By Jeffrey T. Jensen, MD
Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland
Dr. Jensen reports he is a consultant for and receives grant/research support from HRA Pharma, Bayer Healthcare, Merck, Agile Pharm, Population Council, AbbVie, Evofem, and ContraMed; and is a consultant for Teva Pharmaceuticals and Microchips.
Synopsis: On the third attempt, the FDA approved the mixed serotonin agonist/antagonist flibanserin for the treatment of generalized hypoactive sexual desire disorder in premenopausal women.
Sources: U.S. Food and Drug Administration. FDA Briefing Document: Joint Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) and the Drug Safety and Risk Management (DSaRM) Advisory Committee. Available at www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM449088.pdf. Accessed August 24, 2015.
Katz M, et al. Efficacy of flibanserin in women with hypoactive sexual desire disorder: Results from the BEGONIA trial. J Sex Med 2013;10:1807-1815.
Thorp J, et al. Treatment of hypoactive sexual desire disorder in premenopausal women: Efficacy of flibanserin in the DAISY study. J Sex Med 2012;9:793-804.
On August 18, the FDA approved flibanserin to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. The dose of flibanserin is 100 mg orally daily taken at bedtime. A total of 3548 patients were randomized to treatment (flibanserin n = 2310; placebo n = 1238) in the combined data from the three pivotal trials submitted in the new drug application (NDA) (the two published trials are referenced above). In the combined evaluation group, the mean age of participants was 36 years, and most (~89%) were white and reported being in a relationship with a mean length of 11 years. The overall completion rate was 78% for placebo and 70% for flibanserin (24 weeks of treatment).
The two co-primary endpoints in the published studies were: 1) change in the number of satisfying sexual events (SSEs) from baseline (28-day interval) to end of study (28-day interval), and 2) change in the eDiary sexual desire score from baseline to end of study (sum of daily sexual desire scores over 28 days). In these studies, subjects used a personal handheld electronic device (eDiary) to record on a daily basis information about sexual activity, including sexual encounters, orgasms, and desire. The third (unpublished) study referenced in the NDA did not use the eDiary to capture data for sexual desire. Instead, the Female Sexual Function Index (FSFI) sexual desire domain questions were assessed every 4 weeks at clinic visits, and the baseline and final clinical visit data were used for the co-primary efficacy endpoint (the FSFI was a secondary endpoint in the other studies). Key secondary endpoints included: 1) how often subjects reported being bothered by low sexual desire (“never,” “rarely,” “occasionally,” “frequently,” or “always”), and 2) the number of “satisfying sexual episodes (SSE),” each assessed for the 28-day baseline and end-of-study intervals.
The FDA review panel concluded that flibanserin’s treatment effects were consistent across the three trials with respect to increasing overall satisfying sexual events (statistically significant, P < 0.05; median increase of 0.5 to 1.0 episodes in 28 days) and reducing distress (mean treatment difference [95% confidence interval]: -0.3 [-0.4 to -0.1], -0.4 [-0.5 to -0.2], and -0.3 [-0.4 to -0.1] in the three studies). Although treatment benefit was also consistently demonstrated for sexual desire, this became statistically significant only when measured using the FSFI-desire domain questions (mean treatment difference [95% CI]: 0.3 [0.2-0.4], 0.4 [0.2-0.5], and 0.3 [0.2-0.5]) but not with the eDiary. Descriptive data presented suggest that the clinical effect takes about 4 weeks to develop.
Side effects occurred significantly more frequently in the treatment group, with twice as many (12.8% vs 5.9%) discontinuations for adverse events (AEs). The most common AEs included dizziness (11.4% vs 2.2%), somnolence (11.2% vs 3.1%), nausea (10.4% vs 3.7%), fatigue (9.2% vs 5%), and insomnia (4.9% vs 2.4%). There was no difference with respect to depression. In a small substudy where subjects consumed moderate (2-4 drinks) amounts of ethanol with and without flibanserin, the combination precipitated hypotension and presyncope/syncope in some participants. Due to these findings, the FDA approved flibanserin with a risk evaluation and mitigation strategy (REMS) to assure safe use. The REMS requires that prescribers and pharmacies complete training and be certified with the REMS. Certified prescribers must counsel patients using a Patient-Provider Agreement form about the increased risk of severe hypotension and syncope and about the importance of not drinking alcohol during treatment. The labeling for flibanserin (Addyi™) will include a black box warning to highlight the risks of severe hypotension and syncope in patients who drink alcohol during treatment, in those who use moderate or strong CYP3A4 inhibitors, and in those who have liver impairment.
