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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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March 12, 2008

Taranabant in Trouble?

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Posted by Derek

Well, I wish I hadn’t been right about this one. Last month I spent some time expressing doubts about Merck’s new obesity drug candidate taranabant, a cannabinoid-1 ligand similar to Sanofi-Aventis’s failed Acomplia (rimonabant). S-A ran into a number of central nervous system side effects in the clinic, and although they’ve gotten the drug approved in a few markets, it’s not selling well. US approval, now long delayed, looks extremely unlikely.

I couldn’t see why Merck wouldn’t run into the same sort of trouble. If a report from a Wall St. analyst (Aileen Salares of Leerink Swann) is correct, they have. Merck’s presenting on the compound at the next American College of Cardiology meeting (at the end of this month in Chicago), and information from the talk has apparently leaked out in violation of the ACC's embargo. There appears to be some difficulty both on the efficacy and side effect fronts – bad news all around.

The company was aiming for a 5% weight loss, but only reached that at the highest dose (4 mg). The report is that CNS side effects were prominent at this level, twice the rate of the placebo group. The next lower dose, 2 mg, missed the efficacy endpoint and still seems to have shown CNS effects. According to Salares, nearly twice the number of patients in the drug treatment group dropped out of the trial as compared to placebo, citing neurological effects which included thoughts of suicide.

While there’s no confirmation from Merck on these figures, they’re disturbingly plausible, because that’s just the profile that got rimonabant into trouble. If this holds up, I think we can say that CB-1 ligands as a CNS therapeutic class are dead, at least until we understand a lot more about their role in the brain. Two drugs with different structures and different pharmacological profiles have now run into the same suite of unacceptable side effects, and the main thing they have in common is CB-1 receptor occupancy. There’s always the possibility that a CB-1 antagonist (or inverse agonist) might have a use out in the periphery – they could have immunomodulatory effects – but anyone who tries this out would be well advised to do it with a compound that doesn’t cross the blood-brain barrier.

And as for taranabant, if the data are as reported I don’t see how Merck can get this compound through the FDA. Even if they did, by some weird accident, I don’t see why they’d pull the pin on such a potential liability grenade. Can you imagine what the labeling would have to look like in order to try (in vain, most likely) to insulate the company from lawsuits? That makes a person wonder how on earth the company could have been talking about submitting it for approval later this year, which is what they were doing just recently. They must have had these numbers when they made that statement – wouldn’t you think? And they must have immediately realized that this would be trouble – you’d think. If that Leerink Swan report is correct, the company’s recent statements are just bizarre.

Comments (32) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | The Central Nervous System | Toxicology


COMMENTS

1. sroy on March 12, 2008 9:30 AM writes...

It is disconcerting to watch a very well regarded company like Merck put drugs such as rofecoxib, ezetimibe, etoricoxib, gaboxadol in Phase III and beyond.

Now we have taranabant even though they knew about rimonanbant. To the best of my knowledge the data on torcetrapib has not stopped merck from going ahead with anacetrapib.

Forget about the laypersons image of merck, what are the investors thinking? That is all I have to say about this unfortunate episode.

Permalink to Comment

2. Anonymous on March 12, 2008 9:43 AM writes...

What is wrong with ezetimibe? One of the safest drugs on the market! And rofecoxib safer than many with real clinical benefits. I do agree the ...cetripibs seem like are huge gamble at great cost.

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3. A-non-y-mous on March 12, 2008 10:09 AM writes...

Acomplia got the approvable letter in mid-late 2006, and facts didn't really start rolling in from S-A until mid-2007 - somewhere along those lines.

By then, Merck was already in a 2-year safety and efficacy study: 2400 patients, start in July 05, end in Dec 07. They also had several other phase II and III studies going on at that time. We're talking probably 100+ kilos of taranabant having been made and lots of $$$ in trials.

Do we expect them to pull the plug because of S-A data? If they were in phase-I, sure, but not when they are in phase-III and beyond. So they do what they are supposed to do: run the trials, get the results, make decisions, let the FDA shoot them down.

Let's not pile on too much. Would you want to be the one to pull the plug on a $250 million investment based on S-A data, or would you ride it out for an extra $50 million and take your chances? [numbers are from Enron - i.e. made up] Come to think of it, more pharmas should be based in Vegas - it's all a crapshoot.

