Female sexual dysfunction therapy pipeline

Female sexual dysfunction (FSD) pertains to persistent or recurrent problems with sexual response or desire in women. According to commonly cited prevalence estimates, 43 per cent of women aged 18-59 years have FSD, a figure that is disputed among leading researchers.

Although the definition of FSD continues to evolve, it currently comprises four recognised components that are not mutually exclusive: decreased sexual desire, decreased sexual arousal, dysparenuria (pain during sexual intercourse), and persistent difficulty in achieving or inability to achieve orgasm (anorgasmia). These components must be associated with personal distress, as determined by the affected individual, to validate a diagnosis of FSD.

One of the most well known sexual dysfunction conditions is hypo-active sexual desire disorder (HSDD), also commonly referred to as decreased libido. HSDD is thought to be the most prevalent sexual disorder in women of all ages. HSDD is characterised by a deficiency or absence of sexual fantasies or desire for sexual activity for a marked period of time, causing distress and/or interpersonal difficulties.

Both physical and psychosocial factors may be implicated in sexual dysfunction, although the exact cause cannot always be identified. FSD can be caused by hormonal imbalances associated with low levels of oestrogen or testosterone. Sexual activity may also be impacted by factors such as the use of drugs and alcohol. Although common, increased awareness of FSD is still relatively new. This is confounded by FSD being a seemingly contested diagnosis, with controversy surrounding attempts to 'medicalise' sexual problems.

Following the success of Pfizer's Viagra (sildenafil), the first drug approved for erectile dysfunction, an equally valid treatment option has been sought for sexual dysfunction in women. A number of pharmaceutical companies are researching therapies for the treatment of FSD, often by involving low doses of testosterone, although the long-term safety of testosterone in women is unknown. Testosterone, which is a naturally occurring steroid hormone, is believed to have a direct role in sexual function and desire.

It is the primary circulating androgen in women and is secreted by the ovaries and adrenal glands. In comparison to the sudden decline in oestrogen that women experience during menopause, serum levels of androgens decline in a more gradual manner as women age, due to a decrease in the production of adrenal oestrogen precursors. Other examples of therapies in development for FSD include prostaglandin E1 agonists and melanocortin type 4 receptor agonists.

Current therapies
The testosterone patch Intrinsa has been launched by Warner Chilcott in the EU for the treatment of FSD in surgically menopausal women who are also receiving concomitant oestrogen therapy. The European Commission granted marketing authorisation under the EU-wide centralised procedure in July 2006. Warner Chilcott sought to extend the use of the testosterone patch to include HSDD in naturally menopausal women; however, the company withdrew its application in September 2010 based on commercial considerations.

In the US, Procter & Gamble (now Warner Chilcott) withdrew its New Drug Application (NDA) for the testosterone patch in the treatment of FSD after negative feedback from the US Food and Drug Administration's (FDA) Reproductive Health Drugs Advisory Committee in December 2004. Procter & Gamble planned to work with the FDA to provide additional safety data; however, the company subsequently put development on hold.

In order to support development of therapies for FSD, the FDA issued a draft guidance entitled, 'Female Sexual Dysfunction: Clinical Development of Drug Products for Treatment' in May 2000. In this document, it states that two adequate, well-controlled phase III trials of approximately six months' duration are recommended for approval of drug products for FSD. The primary endpoint of these trials should be based on the number of satisfactory sexual events or episodes over time. The short duration of prior clinical trials may be viewed as a concern regarding potential serious adverse effects.

Testosterone congener stimulants
LibiGel is a transdermal, once-daily gel formulation of testosterone being developed by BioSante Pharmaceuticals for the treatment of FSD, specifically HSDD. The company has completed two phase III registrational trials, collectively known as BLOOM, under a Special Protocol Assessment (SPA) agreement with the FDA. The randomised trials were conducted in the US and Canada in surgically menopausal women with HSDD.

As reported in December 2011, LibiGel did not meet the co-primary endpoints in these trials, indicating that it was no more effective than placebo in increasing the number of satisfying sexual events or sexual desire scores. BioSante Pharmaceuticals anticipates an NDA submission for LibiGel in the US in the fourth quarter of 2012. The European Medicines Agency (EMA) had also previously confirmed that the two BLOOM studies would support potential European registration.

