteria are doing inside us and how they fit into what is clearly a very complex and variable ecosystem. A look at the genes present in the samples shows the usual common pathways, then a list that seem to be useful for survival in the gut (adhesion proteins, specific nutrient uptake), and then a massive long tail of genes that do we know not what nor why. Not only do we not know what's happening on other planets, or at the bottom of our own oceans, we don't even know what's going on in our own large intestines. It's humbling.

Dr. Wang surely realizes this; I just wish he'd sound as if he does.

Comments (25) + TrackBacks (0) | Category: Biological News | Diabetes and Obesity | Infectious Diseases

February 24, 2010

Steve Nissen's Meeting with GSK

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Posted by Derek

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

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

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

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

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

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

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

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

February 22, 2010

Avandia: Off the Market or Not?

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Posted by Derek

The Senate report that leaked on Avandia (rosiglitazone) over the weekend has made plenty of headlines. It quotes an internal FDA report that recommends flatly that the drug be removed from the market, since its beneficial effects can be achieved by use of the competing PPAR drug Actos (pioglitazone), which doesn't seem to have the same cardiovascular risks. The two drugs have been compared (retrospectively) head to head, and Avandia definitely seems to have come out as inferior due to safety concerns.

There had been worries for several years about side effects, but the red flag went up for good in 2007, and the arguing has not ceased since then. According to another FDA document in the Senate report, there are "multiple conflicting opinions" inside the agency about what to do. The agency ordered GSK to set up a prospective head-to-head trial of Avandia and Actos, but other staffers insist that the whole idea is unethical. If the cardiovascular risks are real, they argue, then you can't expose people to Avandia just to find out how much worse it is. The trial is enrolling patients, but will take years to generate data, and Avandia will be generic by the time it reports, anyway. (Presumably, the only reason GSK is running it is because the drug would be taken off the market for sure if they didn't).

The FDA's internal debate is one issue here (as is the follow-up question about whether the agency should be restructured to handle these questions differently). But another one is GlaxoSmithKline's response to all the safety problems. Says that New York Times article:

In 1999, for instance, Dr. John Buse, a professor of medicine at the University of North Carolina, gave presentations at scientific meetings suggesting that Avandia had heart risks. GlaxoSmithKline executives complained to his supervisor and hinted of legal action against him, according to the Senate inquiry. Dr. Buse eventually signed a document provided by GlaxoSmithKline agreeing not to discuss his worries about Avandia publicly. The report cites a separate episode of intimidation of investigators at the University of Pennsylvania.

GlaxoSmithKline said that it “does not condone any effort to silence” scientific debate, and that it disagrees with allegations that it tried to silence Dr. Buse. Still, it said the situation “could have been handled differently.”

Well, yeah, I should think so. I don't know what the state of the evidence was as early as 1999, but subsequent events appear to have vindicated Buse and his concerns. And while you can't just sit back and let everyone take shots at your new drug, you also have to be alert to the possibility that some of the nay-sayers might be right. We honestly don't know enough about human toxicology to predict what's going to happen in a large patient population very well, and companies need to be honest with the public (and themselves) about that.

Comments (16) + TrackBacks (0) | Category: Diabetes and Obesity | Regulatory Affairs | Toxicology

January 15, 2010

Sirtuin Scenarios

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Posted by Derek

So, after reading what Pfizer has to say about Sirtris (and by extension, about GlaxoSmithKline's heavy investment in them), let's go over the possibilities. What happened, and what's going on?

We'll start out with the first branch point: either Pfizer (and Amgen) are right that there's trouble with the Sirtris assays and compounds (Reality A, I'll call it), or they're wrong (Reality B). For the rest of this piece, I'm going to assume that they're right, because I think that this is almost certainly the case. At least two separate groups of competent investigators have reported trouble, and that's good enough for me. (We'll discuss the implications of that in a bit).

Now we come to the second branch point: either Glaxo did enough due diligence to be aware of the problems (scenario A1) or they didn't realize them at the time of the deal (scenario A2). If A1 is the case, then we'd have to assume that the most likely consequence (A1a) is that Sirtris had other non-public assets that did check out, and that GSK's management felt that these justified the purchase. (A1b would be the scenario where GSK was well aware of the Sirtris problems, knew also that they didn't have anything else to offer, and bought them anyway, which doesn't make sense). These assets could have been other compounds, and/or a leg up on the complicated biology of this field. The difficulty with that line of thinking is that having found the fundamental assay problems with the Sirtris work, the GSK people would surely have been much more cautious about drawing sweeping conclusions about the rest of the company's intellectual property.

If A2 is the case, then we're looking at sheer fecklessness on the part of GSK's upper management. I'd like to be able to rule this out, but there have been other deals in the history of this industry that make that hard to do. I have witnessed at least one such personally. One problem is that these deals tend to be initiated near the highest levels of a company, and these people are not always the most technically savvy (or up-to-date) members of an organization. Even with a science background, the CEO of a large company does not have the time to be a scientist. (I'm reminded of Peter O'Toole's character in My Favorite Year: "I'm not an actor - I'm a movie star!"

Overall, though, I find it hard to believe that no one would have noticed the reported problems at all, which leads me to favor what I'll call scenario A3: the problems with the Sirtris assays may well have been known/realized at the lower scientific levels of GSK's organization, but these concerns may not have made it to the top in a sufficiently timely or vigorous manner. The deal would have gone through under its own momentum, then, in a flurry of last-minute misgivings which would have been hard to distinguish from the usual butterflies that accompany any large transaction or the preliminary stirrings of buyer's remorse. The sorts of reasons advanced in the A1 paragraph above would have been used to justify pushing ahead. With that in mind, this scenario could be broken down further into A3a, where Sirtris also had some other assets that the rest of us haven't seen, and A3b, where they didn't. I think that A3a is more likely, since that would have provided some of the momentum to get the deal done regardless. A3b is basically A2 with different timing and slightly less cluelessness.

