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Flibanserin (code name BIMT-17; proposed trade name Girosa) is a drug being studied as a non-hormonal treatment for pre-menopausal women with hypoactive sexual desire disorder (HSDD). Development by Boehringer Ingelheim was halted in October 2010 following a negative report by the U.S. Food and Drug Administration. The rights to the drug were then transferred to Sprout Pharmaceuticals which is continuing the drug development process.
HSDD is the most commonly reported female sexual complaint and characterized by a decrease in sexual desire that causes marked personal distress and/or personal difficulties. According to prevalence studies about 1 in 10 women reported low sexual desire with associated distress, which may be HSDD. The neurobiological pathway of female sexual desire involves interactions among multiple neurotransmitters, sex hormones and various psychosocial factors. Sexual desire is modulated in distinct brain areas by a balance between inhibitory and excitatory neurotransmitters, serotonin acting as an inhibitor while dopamine and norepinephrine act as a stimulator of sexual desire. Flibanserin is a 5-HT1A receptor agonist and 5-HT2A receptor antagonist that had initially been investigated as an antidepressant. Preclinical evidence suggested that flibanserin targets these receptors preferentially in selective brain areas and helps to restore a balance between these inhibitory and excitatory effects. HSDD was recognized as a distinct sexual function disorder for more than 30 years, but was removed from the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders in 2013, and replaced with a new diagnosis called female sexual interest/arousal disorder, or F.S.I.A.D.
Mechanism of action
The proposed mechanism of action refers to the Kinsey dual control model. Several sex steroids, neurotransmitters, and hormones have important excitatory or inhibitory effects on the sexual response. Among the neurotransmitters, the excitatory activity is driven by dopamine and norepinephrine, while the inhibitory activity is driven by serotonin. The balance between these systems is relevant for a healthy sexual response. By modulating these neurotransmitters in selective brain areas, flibanserin, a 5-HT1A receptor agonist and 5-HT2A receptor antagonist, is likely to restore the balance between these neurotransmitter systems. 5-HT1A receptor activation likely plays a significant role in the empathogenic effects of serotonin releasing agents (SRAs) like MDMA ("Ecstasy") as well.
Several large pivotal Phase III studies with flibanserin were conducted in the US, Canada and Europe. They involved more than 5,000 pre-menopausal women with generalized acquired Hypoactive Sexual Desire Disorder (HSDD). The results of the Phase III North American Trials demonstrated that:
Although the two North American trials that used the flibanserin 100 mg qhs dose showed a statistically significant difference between flibanserin and the placebo for the endpoint of [satisfying sexual events], they both failed to demonstrate a statistically significant improvement on the co-primary endpoint of sexual desire. Therefore, neither study met the agreed-upon criteria for success in establishing the efficacy of flibanserin for the treatment of [Hypoactive Sexual Desire Disorder].
These data were first presented on November 16, 2009 at the congress of the European Society for Sexual Medicine in Lyon, France. The women receiving flibanserin reported that the average number of times they had “satisfying sexual events” rose from 2.8 to 4.5 times a month. However, women receiving placebo reported also an increase of “satisfying sexual events” from 2.7 to 3.7 times a month. Evaluation of the overall improvement of their condition and whether the benefit was meaningful to the women, showed a significantly higher rate of a meaningful benefit in the flibanserin-treated patient group versus the placebo group. The onset of the flibanserin effect was seen from the first timepoint measured after 4 weeks of treatment and maintained throughout the treatment period. The overall incidence of adverse events among women taking flibanserin was low, the majority of adverse events being mild to moderate and resolved during the treatment. The most commonly reported adverse events included dizziness, nausea, fatigue, somnolence and insomnia.
On June 18, 2010, a federal advisory panel to the U.S. Food and Drug Administration (FDA) unanimously voted against recommending approval of flibanserin. Earlier in the week, a FDA staff report also recommended non-approval of the drug. While the FDA still might approve flibanserin, in the past, negative panel votes tended to cause the FDA not to approve.
On October 8, 2010, Boehringer Ingelheim announced that it would discontinue its development of flibanserin in light of the FDA advisory panel's recommendation.
On June 27, 2013, Sprout Pharmaceuticals confirmed they had resubmitted flibanserin for FDA approval.
In December 2013, a Formal Dispute Resolution was filed, which contained the requirements of the FDA for further studies. These include two studies in healthy subjects to determine if flibanserin impairs their ability to drive, and to determine if it interferes with other biochemical pathways. Sprout expects to resubmit the NDA in the 3rd quarter of 2014.
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