Merck diet drug taranabant, which targets the same CB-1 receptor as Sanofi's obesity treatment Acomplia (rimonabant), also produces psychiatric side effects but results in almost-as-good weight loss at one-tenth the dosage, according to study results presented to the American College of Cardiology.

Merck said one-year results from a two-year Phase III trial showed that patients taking a 2 mg dose of taranabant had a mean weight loss reduction of 14.5 pounds compared to 5.7 pounds for patients on a placebo.

The researchers said 57 percent of the patients taking the 2 mg dose of taranabant lost five percent of their body weight, and 28 percent lost 10 percent of their body weight.

In contrast, Sanofi in Nov. 2004 reported that in its Phase III trial, 62.5 percent of patients taking the 20 mg dose of Acomplia lost more than 5 percent of their body weight, and 32 percent lost more than 10 percent of their body weigh.

But Sanofi also tested a 5 mg dose of Acomplia -- which has never been brought to market -- and said only 36.7 percent of those on the low dose lost more than 5 percent of their body weight, and only 20 percent lost 10 percent of their bodyweight.

While Merck also tested 4 mg and 6 mg doses of taranabant, it said the incidence of psychiatric side effects -- the problem that has thus far blocked approval of rimonabant for sale in the U.S. -- was greater at the higher doses, and that further development of taranabant would focus on the 2 mg dose.

The big question, of course, is whether the incidence and severity of psychiatric side effects -- which has kept Acomplia / Zimulti off the U.S. market -- is better for a 2 mg dose of taranabant than for a 20 mg dose of rimonabant.

It thus far has been hard to draw any meaningful comparisons between the psychiatric side effects noted for Acomplia and taranabant, in part because the measurement and recording of these appears to have been considerably enhanced in anticipation of a more rigorous FDA approval process.

Researchers reported that the incidence of psychiatric adverse events was 28 percent for patients on taranabant 2 mg, 40 percent on taranabant 4 mg, and 38 percent on taranabant 6 mg. How severe these may have been is not known.

But Merck made it clear today that as it continues efforts to get taranabant to a point where it can be submitted for FDA approval later this year, it intends to focus on development of a drug that produces significant weight loss at the lowest dosage possible.

Taranabant Trial

The double-blind study included 533 obese people randomly assigned to treatment with either placebo or 0.5 milligrams, 2 milligrams, 4 milligrams, or 6 milligrams of taranabant. All the participants received counseling on diet and exercise throughout the trial.

At the end of 12 weeks, the placebo-treated participants had lost the least weight and those treated with the highest dose of taranabant had lost the most.

Patients treated with 0.5 milligrams of the drug lost an average of 3.5 pounds, compared with 5 pounds among people treated with 2 milligrams of the drug and almost 9 pounds among those treated with 6 milligrams.

A total of 27% of patients who took 0.5 milligrams of taranabant lost 5% or more of their body weight, compared with 61% in the 6-milligram group.

But patients taking the higher dosages of the drug also had higher rates of side effects, including anxiety, nausea, and vomiting.

The study drop-out rate due to side effects was also twice as high among patients treated with the highest dosage of the drug, compared with the lowest dose (10.2% vs. 4.7%). But no patients dropped out because of serious events.

The study appears in the January issue of the journal Cell Metabolism.

Heymsfield says he was surprised to find that patients treated with the lowest dose of the drug lost weight.

"We didn't expect weight loss at all doses," he says.

Taranabant in Trouble?

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.

More On Merck and Taranabant

My piece on Merck last week seems to have touched a few nerves, if some of the comments and e-mails I’ve received are any sign. To clarify things: I agree that Merck is still doing some excellent science, as they always have. And they still have a lot of good people there, as they always have. Those aren’t the problems. And they’re still introducing some innovative drugs, arguably more than a lot of other companies, and that’s not the problem, either. These are all are admirable things.

And Vioxx, as I said here at the time, was not, in my opinion, necessarily a bad drug. It and the other COX-2 inhibitors have a real place in the pharmacopeia. The problem is that Merck – or, to put the usual face-saving perspective on it, Merck’s marketing department – oversold the stuff. The prospect of an aspirin-sized market was too much for them to resist, so the company pushed Vioxx just about as hard as they possibly could.

Yep, Vioxx was for all kinds of patients, all kinds of pain, all the time – and under those conditions, whatever side effects were there were finally revealed. It’s the company’s bad luck (not to mention the bad luck of their patients) that those effects were as potentially severe as they were. Even so, the increased risk of a heart attack with Vioxx use is extremely small in any absolute sense. For people with severe pain who can’t get relief with other drugs, I think a COX-2 inhibitor is absolutely worth it.

But that’s not what you’d think from reading the newspapers, or from listening to the lawyers. It was expedient to paint the company as a bunch of callous poisoners; Merck’s reputation has been hooked to the back of a pickup truck and pulled through a swamp. (They didn't always do themselves much good during that period, either). And while the good name was bouncing off the tree stumps and scooping up the mud, the company had to spend vast amounts of money to deal with all those lawsuits, which is money that presumably could have been used for something else. (OK, some of that is coming from insurance – but think of how much more they’ll be paying for that coverage now).

Which is what worries me about taranabant. I realize, as several commenters to the previous post pointed out, that it may well differ in selectivity and CB-1 receptor activity from rimonabant. If the compound is an inverse agonist instead of an antagonist at the receptor, that could well be good news. Or, you know, it might not be, since we have no idea of what an inverse agonist will do, either. (More on the difference between those terms in a future post). At any rate, discovering new things about human CNS functions while a bunch of lawyers watch doesn’t sound like a good idea. If Merck does end up going down the Vioxx path again, another run through the swamp will do it no good at all.