Following the FDA's Reproductive Health Drugs Advisory Committee decision not to recommend Intrinsa for this indication, BioSante Pharmaceuticals decided to incorporate FDA recommendations regarding additional safety data required for the approval of testosterone products for FSD in future trials. A phase III BLOOM trial investigating the long-term safety of LibiGel is ongoing. In light of the reported results, BioSante Pharmaceuticals continues to evaluate the future development of LibiGel. Currently, there is no FDA-approved product for the treatment of HSDD.

Luramist is a transdermal spray formulation of testosterone that is under development with Acrux. The product comprises a small, handheld spray that delivers testosterone once daily at a pre-set dose via Acrux's proprietary ACROSS skin penetration enhancers. Luramist is set to enter phase III development for HSDD in the US, and is in phase II trials in Australia.

Trimel Pharmaceuticals is developing a low-dose intranasal gel formulation of testosterone (TBS-2). Results from a completed phase II trial are scheduled for presentation at a Trimel Pharmaceuticals R&D Event on February 14, 2012 in Toronto, Canada. Favourable interim results of the Canadian-based Vibrotactile Stimulation Study (VTS) have been reported. The study measured the ability of low-dose intranasal testosterone to induce orgasm in women with primary or secondary anorgasmia, a form of FSD with no approved treatment options.

A topical testosterone lotion (ESP 210) is being developed by Novavax for the treatment of conditions relating to testosterone deficiency, particularly FSD. Phase II trials are currently under way in the US.

Prostaglandin E1 agonists
Femprox, a topical formulation of alprostadil, is undergoing clinical development for female sexual arousal disorder (FSAD) with Apricus Biosciences in the US, and its Asian licensee, Vergemont International, in China. A randomised, phase III trial was completed in China in 2005 among 400 premenopausal and postmenopausal women. Apricus Biosciences intends to utilise preliminary trial findings to advance its clinical programme for Femprox in the US, where it is planning a phase III programme in support of a marketing approval application. Canadian authorities will also be approached to determine whether the previously conducted 400-patient phase III trial is sufficient for a New Drug Submission filing in Canada.

Melanocortin Type 4 receptor agonists
Bremelantotide is a melanocortin type 4 receptor agonist being developed by Palatin Technologies for the treatment of FSD. The company has initiated a randomised, double-blind, placebo-controlled, dose-finding phase II trial of subcutaneously administered bremelanotide (PT 141) in approximately 400 premenopausal women with FSAD and/or HSDD in the US and Canada.

European development
BioSante Pharmaceuticals and its licensee, Pantarhei Bioscience, are co-developing a patented, oral triple-hormonal contraceptive called Pill-Plus, which could potentially treat FSD in women using contraceptives. The new combination adds an androgen to the typical two-hormone (oestrogen and progestogen) contraceptive. The addition of androgen is believed to prevent androgen deficiency-related loss of libido, which is known to occur in women using combined oestrogen and progesterone contraception. A phase II trial has been completed in the Netherlands.

Boehringer Ingelheim (BI) was developing flibanserin, a benzimidazole with a high affinity for cortical serotonin1A and serotonin2A receptors, for the treatment of HSDD in the US, Canada and the EU. However, after the FDA's Reproductive Health Drug Advisory Committee advised that further data would be required, BI discontinued development of the drug in October 2010.

Conclusion
In order to advance new therapies, drug developers must have confidence that they can conduct large, randomised, controlled clinical studies to assess safety and efficacy and to support regulatory approval. The conduct of such trials in FSD has been an evolving process, made more difficult by the complexity of the disorder and an incomplete understanding of the female sexual response cycle.

The majority of current clinical development surrounding FSD appears to be taking place in North America. A number of pharmaceutical companies have previously attempted to break into the US market, with many since discontinuing development in this area.

Since the launch of Intrinsa, few companies appear to be developing therapies for FSD in Europe. FSD remains an unmet need in many markets, particularly in naturally menopausal women. It has been more than a decade since the FDA approved Viagra for the treatment of male sexual dysfunction; the general consensus among clinicians is that it is time for female counterparts to be provided with a safe and effective option for FSD.

The Author
R&D pipeline was written by Leah Jacobsen of Adis International (Springer Healthcare), using data derived from Adis R&D Insight, Clinical Trials Insight and inThought. For further information on Adis' services, please contact Daniela Ranzani on +39 02 423 4562 or email daniela.ranzani@wolterskluwer.com