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4. Insider on March 12, 2008 10:45 AM writes...

Dont forget Pargluva!

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5. Phil on March 12, 2008 12:14 PM writes...

"The company was aiming for a 5% weight loss".

Only 5% weight loss? I don't know much about obesity treatments, is it what people are typically aiming for in this market, or is this value only relevant to this trial?

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6. 7374e9 on March 12, 2008 12:17 PM writes...

Re: #3 saying 'Come to think of it, more pharmas should be based in Vegas - it's all a crapshoot.'

If "Skeptic" was around he'd probably say that pharma should all be based in California and do more of mathematical modeling of Drug and Disease. Try out your disease-drug interaction scenarios in the computer first. Rational drug development, anyone?

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7. gattsuru on March 12, 2008 3:44 PM writes...

Only 5% weight loss? I don't know much about obesity treatments, is it what people are typically aiming for in this market, or is this value only relevant to this trial?

It looks like the 5%/year number was used for rimonabant and lorcaserin as well, and it seems like a reasonable value to use. It's significantly far from the effects of placebo, since only one in fifty of those on placebo for lorcaserin's one-year test lost that much weight, and it's not particularly likely to be a threat to the health of those individuals. Rimonabant had a 39% of those taking it lose 10% of their body weight over a year; I can't say one way or the other for lorcaserin or taranabant's numbers with what information I could scrounge up.

I expect Merck was hoping to get lucky and dodge the bullet that took down rimonabant, but it looks like taranabant is as bad or worse.

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8. sroy on March 12, 2008 3:51 PM writes...

My thoughts on Derek's last paragraph-

There are no worthwhile laws/ accountability mechanisms against "optimistic thinking" and "creative accounting" by major companies in any field - Sarbanes-Oxley not withstanding. The whole game has always been pumping shares so that those in the know can sell their shares/ vest options to the greater fool before the truth comes out.

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9. rosko on March 12, 2008 4:20 PM writes...

The whole thing with rimonabant illustrates so nicely what is wrong with our legal and political system here. The CNS side effects could be a problem for many people, but for many they could be quite manageable.

Importantly, the effects in question are not something like carcinogenic properties, where
people could be taking it for years, and then much later all start developing cancers without having known what was going on in the mean time. If it makes you depressed or anxious, stop taking it! I'm not aware of any data that show the side effects are not reversible on stopping treatment.

For it to come down to either the FDA not approving it, or the company being open to lawsuits even with a warning on the packaging, that shows how lawsuits have moved beyond fraud protection to just a tool for people to pass blame around. Maybe it's just because I'm the resident libertarian who's always agitating for less drug regulation, but I find this to be a very negative trend

Now if the efficacy is low, that's another question. That means that in any case we should be looking for better targets.

Permalink to Comment

10. Rodmac on March 12, 2008 4:29 PM writes...

sroy said:

'The whole game has always been pumping shares so that those in the know can sell their shares/ vest options to the greater fool before the truth comes out.'

This is a statement not to be taken lightly. Although I toil daily in the drug detox arena and should have reason to want Big Pharma to suffer and die, it's not what I want to see and is not in anyone's best interests. A system slanted for profit-over-safety is a system of short-term gain and long-term suicide. It appears the gain term is reaching its end. Public trust is at its lowest ever, elected officials and a few within the FDA and Big Pharma itself are disenchanted, and even investors are rebelling. Unless basic risk/benefit and testing/approval scenarios are replaced with viable approaches, the industry itself is at risk - a situation no one wants to see. Our blog at novusdetox.com/views/ is squarely on this discussion.

Permalink to Comment

11. Analytical Scientist on March 12, 2008 5:31 PM writes...

Phil,

The 5% weight loss vs placebo group (which also will be losing weight) is the de facto FDA standard for sufficient efficacy for approval. In Europe the standard is 10% total (including the effects of the placebo group). The reason that this was set as the bar to get over by both Merck and Sanofi-Aventis is that it has that regulatory significance. This is the same standard that orlistat (Alli anyone?) and sibutramine demonstrated. I'm sure that Merck would have wished for more weight loss, but no doubt they knew they were ballancing efficacy with AEs.