So where do things go from here? That obviously depends on which of those three realities obtains. If A1 (specifically A1a) is the case, then GSK plows ahead with their secret Sirtris assets and compounds, and good luck to all concerned. It's worth keeping in mind that sirtuins are quite interesting and important, and that it's an area worth investigating on its own merits. (Pfizer and Amgen, among others, must think so too; that's the only reason that they would have been trying to replicate the Sirtris work).

If A2 is the real story, well, I'm very sorry to hear it. A lot of people seem ready to believe this one, partly because of anger over the layoffs the company has been going through. The most likely consequence of A2 is that $720 million dollars disappears, never to yield anything that's of use to anyone, so I hope that this isn't what happened.

And if, as I think, A3 is what actually happened, then that sort of depends on whether we're looking at A3a or A3b. If the former, then Glaxo overpaid, but has a fighting chance to redeem itself. If the latter, then Glaxo not only overpaid, but (as with A2) is in danger of losing its whole investment as well. We'll all find out.

But we may not find out very quickly. GSK has (like many other companies) a tendency to be rather close-mouthed about the progress of some of its research. When I worked in the nuclear receptor field, we all were very interested in the fate of a particular Glaxo compound, the first selective PPAR-delta ligand to go into the clinic. The company had talked about some animal and preclinical data, but we knew that they were taking it into humans (after all, it was listed that way in their pipeline updates). But it stayed listed like that. . .and stayed. . .and stayed. . .until, as the months and years passed, it became obvious to even the most optimistic observer that the compound's development was (at the very least) extremely complicated, and (more likely) had actually quietly ceased a good while before, albeit with no change in its public status.

In this case, now that these doubts have come up, GSK has a real interest in pointing out any success it may have. If its sirtuin compounds go into the clinic and just sort of hang there, that will probably be an even worse sign than usual. And if no sirtuin compounds even go into the clinic at all, well, the question has answered itself. I hope that's not what happens.

Comments (61) + TrackBacks (0) | Category: Aging and Lifespan | Clinical Trials | Diabetes and Obesity | Drug Development

January 14, 2010

Gaining and Losing and Discovering and Selling

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Posted by Derek

Obesity has been one of those therapeutic areas that drug companies can't quite stay away from. A glance at the potential patient ranks, expanding in every sense of the word, is enough to explain why. But as I've detailed here in the past, finding an effective obesity drug is not easy, for many good reasons.

One response has been that such a drug wouldn't have to work spectacularly well to be effective, since calories add up so alarmingly. The "one cookie a day" model of weight gain is often referenced. But just how useful is it? According to this paper in JAMA (PDF), not so much (emphasis added):


How much weight would an individual gain by eating an extra chocolate chip cookie every day for life? One approach to answering this question, frequently used in textbooks and scientific articles, is based on the assumption that a pound (454 g) of fat tissue has about 3500 kilocalories (kcal). Thus, a daily 60-kcal cookie would be expected to produce 0.2 kg (0.5 lb) weight gain in a month, 2.7 kg (6 lb) in a year, 27 kg (60 lb) in a decade, and many hundreds of pounds in a lifetime. This of course does not happen. . .

So what does happen? If a person takes in a steady excess of calories, they most certainly will gain weight. But some of those extra calories then go into maintaining (and carrying around) that new weight. The result is a slow climb up to a new equilibrium weight. The 60-calorie cookie example above would be expected to lead to about 6 lbs of total weight gain over a period of years. Most of that will be put on early, with an asymptotic rise to the final value.

Now, if you're trying to avoid gaining weight, this is probably good news. The effects of having some extra food now and then aren't quite as catastrophic as the usual calculations would make you think (although there is that faster-weight-gain-at-first effect, so you have to separate the short-term and long-term consequences a bit). For someone that's significantly overweight and wants to lose it, the implications are mixed. One way to look at it is that the maintenance costs of extra body mass are substantial, meaning that a person doesn't have to suddenly go on a 1400-calorie-a-day diet to see results. Another thing this paper tells us that significantly overweight people have gotten to that point only by having significant calorie imbalances. A cookie a day is not going to do it. A lot of people are taking in a lot more excess calories than that:

These calculations suggest that small changes in lifestyle would have a minor effect on obesity prevention. Walking an extra mile a day expends, roughly, an additional 60 kcal compared with resting—equal to the energy in a small cookie. Physiological considerations suggest that the apparent energy imbalance for much of the US population is 5- to 10- fold greater, far beyond the ability of most individuals to address on a personal level. . .

The authors go on to call from greater regulation of the food supply, greater public health efforts, and so on, but I have to say that I'm skeptical of the ability of these to do the trick (or, given my political leanings, of the amount of coercion that might be needed to make them really work). It's clear that many people would like to be less overweight than they are, but (revealed preference time), it's also clear that they have enjoyed running up their caloric imbalances even more. So while the authors may be right that significant weight loss may be beyond most people's ability to address on a personal level, it's hard for me to see any other level that's really going to work.

So what would help? Would an anti-obesity drug? On the one hand, a good one might alter the physiological underpinnings of weight gain (and weight loss) in such a way to help people escape the squirrel-cage aspects of dieting and rebound weight gain. But that's asking a lot, and I remain uncertain about whether a really good weight-loss drug is even possible. The other difficulty is that any such treatment still has to be coupled with all those things that patients don't want to hear about: less food, more exercise. The time course needed is also a hard sell, particularly when you consider all the scam ads that bombard everyone. It seems clear that any sustainable weight loss probably should take about as much time as the initial weight gain did, which is not what many people are wanting to hear, particularly when someone else is promising umpteen pounds a week of magic weight loss.

Then there's the commercial consideration: that a new approved obesity drug, regardless of whether it works very well in the real world or not, would nonetheless sell like crazy. And if it doesn't work quite as well as the rigorously controlled clinical trials indicated it would, well, you can always blame the patients themselves (and for that matter, in many cases you'd be right). It's enough to make me think that the whole therapeutic area is a moral hazard.

