Taranabant and Rimonabant: Same Class, Same Risk?

After an increased risk of suicidality led to the demise of Sanofi-Aventis' rimonabant (Zimulti), another drug in the same class of cannabinoid-1 receptor blockers (Merck's taranabant) is showing a similar signal in Phase III trials. Merck has vowed to push ahead with an NDA filing.

After an increased risk of suicidality led to the demise of Sanofi-Aventis’ rimonabant (Zimulti), another drug in the same class of cannabinoid-1 receptor blockers—Merck’s taranabant—is showing a similar signal in Phase III trials.

Merck & Co. Inc.’s taranabant may be the next drug to blow up over psychiatric adverse events.

According to 52-week results of a two-year Phase III study, high doses of taranabant (4 mg and 6 mg) demonstrated statistically significant differences in crying, mood swings, anxiety and depression. At the lowest dose (2 mg), patients reported the same adverse events, although the results were not statistically significant.

Patients lost weight on taranabant, but the efficacy wasn’t terribly impressive. Among patients taking the 2 mg dose, 57% lost 5% of their body weight and 28% lost 10% of their body weight. That sounds nice, but when you consider that these are obese patients with a body mass index of at least 30 kg/m2, it’s really not that much to lose.

Unremarkable efficacy. Psychiatric safety signal. A cannabinoid-1 receptor blocker. Generic name ends in "nabant." Does any of this sound a familiar?

Indeed, taranabant would appear to have a similar risk-benefit profile to Sanofi-Aventis’ cannabinoid-1 receptor blocker rimonabant (Zimulti). That drug crashed and burned after FDA found near two-fold increase in psychiatric adverse events. (Also see "Sanofi-Aventis' Zimulti: Knowing When to Say When" - Pink Sheet, 1 Jul, 2007.)

FDA was particularly concerned with what might happen if rimonabant were available to a broader population: "The signals we are seeing are in a relatively small and highly select population, carefully screened and receiving drug in a controlled setting," FDA medical officer Amy Egan said at the time. "What remains unknown is what the experience with rimonabant will be in a less highly screened and potentially more depressed patient population."

Merck certainly sees the trouble ahead. In light of the Phase III results, it has decided to drop the two high doses of taranabant and continue development with the 2 mg dose. But that might not be enough to assuage FDA, given the agency’s past experience with rimonabant and its attention on psychiatric adverse events in general. (Also see "Psychiatric Adverse Events: Navigating a New Drug Safety Landmine" - Pink Sheet, 1 Apr, 2008.)

Expect Merck to continue to press on to an NDA filing. The company’s attitude appears to be that taranabant has come this far, so it might as well try to win approval. That shouldn’t be surprising: after all, this is the same company that brought Arcoxia to an advisory committee despite all the trouble with the COX-2 inhibitor class—only to have an overwhelming vote against approval. (Also see "The Death of Arcoxia: Drug Regulation in a "Whistleblower" Climate" - Pink Sheet, 1 May, 2007.)

It’s certainly not a given that all drugs in the same class will have the same safety concerns or the same regulatory outcome. But we’ve been here before. And given the data, it’s not looking good for taranabant.