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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 se