Comments (32) + TrackBacks (0) | Category: Diabetes and Obesity

January 11, 2010

MAGL: A New Cancer Target

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Posted by Derek

I do enjoy some good chemical biology, and the latest Cell has another good example from the Cravatt group at Scripps (working with a team at Brigham and Women's Hospital over here on this coast). What they've done is profile various types of tumor cells using an activity-based probe to search for changes in serine hydrolase enzymes. Those are a large and diverse class (with quite a few known drug targets in them already), and there had already been reports that activity in this area was altered as cancer cell lines became more aggressive.

What they tracked down was an enzyme called MAGL (monoacylglyceride lipase). That's an interesting finding. Cancer cells have long been known to have different ideas about lipid handling, and several enzymes in that metabolic area have been proposed over the years as drug targets. (The first one I can think of is fatty acid synthase (FAS), whose elevated presence has been correlated with poor outcome in several tumor types). In general, aggressive tumor cells seem to run with higher levels of free fatty acids, for reasons that aren't quite clear. Some of the downstream products are signaling molecule, and some of these lipids may just be needed for elevated levels of cell membrane synthesis.

But it looks from this paper as if MAGL could be the real lipid-handling target that oncology people have been looking for, though. The teams inhibited the enzyme with a known small molecule (well, relatively small), and also via RNA knockdown, and in both cases they were able to disrupt growth of tumor cell lines. The fiercer the cells, the more they were affected, which tracked with the MAGL activity they had initially. On the other hand, inducing higher expression of MAGL in relatively tame tumor cells turned them aggressive and hardy. They have a number of lines of evidence in this paper, and they all point the same way.

One of those might be important for other reasons. The teams took the cell lines with impaired MAGL activity, and wondered if this could be rescued by providing them with the expected products that the enzyme would deliver. Stearic and palmitic acid are two of the fatty acids whose levels seem to be heavily regulated by MAGL, and sure enough, providing the MAGL-deficient cells with these restored their growth and mobility. As the paper points out specifically, this could have implications for a relationship between obesity and tumorigenesis. (I'd add a recommendation to look with suspicion at other conditions that lead to higher-than-usual levels of circulating free fatty acids, such as type II diabetes, or even fasting).

It may be that I particularly enjoyed this paper because I have a lipase-inhibiting past. As anyone who's run my name through SciFinder or Google Scholar has noticed, I helped lead a team some years ago that developed a series of inhibitors for hormone-sensitive lipase, a potential diabetes target. We were scuppered, though, by the fact that this enzyme does (at least) two different things in two totally different kinds of tissue. Out in fat and muscle, it helps hydrolyze glycerides (in fact, it's right in the same metabolic line as MAGL), and that's the activity we were targeting. But in steroidogenic tissues, it's known as neutral cholesteryl ester hydrolase, and it breaks those down to provide cholesterol for steroid biosynthesis. Unfortunately, when you inhibit HSL, you also do nasty things to the adrenals and a few other tissues. There's no market for a drug that gives you Addison's disease, I can tell you.

So I wondered when I saw this paper if MAGL has a dual life as well. If I'd ever worked in analgesia or cannabinoid receptor pharmacology, though, I'd have already known the answer. MAGL also regulates the levels of several compounds that signal through the endocannabinoid pathway, and has been looked at as a target in those areas. None of this seems to have an affect on the oncology side of things, though - this latest paper also looked at CB receptor effects on their cell lines that were deficient in MAGL, and found no connection there.

So, what we have from this paper is a very interesting cancer target (whose crystal structure was recently reported, to boot), a new appreciation of lipid handling in tumors, and a possible rationale for the connections seen between lipid levels and cancer in general. Not bad!

Special bonus: thanks to Cell's video abstracts, you can hear Ben Cravatt and his co-worker Dan Nomura explain their paper on YouTube. The journal has recently enhanced the way their papers are presented online, actually, and I plan to do a whole separate blog entry on that (and on video abstracts and the like).

Comments (9) + TrackBacks (0) | Category: Biological News | Cancer | Diabetes and Obesity

September 24, 2009

Obesity: Hope Springs Eternal (Summer 2009 Version)

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Posted by Derek

Some very interesting papers from the obesity research field have been published in the last few months. There have been a number of these over the years, and (as is widely apparent), none of them have quite lived up to their initial promise. This latest mechanism has been written up by both academic groups and industrial ones, which leads to some speculation about the state of the field - read on.

First, some background: GLP-1 (glucagon-like peptide 1) is a very important metabolic regulator. Peptides that mimic it at its receptor (but with a longer half-life) are marketed diabetes therapies (Byetta (exenatide), liraglutide, and others), and the DPP-IV inhibitors, like Januvia (sitagliptin) and its upcoming competition do something similar by inhibiting the enzyme that normally breaks the peptide down.

In addition to glycemic control, GLP-1 and related ligands also have complex effects on appetite in rodent models. These are still being unraveled, and depend on which peptide you use, and whether it's given out in the periphery or into the brain. More than one mechanism seems to be involved.

Glucagon is another key player in regulating glucose - it's another peptide hormone with its own receptor, and its most noticeable effect is as sort of counterweight to insulin in glucose control. It stimulates the liver to break down glycogen and release glucose, among other things, and people have tried (so far, without success) to develop glucagon blockers as a treatment for diabetes.

There are several other important signaling peptides in this space, such as GLP-2 and oxyntomodulin, and it's been clear for a few years now that there's some sort of opportunity to come up with a mixed-activity ligand that might hit these various piano keys to produce the right chord. (Several such have been reported in the diabetes field). These peptides are all part of the gut-to-brain signaling system, which is rather complex and has been the target of a number of obesity research programs over the years. Signals for satiety, hunger, glucose handling, and energy expenditure are all tangled together there, but in ways that we don't understand well, so it's been a very attractive minefield. For the most part, compounds targeting these systems have been stabilized forms of peptides themselves, and thus have to be given by injection. Small-molecule ligands for these receptors have been much harder to come by.