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12. NJBiologist on March 12, 2008 6:42 PM writes...

I seem to remember that EMEA approved Accomplia before FDA passed judgment. Have Europeans been taking this stuff and committing suicide?

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13. Anonymous on March 12, 2008 8:33 PM writes...

"There’s always the possibility that a CB-1 antagonist (or inverse agonist) might have a use out in the periphery – they could have immunomodulatory effects – but anyone who tries this out would be well advised to do it with a compound that doesn’t cross the blood-brain barrier."

The CB1 actually doesn't have any link to the immune system.. that is the CB2 receptor... which still is of some mystery. It appears to be found primarily within the periphery and not in the brain.

Permalink to Comment

14. rosko on March 13, 2008 12:29 AM writes...

There are in fact some CB1 receptors on immune cells, but they certainly seem to be less abundant than CB2:

http://dx.doi.org/10.1189/jlb.0303101

In most cases I have seen, CB2 antagonists do seem to block most effects of cannabinoids on immune cells, suggesting that CB2 is most important. There is much less evidence, however, for CB2 in the brain, so CB2 agonists should make good non-psychotropic immunomodulators.

I'm actually surprised that none of these (selective CB2 ligands are known) seem to have been clinically tested, despite having strong immune modulating effects in model systems.

Permalink to Comment

15. juniorprof on March 13, 2008 2:21 AM writes...

Hey, anyone ever heard of the peripheral nervous system? Perhaps that what Derek is referring to for peripheral effects.

Permalink to Comment

16. pharmsboys on March 13, 2008 2:31 AM writes...

The information has not "leaked". You can go to the ACC website and look up the abstract, it is published. Dresdner Kleinwort investment bank also did an analysis on it. Side effects are quite high but the question of whether CNS side effects are manageable in these cases is open. Probably the full risk/benefit won't be decided until outcomes studies are out.

Permalink to Comment

17. Anonymous BMS Researcher on March 13, 2008 6:45 AM writes...


Insider on March 12, 2008 10:45 AM writes...

> Don't forget Pargluva!

Where I work we certainly won't forget that one.

Permalink to Comment

18. emjeff on March 13, 2008 7:30 AM writes...

Another example where Phase 2 data were either 1) ignored by Merck bigwigs in search of their next blockbuster or 2) inadequate to inform the decision to go to Phase 3.

Either way, Merck fails again in the most expensive way possible - in Phase 3. Boys and girls, it's time to face facts: money spent in Phase 2 doing GOOD dose-ranging trials is cash well-spent. Sadly, Merck has not yet learned this despite the efforts of many scientists there who are friends...

Permalink to Comment

19. Derek Lowe on March 13, 2008 8:53 AM writes...

Pharmsboys, I spent a little time rooting around on the ACC site and couldn't find the abstracts. Do you have a link? Thanks. . .

Permalink to Comment

20. pharmsboys on March 13, 2008 9:48 AM writes...

I sent the abstract info to your gmail. pb.

Permalink to Comment

21. Obesitymann on March 13, 2008 2:00 PM writes...

Hi Pharmaboys

If possible I would also be very interested in reading the abstract. You can send it to this mail adr.

aktieinvestor1 @ yahoo. com

Thanks

Permalink to Comment

22. SSilverstein on March 13, 2008 7:04 PM writes...

As someone who took diet pills (amphetamine) for a month or two as a young teenager to lose weight, given to me by the family doc, I can say it was an effective drug. I took it as prescribed. It quickly turns ravishing hunger to "I can't even look at food", and used for a limited time, was no problem. It's too bad people can't control themselves when given such medications.

OTOH, as Merck's former Director of Scientific Information Resources and Director of The Merck Index, I've just lost 75 lbs put on over the past decade (partly due to corporate stress in various industries) through simple diet and exercise. 100% willpower-based.

Unfortunately, there's no drug to enhance willpower.

Permalink to Comment

23. faitaccompli on March 14, 2008 1:47 AM writes...

This just came out:

A receptor in the brain called TRPV1, which is central to learning and memory, may be blocked by large doses of rimonabant (Acomplia), resulting in depression, anxiety and suicidal thoughts among some people taking the drug, a new study shows.

