Commentary

DOI: 10.1111/1471-0528.12878 www.bjog.org

Improving prospects for treating hypoactive sexual desire disorder (HSDD): development status of flibanserin J Thorp Jr,a S Palacios,b J Symons,c J Simon,c,d K Barbourc a

Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, NC, USA b Instituto Palacios, Madrid, Spain c Sprout Pharmaceuticals, Inc., Raleigh, NC, USA d Department of Obstetrics and Gynecology, George Washington University, Women’s Health & Research Consultants (r), Washington, DC, USA Correspondence: J Symons, Sprout Pharmaceuticals, 4208 Six Forks Road, Suite 1010, Raleigh, NC 27609, USA. Email [email protected] Accepted 14 April 2014. Published Online 9 June 2014.

Please cite this paper as: Thorp Jr J, Palacios S, Symons J, Simon J, Barbour K. Improving prospects for treating hypoactive sexual desire disorder (HSDD): development status of flibanserin. BJOG 2014;121:1328–1332. Linked article: This article is commented on by Wylie K, pp. 1332 in this issue. To view this mini commentary visit http://dx.doi.org/ 10.1111/1471-0528.12968.

The condition of hypoactive sexual desire disorder (HSDD) has been included in the Diagnostic and Statistical Manual of Mental Disorders
(DSM) since DSM-III-R was first published in 1987. DSM-IV-TR (APA, 2000)1 describes HSDD ‘as persistent or recurrent deficiency or absence of sexual fantasies and thoughts, and/or desire for, or receptivity to, sexual activity, which causes personal distress or interpersonal difficulties and is not caused by a medical condition or drug.’ Recently, the diagnostic criteria for HSDD have been under review as part of the process of producing the fifth edition of the DSM (see www.dsm5.org for more information). The revised criteria combine female sexual desire and arousal disorders to form one disorder, termed sexual interest/arousal disorder (SIAD). Clinicians in the field of female sexual disorders have expressed concerns that the new criteria are excessively restrictive and may result in many women with HSDD going without treatment of a condition that they find a serious detriment to their sexual health. Several large-scale studies have evaluated the prevalence of sexual desire problems and suggest that HSDD is a concern for a significant number of women. Importantly, more recent studies have included an assessment of personal distress in addition to decreased or low desire in women. For example, Leiblum et al.2 examined reports of decreased sexual desire and distress in a demographically representative national sample of 2050 women. In this large, diverse cohort, 24% of premenopausal women aged 20–49 reported persistent low desire or reduced interest in sex. Of those with low sexual desire, 59% reported being ‘very’ or ‘extre-

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mely bothered’ by their loss of sexual interest. Taken together, these findings indicate that as many as 14% of premenopausal women aged 20–49 report decreased interest in sex with marked personal distress. Similarly, in a national research survey, Shifren et al.3 found that the prevalence of sexually related personal distress due to low desire was 12% among 31 581 US women aged ≥18. The prevalence estimates were based on a score of at least 15 on the Female Sexual Distress Scale© (FSDS©), a reliable, validated 12-item self-administered questionnaire that assesses women’s distress associated with their sex lives.4 In a telephone survey of 2207 US women aged 30–70 years in stable relationships, the overall prevalence of low sexual desire was 36.2% (n = 1936) and HSDD prevalence was 8.3%.5 The effects of HSDD on quality of life (QOL) continue to be underestimated. In 1995, the World Health Organization (WHO) acknowledged the impact of sexual dysfunction on QOL using its WHOQOL assessment instrument.6 The widely cited National Health and Social Life Survey reported the association between low sexual desire and low levels of physical and emotional satisfaction and happiness with partners.7 Survey studies in South America also report significant associations between sexual function disorders and QOL.8 Further, HSDD is associated with reduced health-related quality of life to a similar extent to that seen in women with diabetes or chronic back pain.9 Recently, the FDA has identified female sexual dysfunction as a serious unmet condition as part of its program on patient-oriented drug development. However, development of promising therapies for female sexual dysfunctions, as well as for the

