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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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« Rimonabant, Out In the Light | Main | Access To Science »

June 15, 2007

Rimonabant: Down to Earth

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Posted by Derek

Everyone will have heard the news about Wednesday's FDA Advisory Commitee vote on Accomplia / Zimulti (rimonabant). If you'd tried to convince folks a few years ago that this drug wouldn't make it to a vote until summer of 2007, and would be unanimously rejected when it did, you'd have been looked at with pity and concern. No, this drug was going to conquer the world, and now people are talking merger-of-desperation.

Hey, you don't even have to go back a few years. Here's an article from 2006:

"A new anti-obesity pill that market observers say could become the world's biggest-selling drug is close to getting approval from the European Commission. . .

Gbola Amusa, an analyst with research firm Sanford C Bernstein, said that Acomplia could achieve $4.1bn in annual sales by 2010, in part because it has been shown in clinical trials not only to trim fat but to increase levels of good cholesterol and control diabetes.

"In the blue sky scenario, this could become the world's best- selling drug as the indication is so broad," he said. "It has a path to revenues that we rarely ever see from a pharma product."

Oh, the blue sky scenario. I'm no stranger to it myself - I love the blue sky scenario. But how often does it ever descend to earth? It's not going to do it this time. Sanofi-Aventis was reduced to making the suggestion that every potential patient be first screened for depression, which doesn't sound like the sort of iron wrecking ball that usually gets welded to the world's best-selling drugs.

In the wake of this development disaster, here are a few points that may not get the attention they deserve: first, consider the money that S-A has spent on this drug. We're never going to be shown an accurate accounting; no one outside the upper reaches of the company will ever see that. But I seriously doubt if they've ever spent more on any program. There's an excellent chance that most of it will never be recovered, not by rimonabant - it'll have to be recovered by whatever drugs the company can come up with in the future. They'll be priced accordingly.

Second, think about the position of their competitors. All sorts of companies have pursued this wonder blockbuster opportunity. If you run CB-1 antagonists through the databases, all kinds of stuff comes hosing out. Merck and Pfizer are the companies that were most advanced - you don't get much more advanced than Phase III clinical trials - but plenty of others spent time and money on the chase. All of those prospects have taken grievous damage. Odds are that rimonbant's problems are mechanism-related, and proving otherwise will be an expensive job. This is something to consider when you next hear about all those easy, cheap me-too drugs.

And finally, it's worth thinking about what this says about our abilities to prosecute drug development in general. Just as in the case of Pfizer's torcetrapib, we have here a huge, expensive, widely anticipated drug that comes down out of the sky because of something we didn't know about. It's going to happen again, too. Never think it won't. This is a risky, white-knuckle business, and it's going to be that way for a long time to come.

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


COMMENTS

1. Todd on June 15, 2007 11:24 AM writes...

Many lessons to be learned here. I'm struck by the fact that Sanofi never shared the 'approvable' letter they got from FDA the first time. Buyer beware when a company's not willing to show investors such a letter.

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2. Hap on June 15, 2007 2:53 PM writes...

Doesn't the size of these costs imply that trying to shift drug costs from insurance companies to individuals won't be effective (or rather, that it won't fix the system)?

If the costs of drugs are driven by demand, than lowering demand by forcing individuals rather than insurance to pay for drugs might be effective in making drug costs cheaper (or at least resemble their actual costs). In this post and others before it, the costs of finding drugs, testing them and getting them approved, and paying for drugs that don't work the ways they were intended to work are implied to be large in magnitude. Since drug development costs have to be paid in addition to material costs in order for the makers of drugs to simply break even, these costs have to be paid by the purchasers of drugs. In the absence of insurance, fewer people would probably be able to buy the drugs; this would imply that drug costs per purchaser would likely rise.

The rise in drug costs per purchaser would be mitigated if a large portion of pharmaceutical company expenditures were in advertising and sales; a smaller market might mean that less could be spent on sales and advertising, thus decreasing the costs of selling the drugs, but unless they dominate drug costs, it would likely not decrease the prices of drugs relative to their current levels.

I assume that I am missing something. What is it/are they?

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3. Submarine on June 15, 2007 4:19 PM writes...

> Odds are that rimonbant's problems are mechanism-related,
> and proving otherwise will be an expensive job.

Agreed, however Merck has recently shown that many of these cannabinoid (CB) "antagonists" including I believe rimonabant are actually inverse agonists. There remains the possibility that a true antagonist will dissociate the desired antiobesity effect while minimizing undesirable behavior effects such as suicide.

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4. Submarine on June 15, 2007 4:32 PM writes...

In some sense, the adverse CNS effects of rimonabant should not surprise anyone. Think about the effects of marijuana. It gives you the munchies and induces mild euphoria. So what happens when you antagonize that effect? Appetite suppression (good) and opposite of effect of euphoria (bad). What might the opposite effect of euphoria be? Hmmm, depression?

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5. Tom Womack on June 15, 2007 5:53 PM writes...

Chemotherapy seems full of regimes where you take drug X, and then drug Y which covers some of the side-effects of drug X, and drug Z which covers some others, and nutritional supplement T which handles some of the accumulated side-effects of Y and Z.

