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FDA Advisors Question Safety of Women’s Libido Drug Flibanserin

Company makes third try at approval

FDA advisors have once again raised concerns about the safety of flibanserin, an experimental women’s libido drug, saying it increased the risk of fainting and accidental injury, especially when combined with alcohol, according to a report from Reuters.

The review, published jointly on June 2 by the FDA’s Bone, Reproductive, and Urologic Drugs (BRUDAC) Advisory Committee and the Drug Safety and Risk Management (DSaRM) Advisory Committee, came 2 days before a meeting of external advisers who will recommend whether flibanserin should be approved. The FDA is not required to follow the advice of its advisory panels but typically does so.

The drug’s developer, Sprout Pharmaceuticals, is seeking approval of flibanserin for the treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women. The proposed dose is a 100-mg tablet taken by mouth every night at bedtime. The product’s proposed trade name, if approved, is Addyi.

The FDA review found a statistically significant improvement in the number of satisfying sexual events (SSEs) experienced by women taking the drug and a reduction in distress related to low desire. There was an increase in desire as measured on a monthly basis, but not on a daily basis. The differences were numerically small, however, and the question remains whether the drug’s benefits outweigh its risks, the FDA’s advisors said.

From an average baseline of two to three SSEs a month, and after adjusting for a placebo effect, women had an increase of 0.5 to 1.0 SSEs a month. They also had a placebo-adjusted improvement of 0.3 to 0.4 on the distress score, and a 0.3 to 0.4 increase in desire, based on a tool known as the Female Sexual Function Index (FSFI).

The FDA has twice rejected flibanserin for the treatment of HSDD in women. Boehringer Ingelheim, the previous applicant, submitted the original new drug application (NDA) for flibanserin in 2009. The application was discussed at an advisory committee meeting in 2010. The committee voted 10 to 1 that Boehringer had not provided sufficient evidence of efficacy.

Of note, both pivotal phase III trials included in the NDA failed to show a statistically significant improvement compared with placebo in the prespecified co-primary efficacy endpoint, which assessed daily sexual desire using an electronic diary. These trials did show, however, a statistically significant improvement compared with placebo in a secondary endpoint that measured sexual desire using the FSFI. Boehringer stated that the effect of flibanserin on sexual desire was better-assessed with this score, but most of the advisory committee members did not agree with altering the prespecified method of assessing sexual desire. When asked whether Boehringer had shown an overall acceptable benefit/risk profile for flibanserin, the advisory committee unanimously voted no (11 to 0), stating that the demonstrated efficacy with flibanserin was not sufficiently robust to justify the risks. Safety concerns expressed by committee members included adverse events, such as fatigue and somnolence, as well as drug–drug interactions and alcohol interactions with flibanserin.

The FDA agreed that the NDA could not be approved and issued a complete response letter (CRL) in 2010, citing numerous deficiencies.

After the FDA’s first review cycle, Boehringer sold flibanserin to Sprout Pharmaceuticals, who responded to the FDA’s first-cycle criticisms and resubmitted the NDA for review in 2013. The resubmission included results from a third phase III trial and additional phase I studies. The FDA again determined that the NDA could not be approved and issued another CRL.

Flibanserin is a selective serotonin reuptake inhibitor (SSRI) that acts as both an agonist at the 5-hydroxytryptamine (5-HT) type-1A receptor and an antagonist at the 5-HT type-2A receptor. Flibanserin is similar to a class of antidepressants that includes fluoxetine (Prozac, Eli Lilly) and was originally developed for that use, but it was found to be ineffective.

A testosterone patch to help improve female sexual dysfunction developed by Proctor & Gamble failed to win FDA approval after a negative advisory committee meeting in 2004, and a testosterone gel from BioSante failed in clinical trials in 2011, according to Reuters.

Sources: FDA; June 2, 2015; and Reuters; June 2, 2015.

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