Now for the new results. A team from Indiana, Kentucky, and Cincinnati reported back in July in Nature Chemical Biology that dual agonist peptides acting at both the GLP-1 and glucagon receptors do a tremendous job on obese rodents. (Here's a PDF from one of the authors). They took two of them into diet-induced-obese mice, and saw very significant weight loss, which appears to have been almost entirely body fat, and was driven by simultaneously higher energy expenditure coupled with lower food intake.

There would indeed be a market for that, and you can bet that the possibility hasn't escaped the metabolics groups at the large companies. At almost the same time, in fact, a group at Merck published a very similar study in obese mice with their own dual-agonist peptide, and saw the same sort of thing: weight loss, improvement in metabolic markers, decreased fat mass, the whole deal.

Now, what does all this mean for the state of the art? Merck wouldn't publish such interesting results without a good reason - you have to wonder if they're far enough along that they felt safe talking about such things, or (alternately) if there are clear problems with the approach that will keep this mechanism from ever being used. Nothing's shown up in the open literature about the latter possibility, as far as I can see. So the race would appear to be on. Is it?

Comments (19) + TrackBacks (0) | Category: Diabetes and Obesity

August 21, 2009

Obesity Shows Up in the Death Rate? Right?

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Posted by Derek

Here's an interesting post at Chemiotics (a new addition to the blogroll): Something is Wrong With the Model

. . . The Center for Disease Control released new data for 2007 (based on 90% of all USA death certificiates) showing that mortality rates dropped again (by over 2%) to 760/100,000 population. It’s been dropping for the past 8 years, and viewed longer term is half of what it was 60 years ago. Interestingly death rates from heart disease dropped a staggering 5% and even cancer dropped 2%.

But the populace is fat and getting fatter. . .

The heart disease death rate is particularly interesting. One explanation, which we can't rule out, is that these improvements are due to other factors (which the post goes on to elaborate), and that the improvement would be even more impressive if everyone weren't packing on the pounds. Another possibility is that excess weight, up to a point, may not have as big an effect on mortality and morbidity as we've been thinking it does.

That's a real possibility, and it's been looked at in the context of these sorts of public heath figures. The current use of BMI, at the very least, doesn't seem to be that useful in that regard. Only the high end of the BMI envelope (>30) seems to show much of a meaningful health effect. Of course, there are other costs to being obese, but (up to a point) bad health may not be one of the major ones. As for what this means to the current health care proposals, you can go here for the arguing.

Comments (24) + TrackBacks (0) | Category: Diabetes and Obesity | Regulatory Affairs

May 22, 2009

Arena, Lorcaserin, and the FDA

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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 (9) + TrackBacks (0) | Category: Business and Markets | Clinical Trials | Diabetes and Obesity | Regulatory Affairs

May 18, 2009

Arena / Lorcaserin Update

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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

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

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Posted by Derek

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

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

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

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

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

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

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

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

March 31, 2009

A DPP-IV Compound Makes It Through

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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

Another Obesity Drug? Not Likely.

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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 (34) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity

March 17, 2009

Takeda Gets A Surprise

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Posted by Derek

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

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

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

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

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

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

February 26, 2009

Does Glucophage Make Alzheimer's Worse?

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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 (23) + TrackBacks (0) | Category: Alzheimer's Disease | Diabetes and Obesity | Drug Industry History | Toxicology

November 25, 2008

Avandia: Trouble, Run Head to Head

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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

CB-1 Obesity Drugs: Farewell to the Whole Lot

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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 (12) + TrackBacks (0) | Category: Diabetes and Obesity | Drug Development

October 31, 2008

Fructose In The Brain?

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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 (22) + TrackBacks (0) | Category: Biological News | Diabetes and Obesity | The Central Nervous System

October 2, 2008

Taranabant Is No More

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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.

Comments (15) + TrackBacks (0) | Category: Diabetes and Obesity | Drug Development | The Central Nervous System | Toxicology

July 15, 2008

Metabolic Hope Springs Eternal

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Posted by Derek

Now, if I were still doing metabolic disease work, I'd be all over this target: CAMKK2, which is mercifully short for "Ca2+/calmodulin-dependent protein kinase kinase 2". (Kinase nomenclature has been out of hand for years, in case you're wondering).

CAMKK2 is right in the middle of a lot of pathways that are known to be important for regulation of appetite and glucose levels, namely ghrelin, AMPK, and NPY. These have been rather hard to approach directly with small molecules, or (in the case of NPY) hitting them hasn't been enough by itself. That's the problem with a lot of potential therapies for obesity, as I've mentioned here before. As a behavior, eating is full of overlapping backup redundant pathways, since we're all descendants of creatures that ate whatever they could, whenever they could. The ones whose feeding could be easily shut down or interrupted didn't make it this far.

So even though the field is littered with things that haven't worked out, perhaps a target like this, which seems to be more upstream, might have a better chance of success. We're definitely going to find out. Given the number of companies interested in this area, and the number with kinase expertise, someone's going to be able to take a good swing at this one. The benefits might go beyond weight loss - animals given a known inhibitor (STO-609, a Sumitomo compound) were also resistant to the bad effects of a high-fat diet, putting on less weight than controls and showing better glucose control.

Of course, the fact that Sumitomo had a compound years ago that hits this target so well makes you wonder what ever happened to it. I can't find much about why it didn't progress, but you can be sure that other people are asking that same question right now. . .Update: see this comment for more on this topic. . .

Comments (11) + TrackBacks (0) | Category: Diabetes and Obesity

June 18, 2008

All The Fat Cells You'll Ever Have - Sort Of

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Posted by Derek

I’ve done a fair amount of work against drug targets for metabolic disorders, so a recent letter in Nature caught my eye. The authors have used an ingenious technique to determine the number and age of the adipocytes (fat cells) that an individual has, and have tracked that cell population year by year.