"We think that changes in the strength of connections between neurons in the brain underlie all kinds of important changes in the brain like learning, the development of the nervous system and many other adaptations to the environment, such as responses to pain and responses to drugs," said lead researcher Julie Kauer, an associate professor of molecular pharmacology, physiology and biotechnology at Brown University in Rhode Island.

The report was published in the March 13 issue of Neuron.

In experiments with rat brains, Kauer's group found that TRPV1 controls a brain mechanism called long-term depression, which is thought to be a key component in memory. The team thinks this finding may relate to the psychiatric side effects that have been seen with Acomplia.

"We found that rimonabant blocked TRPV1, and also another receptor CB1. It's possible that when the patient takes the drug, and the dose range is correct, it may not affect TRPV1 at all," Kauer said. "However, in some patients, Acomplia could be hitting TRPV1 and may well have an effect on activating this receptor," she said.

Permalink to Comment

24. dougheuring on March 31, 2008 8:55 AM writes...

FDA's 5 percent weight-loss threshold for approval of a new diet drug.

She added that the safety profile of the 2 milligram

Permalink to Comment

25. dougheuring on March 31, 2008 8:57 AM writes...

In this study, patients taking taranabant 2 mg experienced more than double the amount of weight loss at 52 weeks compared to patients treated with placebo. Patients on taranabant 2 mg demonstrated a mean weight loss reduction from baseline of 6.6 kg or 14.5 lbs (95 percent CI: 7.4 kg to 5.9 kg) compared to 2.6 kg or 5.7 lbs (95 percent CI: 3.3 kg to 1.8 kg) for patients on placebo, which was statistically significant (p

AS FOR THE SIDE EFFECTS AT THE LOW DOSE NOT MUCH WORSE THEN PLACEBO
The most commonly reported adverse events in the study were gastrointestinal and occurred more frequently in patients taking taranabant (42 percent in 2 mg, 47 percent in 4 mg, 46 percent in 6 mg and 29 percent on placebo). The incidences of psychiatric adverse events were greater at higher doses of taranabant (28 percent on taranabant 2 mg, 40 percent on taranabant 4 mg, 38 percent on taranabant 6 mg and 20 percent on placebo).

There were no significant differences in affect (crying, tearfulness, mood altered, mood swings), anxiety and depression adverse events groups between taranabant 2 mg and placebo, but these adverse events occurred significantly more in the taranabant 4 mg and 6 mg groups compared to placebo (affect results: five percent in 2 mg, seven percent in 4 mg and 6 mg, and three percent in placebo; anxiety-related term results: five percent in 2 mg, 11 percent in 4 mg, nine percent in 6 mg, and three percent in placebo; and depression-related term results: nine percent in 2 mg, 11 percent in 4 mg and 6 mg and 7 percent in placebo). Irritability occurred more frequently in patients taking taranabant (five percent in 2 mg, nine percent in 4 mg, seven percent in 6 mg, and two percent in placebo).

Discontinuations due to clinical adverse events were 13 percent in patients on taranabant 2 mg compared to 10 percent in patients on placebo. Discontinuations due to laboratory adverse events were 0.5 percent in patients on placebo; there were no discontinuations due to adverse events in patients on taranabant 2 mg. Rating :
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26. Jennifer on April 8, 2008 2:24 PM writes...

I was briefly on the clinical trial for this drug. I don't know what doesage I had received; however I was compelled to stop the drug after three weeks because of the "nervous system effects".

In real world experience, that translates into nearly being arrested for flying into fits of rage for mundane occurances such as being given incorrect change at the grocery store; my husband coming home and finding me shaking and crying in the floor of the closet; becoming suddenly disoriented and unable to navigate home from work; and constant thoughts of suicide.

I had never experienced anything like this before and the symptoms abated within days after stopping the drug. These "side effects" began a week after I started taking it.

I did lose 12 pounds in the 3 weeks and had very little appetite. Needless to say the weight is all back.

In my opinion, this is a very dangerous drug and should not be allowed on the market at all.

Permalink to Comment

27. Matthias on July 11, 2008 7:04 PM writes...

Some thoughts concerning cannabinoids out of Europe
Please apologize my very bad English!

