Merck will focus development of its weight loss drug taranabant on 2 mg doses or lower after higher rates of psychiatric adverse events were seen in patients treated with 4 mg and 6 mg doses in Phase III.

The company announced the findings of 52-week data from a two-year trial evaluating the cannabinoid-1 receptor blocker March 31 during the American College of Cardiology meeting in Chicago.

"Based on the benefit-risk considerations and the lack of a substantial improvement in the efficacy of taranabant at the 4 mg and 6 mg doses seen in our clinical program compared to the 2 mg dose, we have decided to continue to evaluate taranabant in doses up to and including 2 mg in our Phase III studies," Merck said.

A high level of weight loss with a low incidence of psychiatric adverse events is critical to Merck's quest to secure FDA approval for taranabant. The CB-1 antagonist class faced a setback when FDA's Endocrinologic and Metabolic Drugs Advisory Committee last year rejected Sanofi-Aventis' Zimulti (rimonabant). The panel voted against approval based on questions about the psychiatric and neurological profile, including depression and suicidality.

In a retrospective meta-analysis of four Phase III clinical trials supporting approval of Zimulti, prompted by FDA, 26 percent of patients receiving rimonabant 20 mg experienced a psychiatric adverse event compared to 14 percent for placebo (¹ Also see "Will Zimulti’s Outlook Be Affected By Suicidality Signal?" - Pink Sheet, 12 June, 2007.).

Sanofi had sought to be first to market in the U.S. with a CB-1 antagonist, but withdrew the NDA two weeks after the advisory committee vote (² Also see "Sanofi Withdraws Zimulti NDA For Weight Loss" - Pink Sheet, 29 June, 2007.). Rimonabant is approved in Europe however, where it is marketed as Acomplia . Sanofi continues to pursue approval in the U.S. and could submit data from an ongoing trial, perhaps later this year.

However in comments to "The Pink Sheet" DAILY, Merck said, "With regard to a comparison with rimonabant, taranabant is a different compound and is structurally different from rinonabant. You cannot compare the two drugs without a head-to-head study."

"It's important to note that this is the first of many Phase III trials being presented this year on taranabant and that we continue to look at the benefit risk profile of this drug in these Phase III trials," Merck added.

The company remains on track to file an NDA for taranabant later this year.

In the one-year taranabant data presented at ACC, patients taking 2 mg doses demonstrated a mean weight loss reduction from baseline of 14.5 lbs, compared to 5.7 lbs for patients taking placebo at 52 weeks. In addition 28 percent of patients in the 2 mg arm lost 10 percent of their baseline body weight compared to 8 percent of those on placebo.

The trial enrolled about 2,500 patients with a Body Mass Index between 30 kg/m and 43 kg/m or a BMI between 27 kg/m and 43kg/m for patients with obesity-related comorbidities. After a two-week single-blind placebo plus diet run-in period, patients were randomized to receive placebo or taranabant 2 mg (414 patients), 4 mg (415 patients) or 6 mg (1,256 patients) once daily for up to 104 weeks with continued diet and exercise.

During the trial, patients in the higher 6 mg dose arm were re-randomized to placebo or taranabant 2 mg after an independent data safety monitoring committee determined the higher dose did not have significantly greater efficacy but did have a higher side effect profile compared to the 4 mg arm.

The most common adverse events were gastrointestinal (42 percent in 2 mg, 47 percent in 4 mg, 46 percent in 6 mg and 29 percent in placebo). Psychiatric events were 28 percent in 2 mg, 40 percent in 4 mg, 38 percent in 6 mg and 20 percent in placebo.

In terms of affect (crying, tearfulness, mood altered and mood swings), anxiety and depression, there were no significant differences between the 2 mg treatment arm and placebo, according to Merck. However, rates were significantly higher in patients in the 4 mg and 6 mg treatment groups compared to placebo.

Discontinuations were 13 percent among patients on taranabant 2 mg due to adverse events, compared with 10 percent of patients on placebo.

Several big pharmas have focused research dollars on blocking CB-1, thought to regulate weight by impacting appetite and satiation. In addition to taranabant and rimonabant, other CB-1 antagonists in late-stage development include Pfizer's CP-945598 in Phase III and Bristol-Myers Squibb/Solvay's SLV-319 in Phase IIb.

-Jessica Merrill (j.merrill@elsevier.com)

Merck To Focus Taranabant Development On Lower Dose

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