One thing that comes out is confirmation of the fact that people basically set their number of fat cells during childhood and/or adolescence, and that number is then constant through their adult life. Several subjects in this study put on or took off weight during it, but that made no real difference to their number of adipocytes. And though liposuction does reduce the number of fat cells (by brute force!), they’re back to their original count after three years or so. So weight changes, as other studies have also indicated, are almost entirely due to individual fat cells becoming larger and smaller.

But that doesn’t mean that you’ve got the same fat cells all the way through. Most interestingly, this study found that about 8% of the adipocyte population turns over every year, which is a higher fraction than anyone realized. Half the fat cells in the body, then, have been replaced after about eight years have gone by. That also means that the stable total number results from a balance between adipocyte death and new cell formation, and it would certainly be interesting to know how these are tied together so well. The authors suggest that this relatively high turnover could be a potential target for weight loss drugs. If we could figure out how, say, to keep the fat cell population from being renewed so exactly, their numbers might naturally decrease. (On the other hand, perhaps the rate at which they die would drop to keep the balance – no one knows yet).

So, how do you tell how old a fat cell is, anyway? That’s the ingenious part I mentioned above, and it involves the same sort of techniques used in radiocarbon dating. The amount of carbon-14 in the atmosphere is relatively constant, with a few minor variations over the last fifty thousand years or so. Well, relatively constant except for the 1950s and 1960s, when we as a species reset the counter but good by atmospheric testing of atomic and nuclear weapons. Those tests released a much larger than usual amount of 14C into the world - in 1963 the count had doubled over normal background - and that's since cycled into the biosphere through uptake by plants and other living creatures.

That process has sent the atmospheric levels of radioactive carbon down steeply over the years, but there’s plenty of signal to detect, and we know just how much it’s gone down every year. In effect, every year of the last 50 or 60 has an anomalous carbon-14 reading, and each one is unique and vintage-dated. We take up the carbon through our food, and as a cell is formed, the particular carbon isotope signature of your body at the time is in all its parts. Many of these are recycled constantly – but the DNA isn’t. Extracting the DNA from cells and looking at the carbon-14 levels through mass spectrometry gives you a “production date” stamp for when that cell was born. (See here for a longer discussion of carbon isotope mass spectrometry as it relates to detection of banned steroid hormone use, specifically in the Floyd Landis case. That post, by the way, led to the longest comment thread ever seen on this blog). The same technique is being used for other cell populations as well.

The confirmation that the number of fat cells seems to be set before adulthood also ties in with the obesity trends seen in the general population. The great majority of obese adults were also obese as children, and the great majority of non-obese children do not become obese as adults. What factors set this adipocyte count in a person’s early life, and how many of them are environmental and could be modified, will be very useful to know. . .

Comments (7) + TrackBacks (0) | Category: Diabetes and Obesity

June 16, 2008

Alli: "Underwhelming"

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Posted by Derek

About a year ago, I wrote about GSK's attempt to sell the lipase inhibitor orlistat over the counter as Alli:

"So my forecast for Alli is strong sales - for a while. Then it takes a dive, never to scale those heights again, as the word gets out. And the demand continues to grow for a weight-loss drug that works. . ."

Thanks to Pharmalot, this week we find this AP story which seems to confirm that suspicion. Sales for Alli aren't up to GSK's hopes, and the company is declining to say how much repeat business there is after people have tried it out, which says all that needs to be said. And this after one of their biggest marketing campaigns ever.

What still throws me is that an analyst quoted in the piece still talks about it as a drug that should, in theory, be a big seller. As that post from last summer makes clear, I've never once understood that, since Roche never could make it a huge seller as Xenical. You'll never be able to get around the unpleasant side effects of a pancreatic lipase inhibitor, as far as I can see, and you'll never be able to advertise one without mentioning them.

I think that the new, slimmed-down GSK organization is wasting money on this whole idea. But hey, Marketing thinks it's a great opportunity. . .

Comments (12) + TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity

May 8, 2008

Merck Bails on Natural Products

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Posted by Derek

Every few years, you hear talk of a renaissance in natural products-based drug discovery. Well, this news should postpone the next round of optimism for a bit longer: Merck is cutting their natural products program entirely. They've had a long history in that area, but no more. That C&E News item includes an interesting detail:

"The company disclosed that it would also be closing its 50-year-old natural products drug discovery operation based in Madrid after a Merck executive inadvertently included the plan in a PowerPoint presentation to an audience that included Merck employees."

Smooth move. I'm sure some interesting e-mails were exchanged around Rahway and Madrid after that one. When, when will we get the powerful regulatory oversight of PowerPoint technology that the masses have cried out for these many years?

The main thing I remember about Merck's operation in Madrid was when they made a big splash about ten years ago with a weird looking indole/quinone thing that directly activated the insulin receptor. It made the cover of Science and all sorts of press releases, and my biology colleagues starting pestering me immediately. "Hey, you chemists keep saying that there's no point in running a small-molecule screen against the insulin receptor!"

Well, as it turned out, we were right. I assured my co-workers on the next floor that the Merck compound was one of the least likely drug candidate structures I'd ever seen, and that I'd be intensely surprised if it went anywhere. In fact, I told them, seeing it on the cover of Science actually decreased the likelihood that it was anything useful. If Merck really had a small-molecule insulin mimetic, I reasoned, the program would be a real stealth bomber, for fear of sending all sorts of other companies into the same chemical space too quickly. This one had all the signs of the people involved saying "You know, the only thing this stuff is good for is getting on the cover of Science"

So it proved, eventually. The compounds never went anywhere. It looks like the most recent natural product-derived compound that Merck got onto the market was Cancidas (caspofungin), and that was seven years ago. Mevacor (lovastatin) will stand as the modern high-water mark of Merck's natural product work - presumably from now on.

