FDA panel decides novel antidepressant does not have favorable risk benefit ratio




SILVER SPRING, MD. – An extended-release formulation of gepirone hydrochloride got a thumbs up for safety, but received a recommendation against approval for major depressive disorder from a Food and Drug Administration advisory panel.

At a Dec. 1 meeting, the FDA’s Psychopharmacologic Drugs Advisory Committee voted 11-2 in favor of gepirone’s safety profile, but concluded by a vote of 9-4 that the drug’s sponsor, Fabre-Kramer Pharmaceuticals, failed to demonstrate the drug’s efficacy.

The drug’s sponsor noted that data from 5 of 12 short-term, randomized, placebo-controlled studies of gepirone ER (extended release) were considered to be interpretable and should serve as the basis for assessment of efficacy. “Of the five interpretable studies, two clinical trials demonstrated statistically significant findings based on difference in adjusted mean change from baseline in Hamilton Depression Rating Scale-17 [HAMD-17] score at end of study,” according to a statement from the drug’s manufacturer. The effect size in those two studies was comparable to the effect size seen for many of the other approved antidepressants.

According to Fabre-Kramer, a meta-analysis of all five interpretable studies demonstrated statistically significant benefits of gepirone ER based on changes in adjusted mean HAMD-17 scores.

Adverse effects were reported by at least 5% of all subjects and included headache, dizziness, somnolence, nausea, dry mouth, diarrhea, constipation, insomnia, upper respiratory tract infection, nasopharyngitis, and fatigue. “In trials conducted to date, there is no evidence that treatment with gepirone ER causes certain side effects common to other approved serotonergic agents including withdrawal effects, high incidence of somnolence, weight gain, seizure risk, and sexual dysfunction,” the drug’s sponsor said in a statement.

The panel, however, concluded that the data from these studies were not substantial enough to warrant approval at this time. They noted that the study drug did not beat either placebo or the active control in three of the five trials that used an active control group. Further, the active control actually beat the study drug. “That is something we hardly ever see,” said Dr. Robert Temple, deputy director for clinical science at the FDA. “We’re not concluding that these studies prove [gepirone] doesn’t work, but it raises doubts about the available data and makes us believe there needs to be more data.”

The FDA previously had issued three nonapproval letters for gepirone since its development began in 1999, which is noted in the FDA’s analysis of the data.

Gepirone’s mechanism of action when formulated for extended release is as a partial agonist of the 5-HT autoreceptors and a full agonist at the postsynaptic 5-HT autoreceptors, allowing there to be fewer serotonin-related side affects, such as sexual dysfunction.

Dr. Dawn F. Ionescu of Massachusetts General Hospital and a member of the panel, summed up the panel’s observations of safety versus efficacy: “If this medication isn’t going to treat patients’ depression, what’s the point in giving them a medication that will also not cause as much sexual dysfunction?”

The FDA typically follows the advice of its advisory panels. None of the panelists involved in the vote had any relevant financial disclosures.

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