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specific diagnosis of HSDD, have been lacking, primarily due to the costs associated with clinical development programs and the uncertain regulatory approval pathway (no approved regulatory guidances). As a result there has been little pharmaceutical research in this area and few therapies focused on women’s sexual health have reach late stage development and regulatory submission, and the few that have sought approval have not been successful. Psychotherapeutic interventions have demonstrated some benefit in the treatment of sexual dysfunction in women.10 However, HSDD comprises biological, psychological and social components (i.e. the biopsychosocial model), as is the case with most types of sexual dysfunction. Although the underlying pathophysiology is not completely understood, functional Magnetic resonance imaging (MRI) studies reveal persistent changes in brain activation and deactivation patterns in women with HSDD, compared with women with no history of HSDD.11–13 Thus, treatment options that include pharmacotherapy to correct or counteract these alterations in brain function are likely to be effective in treating HSDD or able to serve in a combined pharmacological and psychological approach. Currently, there are no approved pharmacotherapies for HSDD in the USA. Intrinsa, a testosterone patch developed by Proctor and Gamble and indicated for surgically menopausal women with HSDD receiving concomitant estrogen therapy, was approved in Europe in 2004, but it is not currently being marketed. Clinical trials of estrogen- and testosterone-based products to treat sexual function disorders in women have shown positive results for sexual functioning efficacy endpoints8 but the balance of hormonal risk versus sexual benefit is not clear, especially for populations at high risk for, or with preexisting, hormone-sensitive cancers, and cardiovascular disease. Some women with HSDD may use off-label therapies, such as testosterone products (often supplied by compounding pharmacies), psychoactive drugs or phosphodiesterase (PDE)-5 inhibitors intended for erectile dysfunction. However, compounded products are advertised without quality control or oversight and contain no package insert-type disclosures. Flibanserin is a non-hormonal therapy that acts on the brain to increase sexual desire. As is often the case with central nervous system (CNS) drugs, the exact mechanism of action is not clearly understood. In laboratory studies, flibanserin has been shown to be a 5-HT1A agonist and 5-HT2A antagonist. In addition, flibanserin binds with moderate affinity to 5-HT2B, 5-HT2C and dopamine D4 receptors. Clinically, the association of selective serotonin (5-HT) re-uptake inhibitor (SSRI)-based antidepressants with decreased sexual desire and difficulty with arousal and orgasm suggests that serotonin receptors are important regulators of sexual function.14–16 The mixed interaction of flibanserin with serotonin and dopamine receptors is

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thought to inhibit serotonergic ‘anti-sexual’ effects, while promoting dopaminergic effects, which are associated with an excitatory impact on sexual function. In addition, serotonin exerts an inhibitory influence over adrenergic tone, and decreased serotonin levels can elevate norepinephrine, which is also known to stimulate sexual function and excitement. The mechanism of action of flibanserin, therefore, may involve the normalisation of CNS neurotransmitter levels to enhance sexual desire. Flibanserin was initially developed by Boehringer Ingelheim (BI) as an antidepressant medication. In clinical trials for depression, flibanserin failed to meet the efficacy endpoints, but was superior to the positive comparator and placebo on the Arizona Sexual Experiences
scale (ASEX
) for increasing ‘sex drive’ in women. BI then initiated the development of flibanserin for the indication of HSDD, conducting Phase 3 double-blind, placebo-controlled trials in North America and in Europe in pre-menopausal women with the disorder (HSDD). In 2009, BI submitted a New Drug Application (NDA) to the FDA for an HSDD indication for flibanserin 100 mg qhs (single daily dose at bedtime) in pre-menopausal women, but discontinued development efforts thereafter. The FDA raised concerns regarding the balance of efficacy and safety. Sprout Pharmaceuticals, Inc. (SPI) acquired flibanserin from BI in 2011 to develop it worldwide for HSDD in pre-menopausal women. To address safety questions raised by the FDA and its consultants, SPI conducted new clinical studies and included additional data from BI-initiated studies that were not available at the time of the FDA initial evaluation. SPI plans to make a resubmission to the NDA in the latter part of 2014 that will include additional information requested by the FDA as part of its continued review. Specifically, SPI will complete additional Phase 1 studies, including more detailed pharmacokinetics and cognitive and motor skills assessments of the effects of possible next day somnolence. SPI also is working toward submission of a Marketing Authorisation Application (MAA) in Europe. Given the paucity of pharmacotherapeutic options for HSDD, a safe and effective medication being approved for this condition would provide the first treatment option specifically indicated for this patient population. Much of the evidence for the clinical efficacy and safety of flibanserin in the HSDD population comes from three large Phase 3 randomised, placebo-controlled trials in which 3548 HSDD patients were treated (2310 with flibanserin and 1238 with placebo).17–19 Efficacy endpoints included the number of satisfying sexual events (SSEs) measured by daily electronic diary entries and scores on the desire domain of the Female Sexual Function Index© (FSFI©), a 19-item self-administered questionnaire validated as a measure of overall sexual function in women, including women with HSDD.20 To measure distress associated with low

