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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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In the Pipeline

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November 6, 2008

CB-1 Obesity Drugs: Farewell to the Whole Lot

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Posted by Derek

The painful saga of Acomplia (rimonabant) has finally come to an end. Sanofi-Aventis has announced that they're completely giving up on the drug. There was really no other option - the compound was never approved in the US, and was never going to be, and late in October the EU ordered it to be withdrawn from Europe. The psychiatric side effects which sank the drug's chances here were showing up in real-world use, and the risk/benefit ratio could no longer be seen as anything but negative.

And Pfizer has just announced that they're giving up work on their own Phase III compound in the area, CP-945,598. They're not citing safety concerns - and as Jim Edwards over at Bnet notes, that puts them in the odd position of saying that they have a safe, effective drug for a huge market that they're not going to do anything with. My guess is that the company is worried that the drug would indeed show an unfavorable safety profile, especially under the sort of scrutiny that any drug in this class would have by now, and that they decided to stop before things got to that point. Otherwise, you'd think that a big, safe, effective first-in-class obesity therapy would be just what Pfizer needs - wouldn't you?

So, goodbye to the CB-1 antagonists. I don't see much work going on in this area for some time to come, unless the pharmacology gets untangled to the point that someone can see a safe way through. There may well not be one.

And before we all try to forget that this all happened, let's spare a thought for the huge amounts of time, effort, brainpower and money that went into this area over the last eight or ten years. Three of the biggest research organizations in the industry have now flamed out trying to develop these drugs, and plenty of smaller players were trying, too, as a glance at the patent literature will make clear. The end result is that we have paid a gigantic amount of money to learn that the biology is more complicated than we thought, and it needed no ghost come from the grave to tell us this. If you think that drug development is a sure road to riches - if anyone still thinks that - then come survey this wreckage and think again.

And to finish, let's hop in the time machine and go back. . .well, not all that far. Just to mid-2006. There we find a world in which rimonabant was poised to become one of the biggest selling drugs in all the world, part of a wave of drugs which would transform the industry and spew profits in all directions. Billions of dollars in revenues are mentioned. Oh, dear.

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


COMMENTS

1. Jose on November 6, 2008 9:39 AM writes...

Priceless!

"It is the first of a new generation of drugs set to hit the market in the next few years that could transform obesity, still a small market, into a gold mine for the pharmaceutical industry."

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2. Jonathan on November 6, 2008 9:47 AM writes...

I'm still a little surprised they never saw any vascular side effects in addition to the neuro ones.

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3. RB Woodweird on November 6, 2008 12:56 PM writes...

Failure? What failure? These anti-obesity drugs took grossly fat profit projections and slimmed them down to emaciated supermodel-cadaverous size.

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4. T on November 7, 2008 11:29 AM writes...

Isn't this somewhat analogous to the PPAR drugs? Potential blockbusters for an ever-expanding market - some drugs withdrawn - troubling side-effects and whatnot leading to problems with the class? I remember not too long ago PPARs seemed all the rage.

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5. leigh on November 8, 2008 3:00 PM writes...

i attended a very good talk on the complications of cannabinoid based drugs in industry (for academics) that explained very concisely what is so painful about these major drug losses. it was much in line with the basics of drug development class i took several years ago but with numbers to indicate how completely screwed companies are. really, amazingly painful numbers. the simple fact that cb1 is so freaking ubiquitous in the brain should be enough to scream "potential side effects" if you ask me. i guess my focus in the field won't be quite so useful when i graduate!

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6. ThomasD on November 9, 2008 3:49 PM writes...

the simple fact that cb1 is so freaking ubiquitous in the brain should be enough to scream "potential side effects" if you ask me.

Potential adverse effects does not always mean product destroyer. But it is one of the reasons we do so much testing. Another ubiquitous neurotransmitters? Dopamine. Any guess how many drugs with significant dopaminergic activity are currently on the market?

But the current situation isn't so much a risk vs. benefit type of analysis, it's a liability vs. profitability analysis.

Given the endemic nature of obesity and type II diabetes - with all its associated morbidity and mortality the nuerologic effects of such agents, although marked, may not be unacceptable when weighed against the alternative costs. Of course compared to losing weight in a 'healthy way' most any pharmacologic intervention is going to look like a bad idea.

