Sprout’s Female Desire Drug: Size Of Safety Studies Doesn’t Matter To FDA

Flibanserin development can move forward after dispute resolution, but women’s health advocates criticize the delay, charging that FDA has a double standard for female sexual dysfunction drugs.

Sprout Pharmaceuticals Inc.’s appeal to FDA on its rejected female sexual dysfunction drug flibanserin resulted in a request for three small, new safety studies, but not the efficacy work that had been suggested in a “complete response” letter for the filing, according to the company.

Following a submission in March 2013, FDA issued a CRL for flibanserin in October of that year requesting additional efficacy and safety work. The company responded with an appeal in December through the agency’s formal dispute resolution process.

Sprout announced on Feb. 11 that it is planning to conduct the select new safety studies outlined by FDA and to resubmit the filing for the drug in hypoactive sexual desire disorder (HSDD) in premenopausal women by the third quarter. Following resubmission, the company expects a six-month review; it is unclear whether the agency will convene an advisory committee panel. The safety studies mean another delay to the application but are clearly preferable to new trials proving efficacy.

Sprout’s success would be ground-breaking. HSDD describes a loss of desire for sex, causing distress, with no known underlying conditions, such as depression. In contrast with male sexual dysfunction, where treatment options abound, nothing is currently FDA-approved for female sexual desire disorder, though testosterone cream is used off label.

Approval of flibanserin had the potential to show the regulatory way for other sponsors (Also see "Resurrected Flibanserin Filing Tests FDA Position On Female Sexual Desire Disorders" - Pink Sheet, 15 Jul, 2013.).

Unlike other therapies which have been tried and failed in HSDD, flibanserin is a centrally-acting drug taken daily, as opposed to a hormonal approach applied on demand.

Sprout is one of a growing number of companies to take advantage of the CDER’s formal dispute resolution process following the rejection of a filing (Also see "If At First You Don’t Succeed, Try Dispute Resolution" - Pink Sheet, 9 Dec, 2013.). The denial rate for these appeals is high and sponsors rarely get the exact outcome they wanted, but the effort can nevertheless pave the way forward for a resubmission.

“The FDA decision is an unfortunate setback, requiring the only promising treatment for female sexual dysfunction to jump through more unnecessary hoops,” says the National Consumers League’s Sally Greenberg.

Such was the case for Sprout. Flibanserin was originally developed and submitted for approval by Boehringer Ingelheim GMBH, but received a CRL in 2010. BI’s filing was supported by two pivotal trials with mixed efficacy results, leading an advisory committee to vote against approval (Also see "Flibanserin Fails To Improve Sexual Desire, FDA Advisory Committee Says" - Pink Sheet, 18 Jun, 2010.). Sprout obtained rights after Boehringer decided not to move forward with development.

Sprout believed it had more than enough data when it filed its NDA, which included data for over 11,000 women in March 2013. This dataset included studies previously submitted by Boehringer and new data for 3,000 people.

The original application included two pivotal trials in which the drug failed to meet a co-primary endpoint of arousal as reported in patient diaries, a measure that FDA has not been requiring as a primary endpoint in recent communications with sponsors of female sexual dysfunction drugs. Sprout submitted a third study with its new filing in which the drug met co-primary efficacy endpoints related to an increase in the number of sexually satisfying encounters and a decrease in distress (Also see "If At First You Don’t Succeed, Try Dispute Resolution" - Pink Sheet, 9 Dec, 2013.).

This was an “extraordinarily large data package by any measure,” commented President and Chief Operating Officer Cindy Whitehead in an interview.

Sprout: “Women Are Not Counters”

Nevertheless, FDA determined that the benefit was too modest in light of exposure to the risks associated with treatment, which include dizziness, nausea, fatigue and sleepiness. Much of the discussion with the agency centered on efficacy, as measured by the number of sexually satisfying events, Whitehead explained. However, in the studies, women reported that the improvement in their symptoms was clinically meaningful. Whitehead sees a modest change as a meaningful change – treatment is not intended to “catapult” the patient above her peer who doesn’t have HSDD, she said.

The exec added that focusing heavily on one endpoint related to the number of sexual events is a relic of male sexual drug trials. Women differ in terms of their baseline number of events and the total that they would find satisfying.

“Women are not counters,” she said.

Moving forward, as part of its agreement with FDA, Sprout plans to perform two Phase I drug interaction studies and a Phase I driving simulator study, each of which will test the drug in 25-50 healthy volunteers. The drug interaction studies will test different enzyme pathways than the ones already studied, while the driving simulation study will evaluate risks associated with the somnolence side effect. As an agonist of serotonin 5HT(1A), an antagonist of 5-HT(2A) receptors and a partial agonist of dopamine 4 receptors, the drug may cause sedation.

The agency has been requesting driving simulation studies for centrally-acting drugs, following reports of impaired driving with prescription sleeping aids (Also see "Insomnia Drug Development Programs Must Include Driving Studies, FDA Says" - Pink Sheet, 10 Jan, 2013.).

Women Speak Out For Sprout

Whitehead said she is very encouraged by the outcome of the dispute resolution process, and the straightforward nature of the next steps. If the drug gets to market, it could open the door for other treatments, the exec said, noting that flibanserin is not a cure-all. The road to development in female sexual dysfunction has been rocky in the past, with failures including Pfizer Inc.’s Viagra (sildenafil), Procter & Gamble Pharmaceuticals Inc.’s. testosterone patch Intrinsa and BioSante Pharmaceuticals Inc.’s testosterone gel LibiGel. Companies with drugs for female dysfunction disorders in the pipeline in recent years include Palatin Technologies Inc., Acerus Pharmaceuticals Corp. and S1 Biopharma Inc.

Female sexual dysfunction was one of the disease areas with high unmet need targeted by FDA for patient-centered drug development meetings required by the FDA Safety and Innovation Act (Also see "FDA’s Patient-Focused Meetings: Round One Selections Include Diseases Broad And Rare" - Pink Sheet, 22 Apr, 2013.).

Women’s health advocacy groups issued a press statement Feb. 11 in support of Sprout’s flibanserin and critical of the agency. The statement – issued by the National Consumers’ League and National Organization of Women, among other organizations – charged that FDA is setting the bar too high for female sexual therapies, creating a double standard compared to male sex dysfunction drugs.

The statement noted that over 11,000 women in trials for HSDD is “more than any approved male sexual health drug,” and that 24 drugs have been approved for male sexual dysfunction, despite serious side effects and smaller datasets, versus zero for women.

“This FDA decision is an unfortunate setback, requiring the only promising treatment for female sexual dysfunction to jump through more unnecessary hoops. It also suggests that a double standard exists for evaluating drugs to treat women for low sexual desire,” said Sally Greenberg, executive director of the National Consumers League, in the statement.

The statement also noted that advocacy groups met with FDA officials in January to highlight the lack of safe and effective treatments for women. National Organization for Women President Terry O’Neill said that there is clearly a bias in FDA standards when it comes to women’s therapies. The agency’s “go-slow tactics are preventing us from having access to a treatment option where we make the decision in consultation with our healthcare provider,” O’Neill said.