Comments (21) + TrackBacks (0) | Category: Diabetes and Obesity | Drug Industry History

April 25, 2008

Why Buy, Anyway?

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Posted by Derek

I don’t want to say that this is a trend, but I notice that GSK is saying that they’re going to leave Sirtris more or less alone as well (as Takeda has said they’ll do with Millennium). The researchers in both shops should feel good about that, and not only because they’ll be keeping their jobs. They’re getting a vote of confidence in the most meaningful way that a large company can give that to its employees: by paying you money and not messing with you.

Of course, these deals have two sides to them. I don’t know what it’s like in Takeda back in Japan – my contacts inside the Japanese pharmaceutical industry aren’t extensive. But I think that some of the people at GSK (where I do know a lot of people) are wondering just what motivated their company to spend $720 million on Sirtris rather than on them.

It’s a fair question, even though I don’t have a problem myself with the Sirtris deal (as I said yesterday). But the sirtuins themselves are targets that anyone can work on, and you’d assume that a big outfit like GlaxoSmithKline could, if they wanted to, make a big push into the area and find some interesting things. So why didn’t they? The most obvious reason would be Sirtris had already done a good deal of that work, and it was more economical for GSK to buy it than to redo it. Another possibility is that the chemical space for drug-like hits in that area may not be very spacious, and that Sirtris may have already carved out a good piece of that real estate.

There’s also a bit of Glaxo history to deal with. The company had already, about fifteen years ago, decided to make a great big push into a promising new research area: nuclear receptors. They set up a whole research institute and did a huge amount of good science trying to figure out how these things worked, what they were good for, and how to get drugs that affected them. I got interested in the field in the late 1990s, and it became clear to me very quickly that Glaxo’s effort was the most serious of the bunch (and that included some really substantial research going on at Merck, Lilly and some other outfits). The company had teams of people who seemed to do nothing else than study the structures of these things, generate reams of X-ray data, synthesize huge lists of ligand molecules of every kind you could want, and so on. Just run "Glaxo nuclear receptor" through PubMed to see what I mean.

And what did it get them? From what I can see, not much. Avandia (rosiglitazone) is a nuclear receptor ligand (for PPAR-gamma), but its activity had already been discovered, and it was in clinical trials without a known mechanism. Figuring out how it worked was one of the Glaxo team’s early triumphs. But Avandia has turned out to be famously troublesome, and no others have come to market, despite multiple tries in the clinic. The huge amount of time and money the company spent generated a lot of interesting science, but appears (at least to me) to have brought in not one dime of revenue. (No doubt someone from GSK will correct me if I’m wrong).

So you can see how the company might be wary of starting a big internal effort to explore a massive, complex, and risky new field of biology. Politically and psychologically, it’s probably easier for them to structure this in terms of an acquisition.

Comments (15) + TrackBacks (0) | Category: Aging and Lifespan | Business and Markets | Diabetes and Obesity | Drug Industry History

April 10, 2008

Exubera, Safety, and No Guarantees

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Posted by Derek

As mentioned yesterday, I would have to say that Mannkind is in big trouble. I’d never heard of the company until the Wonder Drug Factory was closing back in Connecticut, but Mannkind was moving some of their operations into the state around then and interviewed a number of my former colleagues.

The whole inhaled-insulin idea had already taken some pretty severe blows. The massive failure of Exubera was the biggest, although a creative person could always argue that a better product with a more convenient delivery system could succeed in its place. But then Novo Nordisk and Eli Lilly (serious diabetes players, both of them) got out of the area before they’d even launched, deciding that it was better to write off their whole investment than to try to bring it to market. That didn’t help, which is one reason that Mannkind stock was down in the single digits, despite the company's efforts.

Well, as of yesterday it’s down in the really low single digits. And I honestly can’t see how they’re going to revive their flagship program if the Pfizer lung cancer data are real. The FDA is going to be very, very cautious about allowing any sort of inhaled insulin trials to proceed. I’d think that you’d have to show that your product is different from Exubera in its carcinogenic risk just to get one off the ground, and frankly, I have no idea how you’d do that. Anything that could will take years to develop and validate.

This latest result also shows some of the real difficulties and risks of drug development. After all, Pfizer and Nektar spent a very long time developing Exubera. The product was delayed and delayed while more and more clinical work was done. But in a slow-starting condition like lung cancer, those years may still not enough to quite pick things up by the time a product makes it to market. Think of what might have happened if Exubera had been a success. . .

And that brings us back to the regulatory pre-emption topic of the other day. This illustrates why either extreme of that argument is untenable. On the make-‘em-pay side, you have trial lawyers arguing that if companies just wouldn’t put defective products on the market, well, they wouldn’t have anything to worry about, would they? Test your drugs correctly and things will be fine! But Exubera’s pre-approval life was as long and detailed as could be. The testing went on and on – and after all, insulin itself has been on the market for more than half a century. What more would a company need to say something is safe?

Then there’s the other side – total pre-emption, which says that the FDA is there to regulate and sign off on safety and efficacy, and by gosh we should have them do it. Once this mighty agency gives its stamp of approval, that settles it. But again, the FDA put Exubera through all kinds of paces. If every drug took that long and cost that much to develop, we’d be in even worse shape than we are now, believe me. So what’s the agency to do?

The truth, as far as I can see, is that no one can guarantee the safety of a new drug. If you want to take that further, guaranteeing the safety of an existing drug isn’t possible, either. Every known drug is capable of causing trouble at some dose, and every known drug is capable of causing trouble at its normal dose in some people. Every new drug has the possibility of doing things no one ever anticipated, once it gets into enough patients for enough time. Every single one.

Complete safety doesn’t exist, and never has. You can have more safety, if you’re willing to take enough time and spend enough money. But you can take all the time we have on earth, and spend all the money available, and you still won’t be able to promise that nothing bad will ever happen. Pretending that either the drug companies or the regulatory agencies can make that fact go away is a position for fools and demagogues.