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7. lennyjoels on November 9, 2008 6:29 PM writes...

I'm disappointed that rimonabant or other CB1 antagonists will not be coming to market in the US. I have many morbidly obese patients who have failed diets and counseling and the alternative would be bariatric surgery. Effective bariatric surgery (gastric bypass) has at least a 0.2% mortality rate and a 40% complication rate. Surely rimonabant would be safer than that.

It seems that pharmaceuticals are held to higher standards than surgical techniques.

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8. Mack on November 10, 2008 1:34 AM writes...

While looking for alternatives to SSRI's for a friend of mine who had an adverse reaction I came across an internet site www.neuroassist.com which appears to be a physician run organisation that doesn't deal with the general public and hosts AMA courses to train other doctors and clinics in the use of the amino acid precursors for serotonin and dopamine (5-HTP and L-Tyrosine). It's principal Dr. Hinze, appears to be working in conjunction with the University of Minnesota Medical School.

It claims that use of its protocols achieve impressive results in patients for an astonishingly wide selection of ailments, including obesity.

Without going into the bona fides, claims, testimonials from doctors using the protocols etc, I am curious to know if others are of the opinion that the hunger that drives morbid obesity could be driven by a deficiency of neurotransmitters (or a failure to effectively utilise neurotransmitters in the body) and could thus be treated with no side effects by the amino acid therapy and protocols of the kind promoted on the site.

And just so you know, I have no affiliation with this company. They are based in the US, don't have any practitioners in Australia as far as I am aware and don't respond to any inquiries unless they are from a licensed medical practitioner.

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9. Selene on November 10, 2008 11:37 AM writes...

Mack -- Interesting idea, but as someone who actually is obese (lost 25 lbs over past year, still way more to go) I can say that many people become obese for behavioral reasons, as in eating when not hungry. When I really started paying attention I realized I was eating for all kinds of reasons other than hunger: stress, procrastination, husband still eating and wanted to keep him company. I think many people do this sort of thing occasionally, for instance, at a Mexican restarant you might keep just mindlessly putting chips in your mouth if you were very involved in the conversation and suddenly realize the bowl was empty.

That said, I guess all these various stress, urge to procrastinate etc. may themselves be neurologically addressable.

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10. Mack on November 10, 2008 6:24 PM writes...

Very true, Selene. I think even if neurotransmitters took the edge off extreme hunger, you'd still need a calorie counting program and retrain the brain to serve smaller portions. But sometimes you see people who are almost like food addicts and perhaps they need the sugars to surge their insulin to ensure enough trypophan gets into the brain to make themselves feel better. If you fulfilled that need with blood brain barrier crossing precursors like 5-HTP, they might stand a better chance of losing weight. Although others have tried this before, Neuroassist claims that you have to give both 5-htp and L-tyrosine together as they both use the same enzymes and giving one in isolation shuts down the other and ultimately the treatment won't work without both neurotransmitters reaching a balance.

I do marvel at the complexity of the human body. A friend of mine was doing research on diabetes and expressed the view to me that obesity was the main cause and if you lose weight, diabetes goes away. And of course, that's true. But when I asked about the underlying insulin resistance that may exist years before diabetes becomes a factor it wasn't something he'd even looked at.

Thin people can be highly insulin resistant, possibly from underlying low level systemic inflammation from some defect in the immune system or the HPA axis response and of course PCOS is one example where insulin resistance drives high insulin production followed by hormonal dysfunction, infertility and higher probability of cardiovasular events.

And yet some diabetes medications encourage higher insulin production by irritating the beta cells. It worries me that in one instance high insulin causes disease and hormonal dysfunction and in other we deliberately cause high insulin to treat high blood sugar. Sure, the blood sugar levels go down but at what cost? I don't know the answer and that worries me.

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11. leigh on November 10, 2008 8:49 PM writes...

"Another ubiquitous neurotransmitters? Dopamine. Any guess how many drugs with significant dopaminergic activity are currently on the market?"

i agree with the principle you bring up of liability vs profitability. i don't get the comparison between cb and da systems, though. we know the effects of tinkering with these two systems will be very different because they're set up in entirely different ways.

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