I suppose anti-depressants are rather blunt instruments to apply to the side-effects of obesity drugs, but I had the impression that depression was something clinicians had good chemical weapons against - what am I missing in suggesting coprescribing rimonabant and Prozac?

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6. Engllish Major on June 15, 2007 8:19 PM writes...

Would someone be good enough to explain to a lay person the difference between a receptor antagonist (which I had thought rimonabant to be) and a receptor inverse agonist.

Thanks

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7. McPostdoc on June 15, 2007 9:57 PM writes...

They'll be priced accordingly.

Will they really? I don't know much about how companies determine the price of their drugs, but I would imagine that, for the most part, the price is set to maximize profit (just as in any other industry), and that this price is independent of profits/losses incurred because of other projects. If a company could just simply recover any lost R&D money by charging higher prices for future products, then what does that imply for a company coming off a long string of R&D successes? That it would price its drugs lower than the optimal price, simply because it felt like the company could do without the extra profit? That seems like a pretty silly argument to me.

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8. FaitAccompli on June 16, 2007 1:04 AM writes...

Firsthand account: I've taken R for over 6 months now with absolutely no (subjectively detected) deleterious side effects. I know euphoria; during this period, I have never experienced the least aspect of its opposite state (without any help from rosier than usual life circumstances).
The stuff works. My BMI has gone from 24.3 (was never officially overweight) to 22.2 as advertised, slowly but steadily. It's a big shame SNY management has been unable to persuade the keepers of our health gates in time (and they had plenty of it). Le coup de grace will probably be administered by the three Indian companies manufacturing the generic version for pennies a day.

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9. Submarine on June 16, 2007 1:22 AM writes...

Re: English major:
> Would someone be good enough to explain to a lay person
> the difference between a receptor antagonist

My apologizes, I should have done that in my original post. But here goes. And while I am at it, it would also help to explain what agonists and antagonists are.

agonists such as the endogenous endocannabinoids and the active constituent of marijuana delta-9-THC - exert a positive pharmacological effect - euphoria, analgesia, hunger, etc.

inverse agonists including at least some of the synthetically produced cannbinoid receptor ligands including apparently rimonabant - exert a negative pharmacological effect opposite those of agonists

antagonists - exert no pharmacological effects themselves but prevent binding of agonists (like endocannabinoids) or inverse agonists to the receptor

Finally ligands for a given receptor can have a spectrum of effects ranging from

- super agonists (a positive effect greater than the endogenous ligand)
- agonists
- partial agonists (a positive effect less than the endogenous ligand)
- antagonist - no pharmacological effect other than to prevent binding of agonists or inverse agonists
- partial inverse agonist - weak negative pharmacological effect
- inverse agonist - strong negative pharmacological effect

It is possible, but this remains to be proven in humans, that either a antagonist or partial inverse agonist might dissociate the desired pharmacologic effects of hunger and addiction suppression from the undesired side effect of depression.

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10. Submarine on June 16, 2007 5:23 AM writes...

Just to clarify my previous post, positive and negative pharmacologic effects do not necessarily to refer "good" or "bad" but rather effects in opposite directions. Using an automobile analogy, exposing a receptor to an agonist is like putting a car in forward gear and stepping on the accelerator, an inverse agonist puts the car in reverse and also steps on the gas, and finally an antagonist applies the breaks.

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11. Michael on June 16, 2007 6:26 AM writes...

I'm 65 and had gone from 75 to 92 kilos in 4-5 years for no discernible change in lifestyle.
I took Rimonabant for four months, without any change of other than eating habits, and ended up at 75-76kg, which has crept up to 78 after a number of family celebrations.
I had no side-effects other than increased farting, and I felt fitter and the lower back pain that had increased over the same 5 years more or less disappeared. I have doctors in the family, so am not ready to jump at every pharma solution, but I am not put off by this report, and would rather have continued for a couple of months, but I moved house and, after getting a month's supply from my new practice, I was seen by the senior partner, who wasn't prepared to continue prescribing, saying I had no need that outweighed the possible unknown long-term effects, and he wouldn't have prescribed in the first place.
I thought my system had unlearned the desire for more intake than physiologically necessary, but it has slowly returned, along with the, mild, "migraine-like" headaches I had worked out were triggered by eating less than I felt like eating, even though I eat at least as many calories as theory (and my pedometer) suggests I need. I certainly hope there'll be a drug, maybe "over the counter", at a price a pensioner can afford, that will suppress this.

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12. Submarine on June 16, 2007 6:31 AM writes...

RE: FaitAccompli

> I know euphoria; during this period,
> I have never experienced the least aspect of its opposite state

Excellent point and I have no doubt what you say is also applies to the vast majority of patients. If it didn't, rimonabant would never have made it past Phase III clinical trials. The problem is that for a small number of patients (probably only those with a significant predisposition for depression), the drug may have disastrous consequences. With all drugs, one needs to do a risk/benefit analysis. The health benefits of weight reduction are substantial, but how do you weigh that against a small, but statistically significant increases in the rate of suicide? Tough call.

