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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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February 20, 2006

Rimonabant Bangs Into. . .Something

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Posted by Derek

Sanofi-Aventis basically has their future riding on their obesity therapy Acomplia (rimonabant), which was (until a day or two ago) expected to be approved before the middle of this year. But the FDA gave them one of those "Approvable, But. . ." letters which sow fear and confusion whenever they arrive.

The fear is self-explanatory, and the confusion comes because the letters don't have to be made public. No one knows what the FDA's concerns are, because Sanofi-Aventis doesn't have to say - yet. But in the case of a drug that was expected to be this big, and one that S-A's management was telling everyone just the other day was in fine, fine shape, they're going to have to come out with something soon or risk a complete loss of confidence and credibility.

There are quite a few possibilities, as this post at Pharmagossip lays out. I have to say, rimonabant has always made me a bit nervous, and that's not just hindsight talking. Back in 2004 I wrote about some possible bad side effects of the drug, and last year I worried in general about the problems of taking such a drug (huge buildup, huge market, totally new mechanism of action) to market.

You see, the problem is, I did the first half of my career in CNS drug discovery. Drugs that act on central nervous system receptors can do all kinds of odd stuff, and we most definitely do not know enough about brain chemistry to predict what those interesting surprises might be. The endocannabinoid receptor that rimonabant targets is very much an evolving story - it's even less worked out than the other brain targets. The thought of a CNS drug whose target is relatively less well understood than the others should be enough to make anyone gaze thoughtfully out the window for a bit.

The field has other brisk and tangy qualities. For example, the patient population tends to have an alarmingly heterogeneous response to CNS drugs, as a look at the antipsychotic and antidepressant markets will show you. Drugs that work fine for one person do nothing for another, and we don't yet know why. I can see no reason why rimonabant should be any different.

This FDA action may have borne out some of these fears, or it may be that Sanofi is just involved in an argument about a too-aggressive labeling proposal. Here's betting that they fill in some details real soon now. The longer they wait, the worse it'll be for them. By. . .Wednesday, I'd say?

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


1. Jonathan Gitlin on February 21, 2006 10:32 AM writes...

"The thought of a CNS drug whose target is relatively less well understood than the others should be enough to make anyone gaze thoughtfully out the window for a bit."

Surely it's just a return to the heady days of the 1940s, 50s and 60s? Back before all the low lying fruit had been picked and doctors handed out benzos and barbs like skittles?

I sometimes think being a pharmacologist must have been a little bit easier back then, not to mention more exciting.

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2. NJBiologist on February 21, 2006 6:37 PM writes...

"Drugs that act on central nervous system receptors can do all kinds of odd stuff, and we most definitely do not know enough about brain chemistry to predict what those interesting surprises might be."

We most definitely do not. In addition, we will not for some time to come. So we can either stop work or find ways to manage the risks. If I were running a big enough pharma, I'd probably go for a mixed-risk package (a me-too target, a target with no clinical data but a good preclinical package, and something fun). If I ran a small, one-program company, I'm not sure what I'd do.

#1: I think you'd enjoy some of PAJ Janssen's old papers. He does make it sound exciting.

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3. peej on February 22, 2006 10:22 PM writes...

We'll know Friday. Thats the day S-A stockholders have a conference call/meeting with management. I also heard that Acomplia will not be the brand name... apparently there are some safety issues surrounding it and the brand will have to be renamed.

I wonder if the 50% fdrop out rates in the trial is the issue with the FDA... or maybe the higher incidence of depression. I bet dysphoria is another problem- just makes sense, given the mechanism- but I havent seen that reported at all.

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4. Abel PharmBoy on February 23, 2006 10:10 AM writes...

Congratulations, Derek, on having your comments picked up by Scott Hensley in yesterday's WSJ. He even referred to you as Dr instead of Mr; an amazing feat since the WSJ style guide only uses Dr for physicians.

His story is that S-A was going after too many indications for a first-in-class compound.

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5. Jack Friday on February 27, 2006 6:12 AM writes...

So. It's now well past Derek's and peej's deadlines, and what do we now know?


From Acomplia Report:

"In the 'approvable' letter we received on rimonabant, no additional trial in obesity has been requested by the agency," Senior Executive Vice President Gerard Le Fur said. "We will meet with the FDA in the coming weeks to address remaining issues."

So what issues did the FDA raise?

"I am pretty sure you will understand I will not comment any more on rimonabant because we first need to meet with the FDA and work with them on rimonabant," Le Fur declared.

Well, guess what? While some financial analysts still seem willing to buy Sanofi's guidance du jour, others made it clear during the question-and-answer session at the end of the Feb. 24 briefing they do not understand Sanofi's refusal to explain what issues have been raised about their self-proclaimed "fantastic product."

Analyst after analyst refused to take "no comment" for an answer, and raised questions that one would have thought Sanofi might be motivated to answer if indeed the outstanding issues -- as a projected fall launch would suggest -- are relatively small.

Q. Do you have "updated thoughts" on whether Acomplia might have to be considered by an FDA advisory panel prior to agency action -- (a prospect many consider a near certainty given that rimonabant is a novel drug that targets receptors in the brain)?

A. Question is ignored by Spek.

Q. What about other use of the drug you filed on (ie, treatment of metabolic syndrome). Are they still under FDA review?

A. One more time, we are not discussing our discussions with the FDA. We just need to meet with the FDA and work with them on the dossier, and that’s all.

Q. When will we hear more from you about your discussions with the FDA?

A. First, we have to meet them, our first priority is to meet them, and to work on the dossier. It's too early to say.

Q. While no new studies are needed, is the FDA seeking further analysis of existing studies?

A. You can try to ask, that's all. We do not comment more.

Q. The FDA sent you a "non-approvable" letter on Acomplia for promoting smoking cessation but suggested you conduct a new study if you were still interested. Are you going to conduct such a study?

A. One more time, really sorry. Let us work and discuss this with the FDA. We do not want to comment more on rimonabant.

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