Comments (12) + TrackBacks (0) | Category: Diabetes and Obesity | Drug Development | Toxicology

April 9, 2008

And You Thought Exubera Was A Disaster Before

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Posted by Derek

I don't usually do more than one post a day, but this really caught my eye. In an ongoing review of Pfizer's (now discontinued) inhaled insulin (Exubera), an increased chance of lung cancer has turned up among participants in the clinical trials. Six of the over four thousand patients in the trials on Exubera have since developed the disease, versus one of the similarly-sized control group. Six isn't many, but with that large a sample size, it's something that statistically can't be ignored, either.

The concerns would have to be, naturally, that this number could increase, since damage to lung tissue might take a while to show up. This, needless to say, completely ends Nektar's attempts to find another partner for Exubera. Their stock is getting severely treated today (down 25% as I write), but things are even worse for another small company, Mannkind, that's been working on their own inhaled insulin for years now (down 58% at the moment).

There's no guarantee that another inhaled form would cause the same problems, but there's certainly no guarantee that it wouldn't, either. Whether this is an Exubera-specific problem, an insulin-specific one, or something that all attempts at inhaled proteins will have to look out for is just unknown. And unknown, in this case, is bad. It's going to be hard to make the case to find out, if this is the sort of potential problem waiting for your new product. Inhaled therapeutics of all sorts have taken a huge setback today.

Comments (20) + TrackBacks (0) | Category: Cancer | Clinical Trials | Diabetes and Obesity | Toxicology

April 3, 2008

Whose Guess Is Better?

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Posted by Derek

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

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

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

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

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

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

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

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

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

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

March 12, 2008

Taranabant in Trouble?

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Posted by Derek

Well, I wish I hadn’t been right about this one. Last month I spent some time expressing doubts about Merck’s new obesity drug candidate taranabant, a cannabinoid-1 ligand similar to Sanofi-Aventis’s failed Acomplia (rimonabant). S-A ran into a number of central nervous system side effects in the clinic, and although they’ve gotten the drug approved in a few markets, it’s not selling well. US approval, now long delayed, looks extremely unlikely.

I couldn’t see why Merck wouldn’t run into the same sort of trouble. If a report from a Wall St. analyst (Aileen Salares of Leerink Swann) is correct, they have. Merck’s presenting on the compound at the next American College of Cardiology meeting (at the end of this month in Chicago), and information from the talk has apparently leaked out in violation of the ACC's embargo. There appears to be some difficulty both on the efficacy and side effect fronts – bad news all around.

The company was aiming for a 5% weight loss, but only reached that at the highest dose (4 mg). The report is that CNS side effects were prominent at this level, twice the rate of the placebo group. The next lower dose, 2 mg, missed the efficacy endpoint and still seems to have shown CNS effects. According to Salares, nearly twice the number of patients in the drug treatment group dropped out of the trial as compared to placebo, citing neurological effects which included thoughts of suicide.

While there’s no confirmation from Merck on these figures, they’re disturbingly plausible, because that’s just the profile that got rimonabant into trouble. If this holds up, I think we can say that CB-1 ligands as a CNS therapeutic class are dead, at least until we understand a lot more about their role in the brain. Two drugs with different structures and different pharmacological profiles have now run into the same suite of unacceptable side effects, and the main thing they have in common is CB-1 receptor occupancy. There’s always the possibility that a CB-1 antagonist (or inverse agonist) might have a use out in the periphery – they could have immunomodulatory effects – but anyone who tries this out would be well advised to do it with a compound that doesn’t cross the blood-brain barrier.

And as for taranabant, if the data are as reported I don’t see how Merck can get this compound through the FDA. Even if they did, by some weird accident, I don’t see why they’d pull the pin on such a potential liability grenade. Can you imagine what the labeling would have to look like in order to try (in vain, most likely) to insulate the company from lawsuits? That makes a person wonder how on earth the company could have been talking about submitting it for approval later this year, which is what they were doing just recently. They must have had these numbers when they made that statement – wouldn’t you think? And they must have immediately realized that this would be trouble – you’d think. If that Leerink Swan report is correct, the company’s recent statements are just bizarre.

Comments (32) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | The Central Nervous System | Toxicology

March 4, 2008

Off Target? Which Target Did You Mean?

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Posted by Derek

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

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

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

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

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

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

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

February 25, 2008

More On Merck and Taranabant

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Posted by Derek

My piece on Merck last week seems to have touched a few nerves, if some of the comments and e-mails I’ve received are any sign. To clarify things: I agree that Merck is still doing some excellent science, as they always have. And they still have a lot of good people there, as they always have. Those aren’t the problems. And they’re still introducing some innovative drugs, arguably more than a lot of other companies, and that’s not the problem, either. These are all are admirable things.

And Vioxx, as I said here at the time, was not, in my opinion, necessarily a bad drug. It and the other COX-2 inhibitors have a real place in the pharmacopeia. The problem is that Merck – or, to put the usual face-saving perspective on it, Merck’s marketing department – oversold the stuff. The prospect of an aspirin-sized market was too much for them to resist, so the company pushed Vioxx just about as hard as they possibly could.

Yep, Vioxx was for all kinds of patients, all kinds of pain, all the time – and under those conditions, whatever side effects were there were finally revealed. It’s the company’s bad luck (not to mention the bad luck of their patients) that those effects were as potentially severe as they were. Even so, the increased risk of a heart attack with Vioxx use is extremely small in any absolute sense. For people with severe pain who can’t get relief with other drugs, I think a COX-2 inhibitor is absolutely worth it.

But that’s not what you’d think from reading the newspapers, or from listening to the lawyers. It was expedient to paint the company as a bunch of callous poisoners; Merck’s reputation has been hooked to the back of a pickup truck and pulled through a swamp. (They didn't always do themselves much good during that period, either). And while the good name was bouncing off the tree stumps and scooping up the mud, the company had to spend vast amounts of money to deal with all those lawsuits, which is money that presumably could have been used for something else. (OK, some of that is coming from insurance – but think of how much more they’ll be paying for that coverage now).