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13. Fitness Health Zone on June 16, 2007 7:23 AM writes...

I don't people believe they will lose waiting for taking pill. It's not going to happen even if it happens then there will be side effect problems..may not be in short term but in future.

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14. Jumbo on June 16, 2007 10:43 AM writes...

Submarine:
Has there ever been pharmacological proof that a compound characterized in vitro as an inverse agonist actually functions that way in vivo? I have seen lots of posturing about inverse agonism, but to the best of my knowledge, their in vivo effects are not distinctive from simple antagonists.

While we are on the subject of drug mechanism, the path around rimonabant's problems might be negative allosteric modulation. This means a drug, rather than acting directly through the 'natural' ligand binding site, binds elsewhere on the receptor with the effect to dampen the agonistic qualities of the natural ligand...

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15. Submarine on June 16, 2007 11:52 AM writes...

Jumbo:

> Has there ever been pharmacological proof that a
> compound characterized in vitro as an inverse agonist
> actually functions that way in vivo?

The area I am most familiar with is the benzodiazepine receptor (BzR). Here compounds such as DMCM that have been characterized in vitro as inverse agonists most definitely have in vivo activities (convulsions) that contrast markedly with both antagonists (no apparent in vivo effect) and agonists (sedation). In addition, the partial inverse agonist Ro15-4513 has been shown to make rats resistant to the effects of alcohol whereas BzR antagonists have no such effect.

Negative allosteric modulation, while mechanistically distinct from antagonists, may nevertheless be functionally equivalent to antagonism. So if the rimonabant depression problem is linked to inverse agonism and if CB1 antagonists are free of this side effect, a negative allosteric modulator would in principle also be free of this side effect.

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16. BCP on June 16, 2007 2:58 PM writes...

Submarine, does the Merck publication show antagonism vs inverse agonism at the cellular level with rimonabant? Is there a difference in downstream signalling that could be indicative a difference between antagonism and inverse agonism?

The reason I ask is that the question of basal endocannabinoid activity/tone clouds the antagonist/inverse agonist debate when one simply considers pharmacology. In overweight patients, the endocannibinoid system is upregulated -- i.e. it has a sigificantly increased signal (increased receptor density and/or synthesis of endocannabinoids). So if you come in with a pure antagonist that completely blocks the body's own endogenous agonists then you have what appears to be an inverse agonist type response, simply because you block out normal activitation of CB1 and remove that background level of CB mediated pharmacology.

To submarine's initial point, if one partially antagonizes CB1 thereby restoring cannabinoid activity to the levels found in non-obese individuals, it wouldn't be unreasonable to think that you should see some efficacy with less side effects -- however it seems that lower doses studied by SNY were not effective clinically.

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17. FaitAccompli on June 16, 2007 6:08 PM writes...

Re: Submarine:
>With all drugs, one needs to do a risk/benefit analysis. The health benefits of weight reduction are substantial, but how do you >weigh that against a small, but statistically significant increases in the rate of suicide? Tough call.

Well, let's see. I am the developer of the first automobile. I thoroughly weigh the substantial benefits of higher speeds, comfort and power afforded a vast user majority against the small, but statistically significant risk of lethal road accidents. Tough call. Conclusion: forget the car; it's not an acceptable option. Let's keep looking for a safer alternative :-)

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18. Cole B. Emmett on June 17, 2007 12:21 PM writes...

The novel, Wondercillin, is now available for your perusal at:

http://finance.groups.yahoo.com/group/wondercillin/files/

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19. milkshake on June 17, 2007 5:34 PM writes...

The problem is the in the indication of the drug. A very dirty medication is acceptable as a cancer drug - you can get away with lots of nasty side efects as long as you help the cancer patients. And the patients take their anti-cancer drugs for a limited period of time.

A diet pill that is ment to be taken over 10+ years has to be exceptionaly safe. 1 in 5000 frequency of serious adverse effect is very hard to see in the clinic but it quckly adds up to lots of lawsuits. People kill themselves for outher reasons than medication-induced depression but all families of suicidal Rimonabant patients would have a very good case against Sanofi

One possible solution would be to combine Rimonaband with Wellbutrin, this antidepressant has a nice weight-reduction side-effect also. Too bad that wellbutrin can turn you into a laughing maniac. But wou could add lithium carbonate to the mix...

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20. BMI on June 18, 2007 7:14 PM writes...

Doesn't Sanofi have any anti-depressants that they can prescribe with Accompli?

Do both activities signal through the same signaling cascade?

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21. BCP on June 18, 2007 11:01 PM writes...

BMI, the only known "anti-depressant" that works through the same path is a generic that is delivered in a roll-up device that the patient must assemble themselves prior to dosing. As far as I know Sanofi doesn't sell it or the related liquid based delivery platform.

There does seems to be some cross talk with the opiate pathway, but it's not clear that that's an avenue you want to go down either - all that HPA axis stuff interfering with reward and motivation behavior

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22. BMI on June 20, 2007 7:33 PM writes...

BCP
I'm talking about the downstream effectors from the CB1 receptor - here's an example from another GPCR
Nicotinic Acid Receptor Agonists Differentially Activate Downstream Effectors

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