Taranabant, which a year from now may have surged past rimonabant as the world's most eagerly awaited diet drug, made a low-key debut Oct. 24th when researchers reported that participants in a clinical trial achieved encouraging weight loss with "generally mild" gastrointestinal and psychiatric side-effects.

A presentation by Dr. Ngozi Erondu, senior director of clinical research for Merck, at The Obesity Society's scientific meeting in New Orleans was the first official report from Merck on trials of its diet drug, which like rimonabant promotes weight-loss by targeting Endocannabinoid System CB-1 receptors.

When Sanofi-Aventis, which had been trying for three years to get rimonabant (Acomplia / Zimulti) approved for U.S. sale, pulled back its application this summer after FDA expert advisers voiced concern over psychiatric side-effects, many obese Americans waiting for the drug were very disappointed.

Now, it seems the high hopes of dieters for Acomplia may soon shift to the Merck drug as it appears increasingly possible that taranabant might beat rimonabant to the U.S. market.

While both rimonabant and taranabant target CB-1 receptors of the body's Endocannabinoid System, a complex signaling system believed to regulate energy balance, behaviors such as food intake, fear, and anxiety, and to modulate lipid and glucose metabolism, the drugs work in different ways.

An oversimplified explation would be that rimonabant, according to Sanofi, is a CB-1 receptor antagonist, meaning it blocks endocannabinoids -- which would bind to the CB-1 receptors and trigger cravings for food -- from reaching the CB-1 receptors.

Taranabant, according to Merck, is a CB-1 receptor inverse agonist, meaning (again oversimplified) that the drug binds to CB-1 receptors, and triggers a reverse action to the cravings that would be triggered by an agonist like endocannabinoids.

While the mechanisms of action differ, both drugs appear to result in significant weight loss.

In their presentation of results, the Merck researchers reported that in a phase IIa trial involving 533 obese patients, "taranabant significantly reduced body weight and waist circumference compared to placebo" after 12 weeks of treatment.

"Significantly more patients treated with taranabant achieved a weight loss of five percent or greater," the researchers reported.

While rimonabant produced greater weight loss in its longer phase III trials, reports we have received from participants in a phase III trial of taranabant with 2,400 participants -- which has been underway for nearly two years -- suggest the results are comparable.

A Merck spokesperson said the company has no plans to present any data from the phase III taranabant trial until sometime next year, but the company obviously is highly encouraged because it reiterated that it plans to file for FDA approval of taranabant in mid-2008.

But the big question on the minds of many experts watching the taranabant trials is whether the Merck drug has a better side-effect profile than rimonabant.

It was the side-effect profile of rimonabant --particularly the incidence of depression and suicidality -- that is keeping the diet drug off the U.S. market, even though Acomplia is on sale in Europe.

Not many conclusions can be drawn in this regard from the phase II trial of taranabant. The researchers reported that the most commonly reported adverse events suffered by participants in the study were gastrointestinal related, with about half as many suffering psychiatric side effects.

"The gastrointestinal and psychiatric adverse effects were generally mild in intensity and self-limiting," the researchers added.

Some experts attending the Obesity Society meeting suggested that the difference between a CB-1 receptor antagonist and a CB-1 receptor inverse agonist may not be as important in terms of side-effects as the dose of the drug and the drug's affinity to the receptor.

While Sanofi-Aventis tested a 5 mg dose in trials as well as the 20 mg dose now on the market in Europe, the 5 mg rimonabant dose produced disappointing results.

Merck's taranabant, in contrast, is being tested in phase III at lower dosages with a 6 mg dose currently the highest.

"I don't think the amount of side-effects we have seen are related to the properties of the drug," said Dr. Uberto Pagotto of the University of Bologna, an expert on the Endocannabinoid System. "Related to the dose, maybe, I'm not so sure, and to the affinity to the receptor. This is very important."