IEBS Insights: Flibanserin

3-[2-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]ethyl]-1H-benzimidazol-2-one, better known as Flibanserin, was initially studied as an antidepressant drug[1]. It was later repurposed for the treatment of libido for women i.e. hypoactive sexual desire disorder (HSDD). It was first investigated for HSDD, by Boehringer Ingelheim but was rejected by the US FDA in 2010 due to statistically insufficient data to favor the effect on enhancing sexual desire[2]. Later in 2012, Sprout Pharmaceuticals bought Flibanserin from Boehringer Ingelheim[3].

After another FDA rejection, Flibanserin was finally approved by the FDA in August 2015 for the treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women[4]. Soon after receiving the approval, Sprout Pharmaceuticals was acquired by Valeant Pharmaceuticals for USD 1 Billion, which then started marketing Flibanserin under the trade name Addyi™ (100mg oral tablet)[5].

         Figure 1: Timeline to approval of Flibanserin (Source: https://www.sciencedirect.com/science/article/pii/S2050052117300677 )

Timeline to approval of Flibanserin

Drug Mechanism: Flibanserin works in association with serotonin receptors (5-HT1A and 5-HT2A). Both 5-HT1A and 5-HT2A receptors affect anxiety, blood pressure regulation and sexual desire. Sexual desire is mediated by brain circuits that connect prefrontal cortex (PFC) with limbic and cortical areas. Neurotransmitters such as dopamine and norepinephrine and hormones like testosterone and estrogen are major up-regulators for this process. Hypoactive sexual desire disorder is believed to be the result of inhibition of these neurotransmitters. Addyi™ modulates serotonin receptors which cause an increase in the release of these neurotransmitters subsequently enhancing sexual desire[6].

Efficacy and Safety:[7]

Most common side effects of Flibanserin include dizziness, nausea, and tiredness. The intake of the drug should be avoided by women who have hepatic impairment or women who are on moderate or strong cytochrome P4503A4 inhibitors such as azole antifungals or protease inhibitors.

Flibanserin is contraindicated in patients with hepatic impairment as there are main risks of hypotension and syncope.

It is advised to take flibanserin at night to avoid possible adverse effects, which are more prominent when it is taken in the morning. Pregnancy and breastfeeding should be avoided while taking Flibanserin.

Treatment should be discontinued after eight weeks if no improvement in sexual desire and associated distress is observed. Flibanserin is approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU).


Ongoing Clinical Trials

The University of Chicago and the San Diego Sexual Medicine are currently recruiting participants for their clinical trials of flibanserin for hypoactive sexual desire disorder.

  1. Flibanserin and Women with Hypoactive Sexual Desire Disorder: A Double-Blind, Randomized, Electrical Neuroimaging Study[8]

Sponsor: University of Chicago, Chicago, Illinois, United States

Start Date: October 2016

Estimated Completion Date: October 2018

Study Purpose: To determine the extent to which Flibanserin normalizes brain activity in women with HSDD and the extent to which regional brain activation is associated with changes in symptoms and behavior.

  1. Two Arm Open-Label Pilot Study of Flibanserin (Addyi®) vs. Flibanserin and Sex Therapy[9]

Sponsor: San Diego Sexual Medicine, San Diego, California, United States

Start date: January 2017

Estimated Completion Date: March 2019.

Study Purpose: To determine whether efficacy of Flibanserin as determined by changes in the desire domain of the Female Sexual Function Index (FSFI) in women who respond to the study medication is greater when sex therapy is performed concomitant with the use of the medication.


Technology & IP Insights

  • Majority of the patents in the domain have been filed by Boehringer Ingelheim, followed by Pfizer and Rhone Poulenc Rorer; and claim the structure or derivatives of Flibanserin.
  • Contera Pharma has also been actively researching Flibanserin. In 2017, the company was granted a patent claiming the use of Flibanserin in treating movement disorders. The formulation is a solid dosage form and used in the treatment of disorders associated with Parkinson’s disease or associated with drugs such as neuroleptic drugs, antidepressants, etc.
  • Sprout Pharmaceuticals has identified that Flibanserin can also be used for the treatment or reduction of urinary incontinence. The company has also developed a new method for the preparation of a crystalline form of Flibanserin which can be used for treating various CNS disorders, sleep and sexual disorders.


Market & Business Insights

Despite revamping the marketing strategy for Addyi™, drug sales are low. Two possible reasons are:

  1. Pricing: Sprout Pharmaceuticals’ initial pricing strategy for Addyi™ was around USD 400 per month. However, Valeant Pharmaceuticals upped the price to USD 800 a month. The high price of the drug made it unaffordable to a large consumer group.
  1. Comparison with Viagra: The positioning of Addyi™ as a ‘Female Viagra’ has led to it being directly compares to Pfizer’s Viagra™ for men. Since Addyi™ does not cause Viagra™-like dramatic changes in libido, female consumers are left unsatisfied and confused about the efficacy of the drug.

Other factors that may have contributed to the diminished sales of Addyi™ are:

  • Strict ‘no use’ with alcohol due to associated risks
  • Cannot be consumed with common medicines such as those for treating fungal disease, HIV, hepatitis, hormonal birth control etc.
  • Multiple rejections by the US FDA

So far, Addyi™ has been unable to establish itself in the market. This could be the reason why Valeant Pharmaceuticals decided to divest Sprout Pharmaceuticals. However, it may not be the end of the road for Flibanserin or future drugs for treatment of HSDD. Flibanserin is the first drug of its class and has in fact acted like a gateway to research in this field.

[1] http://onlinelibrary.wiley.com/doi/10.1038/sj.bjp.0705341/full

[2] https://www.pharmazeutische-zeitung.de/index.php?id=34358&type=0

[3] Flibanserin: From Bench to Bedside. Erin M.Dooley, Melanie K.Miller, Anita H.Clayton. Sexual Medicine Reviews. 2017 October; 5(4):461-469.

[4] https://wayback.archive-it.org/7993/20170112023753/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm458734.htm

[5] http://ir.valeant.com/news-releases/2015/20-08-2015

[6] Multifunctional pharmacology of flibanserin: possible mechanism of therapeutic action in hypoactive sexual desire disorder. Stahl SM, Sommer B, Allers KA. J Sex Med. 2011 Jan; 8(1):15-27.

[7] https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022526lbl.pdf

[8] https://clinicaltrials.gov/ct2/show/NCT02770768

[9] https://clinicaltrials.gov/ct2/show/NCT02714049