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sexual desire, the trials used a revised version of the FSDS (FSDS-R) that included an additional question (Item 13) to specifically assess distress due to low sexual desire.21 After 24 weeks of treatment with flibanserin administered at a single daily dose at bedtime of 100 mg (100 mg qhs), statistically and clinically significant improvement relative to placebo was seen in the number of SSEs, level of sexual desire measured by the FSFI desire domain, and reduction of distress related to low sexual desire measured by FSDS-R Item 13 (Figure 1A–C).17–19 The most recently completed Phase 3 trial18 included fewer eligibility restrictions to allow inclusion of a population more similar to that treated in clinical practice. Specifically, many concurrent medications such as triptans, antihypertensives, some antifungals, and antidepressants that were excluded in the earlier Phase 3 trials were permitted in this trial. The inclusion of these medications broadened the patient population exposed to flibanserin and increased the generalisability of results to women taking SSRIs and serotonin-norepinephrine re-uptake inhibitors (SNRIs) for mild or resolved depressive disorders. Regarding safety, the rate of serious adverse events (SAEs) in the flibanserin groups was ≤0.9% and no SAE was considered related to treatment. The most common adverse events (AEs) reported by patients were dizziness, nausea, fatigue and somnolence with frequencies of 9–12% in the flibanserin-treated groups versus 3–8% in the placebo groups.17–19 These AEs are common to medications impacting the serotonin system. In a 52-week long-term extension study in North America, 1723 women with HSDD who had participated in Phase 3 clinical trials or Phase 2 pharmacokinetic trials received flibanserin.21 Median duration of exposure was approximately 1 year and the maximum duration was approximately 24 months. Overall, long-term flibanserin treatment was well tolerated and no significant safety concerns were identified. At 15.8%, somnolence was the most frequently AE reported. Other frequently reported AEs occurred in 5.2–7.6% of patients and were consistent with those seen in the randomised, placebo-controlled trials. No treatment-related deaths occurred during the three trials. In summary, HSDD is a prevalent, widespread condition that can cause women and couples significant distress. Ultimately, a patient’s choice in consultation with her healthcare professional should guide treatment decisions. But without regulatory-approved pharmacotherapies, practitioners have limited treatment options, some without proven efficacy and with potential safety concerns. Women’s sexual well-being should be accorded an intrinsic value equal to that of men and there exists the need for a safe and effective product to treat the largely unmet medical need of HSDD.

Disclosure of interests JT, investigator and coordinating center for Study 511.075 (Daisy); SP, consultant for Sprout Pharmaceuticals and

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A

B

C

Figure 1. Mean change from baseline for efficacy endpoint results from three Phase 3 randomised, double-blind, placebo-controlled clinical trials with flibanserin for treatment of HSDD in premenopausal women.14–16

member of its Scientific Research Committee; JSy, full-time employee of Sprout Pharmaceuticals; JSi, investigator and coordinating center for Study 511-130 (Snowdrop);

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Development status of flibanserin

consultant for Sprout Pharmaceuticals and member of its Scientific Research Committee; KB, full-time employee of Sprout Pharmaceuticals.

Contribution to authorship Category 1 Conception and design: JT, SP, JSi. Acquisition of data: JT, JSi. Analysis and interpretation of data: JT, SP, JSy, JSi, KB. Category 2 Drafting the article: JSy, JSi, KB. Revising it for intellectual content: JSy, JSi, KB, SP. Category 3 JT, SP, JSy, JSi, KB.

Details of ethics approval Not applicable.

Funding Financial support for medical writing assistance for this article was provided by Sprout Pharmaceuticals and provided by Susan Berman. The studies summarised in this manuscript were financed by the previous owner of the flibanserin program, Boehringer Ingelheim.

Acknowledgements The authors would like to acknowledge the contributions of all of the investigators who participated in the many flibanserin studies as well as the patients. We would like to acknowledge the technical support in the development of this paper provided by Ms Susan Berman. The authors were responsible for all content and editorial decisions, were involved in the development of the manuscript and have approved the final version.

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