“The inadequacy of dose exploration is clearly the ‘Achilles heel’ of this application,” Office of Drug Evaluation I Deputy Director Ellis Unger declared in his Jan. 21, 2011, decision memo for the approval of Clinical Data, Inc.’s antidepressant Viibryd (vilazodone).

FDA approved Viibryd Jan. 22 at a single dose level of 40 mg, despite widespread speculation among the review team that a lower dose could have better balanced safety and efficacy.

“Overall, it is uncertain whether the 20 mg dose might be effective,” Cross Discipline Team Leader Robert Levin concluded in a Jan. 5 memo. “On the other hand, there are dose-related adverse reactions (nausea and vomiting) that were associated with discontinuation of treatment.”

Hints Of Efficacy At A Lower Dose

“Vilazodone has dose-related side effects, and there are hints from both the Phase II and Phase III studies that a lower dose could be efficacious,” Unger stated.

The Phase III trials were conducted under the auspices of Clinical Data, Inc., where Viibryd came to rest after bouncing between Merck KGaA and GlaxoSmithKline (see chart, Also see "Viibryd Clinical Development" - Pink Sheet, 1 August, 2011.). CDI picked up a product that already had completed – and failed – five Phase II trials, leaving it only responsible for pivotal studies, but also saddling the sponsor with the clinical decisions of others who were no longer involved in the project.

“Of note, a 40 mg/d fixed dose had not been evaluated in Phase II,” Unger commented. The negative fixed-dose Phase II trials studied a lower 20 mg/day dose.

Faced with a legacy of unsuccessful Phase II trials, CDI and its operating business, known for the majority of Viibryd development as PGxHealth, altered the trial design parameters for Phase III to take advantage of positive trends it identified in the data regarding the dose, and the choice of primary endpoint (replacing the HAM-D scale with MADRS, where there was a suggestion of benefit) (see related story,Also see "No Comparison: Viibryd’s Path Of Least Resistance Through FDA Could Mean Rocky Marketing" - Pink Sheet, 1 August, 2011.).

Multiple Doses Would Have Improved Receptor Binding Study

The sponsor looked at receptor-binding data as part of its decision to use the higher 40 mg dose in Phase III. Division of Psychiatry Products Director Thomas Laughren noted that one Phase II study, Study 255, was done to assess occupancy for the 5-HT1A receptor, and that study was considered part of the basis for the 40 mg dose selection for the Phase III trials. In Study 255, “there was little evidence for occupancy at the 20 mg dose, however, 5-HT1A occupancy at the 40 mg dose was found to be in the range of 15-35%,” he noted.

FDA criticized the sponsor’s reliance on Study 255 because its data on receptor occupancy, derived from PET scans, “was conducted with only single doses of vilazodone, and a multiple dose study might have been more relevant and showed greater receptor occupancy,” Unger stated. “Moreover,” the ODE I deputy director commented, “the relationship between 5-HT1A receptor occupancy and clinical effect is unknown.”

Commitment To Post-Market Study Satisfies

That led the review team to request a post-marketing placebo- and active-controlled study using fixed doses of vilazodone (20 mg and 40 mg), “in order to further explore the effective dose range of vilazodone,” Unger said. The sponsor agreed to conduct such a study as a post-marketing commitment.

The approval letter lays out FDA’s rationale for the study. “It is not apparent from the trials you have conducted in major depressive disorder that the lowest effective dose of vilazodone has been identified, because only one dose (40 mg/day) was studied,” the letter states. “However, there are suggestions that 20 mg/day may be effective in at least some subjects.”

“Some important adverse reactions are dose-related,” the letter adds. “Thus we request that you further characterize the efficacy and safety of vilazodone.” The final protocol is due relatively soon – Oct. 31, 2011 – and the final report of the study is to be submitted by Jan. 31, 2014.

By Bridget Silverman

Viibryd Dose Selection Was Weak Spot, But Sponsor’s Gamble Paid Off

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