COMMENTARY
What would you pay for a drug that must be taken daily to have (at best) a marginal impact on female sexual desire and is associated with serious side effects particularly when coadministered with moderate amounts of alcohol? How about $1 billion? That’s the amount of money that Valient Pharmaceuticals paid to acquire Sprout Pharmaceuticals, the company that successfully received FDA approval for flibanserin. The approval came on the third round, and was controversial.1 It took three pivotal studies and a patient advocacy campaign to gain approval. The initial NDA was submitted by Boehringer Ingelheim (BI) in 2010. At that time, the committee voted unanimously that the risks exceeded potential benefits, and BI discontinued development of the drug. Rights were sold to Sprout Pharmaceuticals, a company with no other products. Sprout filed a second NDA in 2013 and the application was again rejected. After the second NDA was denied, an advocacy group called Even the Score was formed to advocate for what it called “gender equality” in access to treatments for sexual dysfunction. The group promoted the claim that there are 26 approved medications for male sexual dysfunction but none for women; however, it failed to mention that none of these treatments were approved for low sexual desire.1 The male products include forms of testosterone and the phosphodiesterase (PDE)-5 inhibitors used to treat erectile dysfunction. Although the claim may have been inaccurate, the advocacy appeared to work and Addyi is now approved.
Flibanserin is classified as a mixed post-synaptic 5HT1A receptor agonist and 5HT2A receptor antagonist.2 It initially was studied for activity as an antidepressant. While the drug was no more effective than placebo in treating depression, flibanserin was more effective than placebo in terms of study participants’ responses to the question, “How strong is your sex drive?” This led BI to the clinical development program for treatment of sexual desire. The Diagnostic and Statistical Manual of Mental Disorders (DSMD), 4th edition, defined HSDD as “persistently or recurrently deficient or absent sexual fantasies and desire for sexual activity” accompanied by “marked distress and interpersonal difficulty” that is not accounted for by a nonsexual mental disorder, medication, severe relationship stress, or general medical condition. In 2013, the DSMD, 5th edition, combined HSDD with female sexual arousal disorder into female sexual interest/arousal disorder (FSIAD). The FDA has recognized that there are no approved treatments for these disorders.3
But is flibanserin the answer? First, this is not like treating an arousal disorder with a PDE5 inhibitor dosed a few times per month. Daily treatment is required. And it appears to take about a month to show any benefit at all. That, coupled with serious side effects like hypotension and syncope in some individuals (particularly with alcohol use) and annoying less serious adverse events like headache and nausea in others, doesn’t make this a dream drug.
Still, the allure of a drug to treat desire is intoxicating. Imagine the conversation that ends with “if you loved me, you would get that medicine that makes you more interested in sex.” While women are generally motivated to improve relationships, it is important to recognize that the diagnosis of FSIAD requires that the lack of desire is accompanied by “marked distress and interpersonal difficulty.” Guilt and desire to please a partner should not be deciding factors.
The FDA did a good thing requiring that providers receive training to become certified to prescribe flibanserin, but I hope that goes far enough. While it is important not to dismiss a therapeutic opportunity, it is critical that you make an accurate diagnosis. In my practice, I refer patients with sexual desire disorders to a qualified sexual therapist for counseling and treatment. I suspect a minority may benefit from flibanserin. However, I imagine that Valient Pharmaceuticals is banking on widespread over-prescription of this product. That’s the $1 billion dollar answer.
REFERENCES
- Gellad WF, et al. Evaluation of flibanserin: Science and advocacy at the FDA. JAMA 2015; July 6 [Epub ahead of print].
- Stahl SM. Mechanism of action of flibanserin, a multifunctional serotonin agonist and antagonist (MSAA), in hypoactive sexual desire disorder. CNS Spectr 2015;20:1-6.
- Nappi RE. Why are there no FDA-approved treatments for female sexual dysfunction? Expert Opin Pharmacother 2015;16:1735-1738.
On the third attempt, the FDA approved the treatment for generalized hypoactive sexual desire disorder in premenopausal women.
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