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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: Twitter: Dereklowe

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July 20, 2004

Worries about Rimonabant?

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Posted by Derek

Continuing on the theme of unexpected toxicity landmines, I wanted to take a look at a highly anticipated obesity drug from Sanofi. Rimonabant is a small molecule antagonist of the CB-1 receptor, and it's been getting a lot of press - both for its impressive efficacy and for its mechanism of action. The "CB" in the receptor name stands for "cannabinoid", and the drug blocks the same receptor whose stimulation causes the well-known food cravings brought on by marijuana.

Interestingly, blockade of this receptor not only seems to affect appetite, but also seems to help with cravings for nicotine. As you can imagine, the market potential for the drug could be immense (and as you can imagine, other drug companies are chasing the same biological target, too.)

But what else does an antagonist do? The receptor has, no doubt, several functions in the brain (all the CNS receptors do multiple duty), and it's scattered around in the nerves and other tissues as well. There have been a couple of reports that bear watching. A team of researchers (German/Italian/US) reported earlier this year that the CB-1 receptor seems to be involved in inflammation of the colon. Mice with the receptor knocked out show great susceptibility to chemical irritants in the gut, and (more disturbingly) the same effect was seen in normal mice treated with a CB-1 antagonist. The authors suggest that CB-1 may be involved in diseases like Crohn's and irritable bowel syndrome, but antagonists would, if anything, make the problem worse.

That's bad enough, but there's a potential disaster that just showed up last month. The authors report that a patient of theirs suddenly came down with multiple sclerosis after having been a subject in a rimonabant trial. Now, there's no way to prove causation, as they freely admit, but there's some evidence that CB-1 has a neuroprotective effect under normal conditions. So blocking its actions might conceivably expose neurons to damage, and when you combine that with the above potential role in inflammation, you have something that you should keep an eye on.

No one can say how this will play out. The most likely outcome is the best one - that the drug isn't associated with MS or Crohn's. After all, it's been through some extensive trials, and Sanofi still seems confident - which, believe me, they wouldn't be if a good fraction of the participants had come down with irritable bowel syndrome, much less multiple sclerosis. But there's another possibility, that the trouble will only show up in some patients under some conditions, and it might be rare enough that you won't see it until it gets out into the general population. There's just no way to run a clinical trial to nail down the statistics on, say, a one in 50,000 side effect. You'll never see it coming.

That MS report in particular must have the Sanofi people a bit worried, and I'm sure it has the attention of the other players in the area, who will be glad to let Sanofi go out and be the lightning rod in case anything bad happens. Odds are that it won't, but there are no sure things, not with this drug or any other. Honestly, it's years before you can relax in this business, if you ever do. Good luck, guys.

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


1. jsinger on July 21, 2004 5:34 PM writes...

Not that the FDA is likely to see it this way, but Michael Fumento's book on obesity mentioned a survey of formerly morbidly obese people asking them what they would rather suffer than go back to their old weight. Majorities, IIRC, said they'd rather lose a limb or go blind than return to their old weight. A weight-loss drug with good efficacy and a 1 in (say) 10,000 chance of MS would be a no-brainer for quite a few people.

This is also a case where wild claims from do-gooders have unexpected consequences. How many deaths does the CDC now claim obesity causes every year? Suddenly Sanofi's benefit/cost picture looks a lot better.

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2. John Johnson on July 21, 2004 8:24 PM writes...

I'd like to offer up the suggestion that we're playing with fire in the pharma industry anyway. Even with the pharmacovigilance guidelines recently passed and coming down the pike, the problem of rare, but serious, adverse events is real, and they are hard to detect even in a good clinical development program.

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3. Gil on July 22, 2004 10:14 AM writes...

Show me a drug that does not have rare but serious side effects. I agree, for most obese people and smokers who'd like some painless help to quit this is a no-brainer.

Consider Viagra - potential side effects include Angina pectoris, myocardial ischemia, cerebral thrombosis, cardiac arrest, even heart failure. Has it deterred usage?

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4. otey on July 22, 2004 11:16 AM writes...

How does the FDA weigh these things? If a new drug will cure obesity in 1MM people but cause 100 to contract MS, is that enough reward for the risk? What if the drug is likely to cure only .5MM people with the same MS incidence?

And what does the drug company do? Does it build into the price of its new obesity drug the anticipated costs of settling lawsuits with the people that contract MS?

Sorry if these are naive questions. just wondering.

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5. Derek Lowe on July 22, 2004 9:26 PM writes...

The FDA weighs risks and rewards when making approval decisions. But the safety bar for something like obesity is set pretty high, because there's always diet and exercise, at least for most of the people who are going to be taking the drug. As big a health problem as it is, it isn't a situation like, say, metastatic melanoma.

A real association with MS would torpedo rimonabant, I'm almost certain. But the thing is, there's not going to be a statistically valid association just based on the clinical trial data, unless the situation is really bad (and I don't think it is at all - Sanofi still sounds like this is their big blockbuster-in-waiting.)

And the issue then isn't so much the FDA as the trial lawyers. If there really is a connection with MS, and I fervently hope there's not, then the lawsuits will come down like hail: that baseball-size hail like they have in Oklahoma.

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6. John Johnson on July 22, 2004 11:03 PM writes...

If you're one of the 100 who contracted MS out of the 1MM people, then you'd probably say that the reward is not worth the risk. It's all a matter of perspective.

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7. otey on July 23, 2004 9:59 AM writes...

Thanks for the responses. Very helpful. Sounds like the FDA reboots the risk/reward analysis with every drug presented for review. No bright line rules; just difficult health policy calls on a case by case basis. I don't envy the people that have to make them.

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8. steve on July 27, 2004 10:20 PM writes...

Just another example of why information is better than regulation. On what basis does the FDA get to decide for patients their private risk/reward ratio? From a basic economic point of view, imposing a uniform risk tradeoff on heterogeneous consumers guarantees a welfare loss. Let the FDA certify drugs as "passes our particular risk/reward judgment" but let people market drugs that do not. A big "FDA certified" sticker would carry a lot of weight with doctors and patients, but people would still be able to use their own superior knowledge of their own situation. Would anyone want a goverment agency to dictate risk/reward for surgeries? The case for regulation there, from the standpoint of customer ignorance, is even stronger than for drugs, but no one would seriously consider it.

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9. Marty on July 30, 2004 8:49 PM writes...

If you're going to take a weight-loss drug for years and years, it had better be safe. Nastech Pharmaceutical (Nasdaq: NSTK) is developing a nasal spray drug using a naturally occurring human hormone, PYY 3-36. Your gut releases this hormone in response to food, which sends a satiety signal to the brain. They have finished phase 1, which excellent results. IMO, I'd rather have an all-natural product to help me lose weight.

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