Which is what worries me about taranabant. I realize, as several commenters to the previous post pointed out, that it may well differ in selectivity and CB-1 receptor activity from rimonabant. If the compound is an inverse agonist instead of an antagonist at the receptor, that could well be good news. Or, you know, it might not be, since we have no idea of what an inverse agonist will do, either. (More on the difference between those terms in a future post). At any rate, discovering new things about human CNS functions while a bunch of lawyers watch doesn’t sound like a good idea. If Merck does end up going down the Vioxx path again, another run through the swamp will do it no good at all.

Comments (26) + TrackBacks (0) | Category: Diabetes and Obesity | The Dark Side

February 20, 2008

What You Become Known For

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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. . .

Comments (20) + TrackBacks (0) | Category: Diabetes and Obesity | Drug Development | Drug Industry History | The Dark Side

January 18, 2008

Eat It, Breath It, Soak in It?

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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.

Comments (3) + TrackBacks (0) | Category: Diabetes and Obesity | Drug Development | Pharmacokinetics

December 5, 2007

Avandia: Going Under for the Third Time?

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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.

Comments (8) + TrackBacks (0) | Category: Biological News | Diabetes and Obesity | Toxicology

November 28, 2007

Bad Luck For Novartis - And For Diabetics

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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?

Comments (34) + TrackBacks (0) | Category: "Me Too" Drugs | Diabetes and Obesity | Drug Development

November 19, 2007

Depressing Figures for Acomplia

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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.

Comments (6) + TrackBacks (0) | Category: Diabetes and Obesity

October 22, 2007

Surveying the Exubera Crater

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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".

Comments (19) + TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity | Drug Industry History

September 6, 2007

More Things Than Are Dreamt Of

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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.

Comments (3) + TrackBacks (0) | Category: Biological News | Diabetes and Obesity

August 9, 2007

Buying What You Can't Make? Or What?

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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?)

Comments (7) + TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity

August 8, 2007

Exubera Spirals Toward the Drainpipe

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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?

Comments (19) + TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity

July 23, 2007

Deactivation, After All

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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.

Comments (2) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | Drug Development

July 17, 2007

Visfatin: Real Or Not?

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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.

Comments (4) + TrackBacks (0) | Category: Biological News | Diabetes and Obesity | The Dark Side

June 18, 2007

Right Down the Alli

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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. . .

Comments (49) + TrackBacks (0) | Category: Diabetes and Obesity

June 15, 2007

Rimonabant: Down to Earth

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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.

Comments (29) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | The Central Nervous System | Toxicology

June 11, 2007

Rimonabant, Out In the Light

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Posted by Derek

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

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

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

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

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

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

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

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

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

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

May 31, 2007

The Avandia Wars Continue

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Posted by Derek

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

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

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

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

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

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

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

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

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

May 25, 2007

More Avandia, And More on Marketing

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Posted by Derek

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

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

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

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

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

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

May 24, 2007

Avandia: Trouble or Not?

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Posted by Derek

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

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

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

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

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

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

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

April 11, 2007

Exubera: This Time With Feeling

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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.

Comments (7) + TrackBacks (0) | Category: Diabetes and Obesity

March 30, 2007

Rimonabant, Slowly

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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. . .

Comments (6) + TrackBacks (0) | Category: Diabetes and Obesity

November 1, 2006

You Can't Make Money If You Don't Get Paid

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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.

Comments (3) + TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity

October 17, 2006

Up Periscope And Fire All Bow Tubes

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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.

Comments (6) + TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity

October 5, 2006

The Inscrutable French

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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

Neuropeptide Y Dies, But It Never Surrenders

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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?

Comments (0) + TrackBacks (0) | Category: Diabetes and Obesity

September 6, 2006

Tell 'Em You Work On Something Else

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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. . .

Comments (22) + TrackBacks (0) | Category: Cancer | Diabetes and Obesity

June 29, 2006

Rimonabant Arrives

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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.

Comments (12) + TrackBacks (0) | Category: Diabetes and Obesity

February 24, 2006

What's French for "Trust Us"?

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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?

Comments (12) + TrackBacks (0) | Category: Diabetes and Obesity

February 20, 2006

Rimonabant Bangs Into. . .Something

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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?

Comments (5) + TrackBacks (0) | Category: Diabetes and Obesity

February 15, 2006

Pfizer Takes a Deep Breath

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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. . .

Comments (18) + TrackBacks (0) | Category: Diabetes and Obesity | Drug Prices

November 29, 2005

Ghrelin and Obestatin

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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. . .

Comments (18) + TrackBacks (0) | Category: Diabetes and Obesity

October 28, 2005

Pargluva Goes Down?

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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

This Had Better Be Good

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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?

Comments (6) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | The Dark Side

October 18, 2005

Waiting for Pargluva

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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

Muraglitazar's Turn

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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 . . .

Comments (7) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity

August 23, 2005

Gritting Our Teeth

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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?

Comments (3) + TrackBacks (0) | Category: "Me Too" Drugs | Clinical Trials | Diabetes and Obesity

March 17, 2005

Symlin, At Last

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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

Worries about Rimonabant?

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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.

Comments (9) + TrackBacks (0) | Category: Diabetes and Obesity | Drug Development | Toxicology

July 19, 2004

Bungee Jumping with PPAR Drugs

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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. . .

Comments (2) + TrackBacks (0) | Category: Cancer | Diabetes and Obesity | Drug Development | Toxicology

May 10, 2004

Why Own the Car, When You Can Own the Road?

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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.

Comments (6) + TrackBacks (0) | Category: Diabetes and Obesity | Patents and IP

November 19, 2002

Ah, Marketing

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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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October 24, 2002

Of All Sad Words. . .

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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

Fighting City Hall

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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

A Treadmill Pill?

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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

Enzymes, Right and Wrong

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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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