In the EU, also a very big market, Sanofi got 2006 the permission of the EDA to sell Rimonabant.
If the FDA won´t allow Merck to sell Taranabant in the USA, they surely will get the permission to push it on the eurpean market.
Kernel problem seems to me the "common sence" that all cannabinoid agonists like THC are classified as "bad drugs" in general and simply because of this reason cannabinoid antagonists therfore must be classified as "good drugs".
If cannabinoid-antagonists are causing depressions, some people like me could conclude from this fact, THC could be used as an antidepressivant drug.
This seems for me to be the pharmacological truth but its not permitted by law to treat depressions like this. It would be possible to consider:
The war on drugs, especially on the soft drug Cannabis, simply a historical mistake?
Nobody, nor in politics neither in established scince would agree to this sentence.

Permalink to Comment

28. Matthias on July 11, 2008 7:26 PM writes...

Its not necessary, to comment Jennifers experience-this is simply the truth concerning (central) CB 1 antagonists. Brains which where "stimulated" like this, are no more able to peek.

Permalink to Comment

29. Matthias on July 11, 2008 7:38 PM writes...

Some thoughts concerning cannabinoids out of Europe
Please apologize my very bad English!

In the EU, also a very big market, Sanofi got 2006 the permission of the EDA to sell Rimonabant.
If the FDA will not allow Merck to sell Taranabant in the USA, they surely will get the permission to push it on the eurpean market.
Kernel problem seems to me the "common sence" that all cannabinoid agonists like THC are classified as "bad drugs" in general and simply because of this reason cannabinoid antagonists therfore must be classified as "good drugs".
If cannabinoid-antagonists are causing depressions, some people like me could conclude from this fact, THC could be used as an antidepressivant drug.
This seems for me to be the pharmacological truth but its not permitted by law to treat depressions like this. It would be possible to consider:
The war on drugs, especially on the soft drug Cannabis, simply a historical mistake?
Nobody, nor in politics neither in established scince would agree to this sentence.

Permalink to Comment

30. John on October 6, 2008 2:10 PM writes...

I have to agree with the observation above that states that this is the negative side of our chosen drug regulatory scheme.

I was one of the 2400 participants in Merck's phase III trial of rimonabant. I lost 24% of my body weight (240 to 183) over a 12 month period without any known side effect. But, because others may have had managable side effects, the most effective weight loss drug that I know of may never make American markets.

Even Taranabant is available in 40 countries with what known tragedies? Now, that is a sorry job of looking out for the people, in my book!

Permalink to Comment

31. Stacy on May 20, 2013 12:04 PM writes...

"A system slanted for profit-over-safety is a system of short-term gain and long-term suicide" in respect to Merck specifically. I spent 20 years in big pharma sales working for Ciba/Novartis, Parke-Davis/Pfizer, and Merck, in that order.
I can tell you that the philosophy at Merck is 360 degrees different than the others. At PD, we were selling Neurontin off-label for Diabetic Neuropathy for 2 years while the company finished trials. Same with Lyrica. This is against the law.
I learned how serious it was to do this upon hire at Merck. The company has a motto which they drill into everyone and broadcast at just about every sales meeting: "The medicine is for the people and if we serve the people, the profits will follow" (George Merck)

So, I am sorry but y'all are way off calling Merck a profit over safety company. I sold Vioxx and the incidence of CV risk was lower than what would be due to chance. The FDA did not even ask Merck to pull the drug. We did it ourselves because the company has very strict policies regarding safety.

Permalink to Comment

32. Edith on April 3, 2014 5:21 PM writes...

I was also in the rimonabant trial in 2007. I went from198 lbs. to168 lbs. I am fairly sure that I was on the low dose for the first 3 months then was off for 3 months and continued to lose weight. When the study resumed, I believe I was given the higher dosage. Within 3 days I had what I later learned was a panic attack. It was awful, I knew I was dying. My heart was racing, I was sweating, shaking, crying uncontrollably and terrified. I went to the ER and asked if it could be the drug and was told no. The hospital was the same one that was conducting the drug trial. The doctor overseeing the trial was a psychiatrist and instantly told me it was a panic attack, gave me Xanax and dismissed me from the trial. Seven years later I still have a mild form of the panic attack occasionally. Lessons learned: the are no magic pills and there are worse things than being fat.

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