While an FDA panel recommended approval of Sprout Pharmaceuticals Inc.’s female sexual dysfunction drug Addyi (flibanserin), several members conditioned their vote on a labeling contraindication and a Risk Evaluation and Mitigation Strategy, despite uncertainties that either would be able to prevent the alcohol use that exacerbates adverse events.

At a joint June 4 meeting, FDA’s Bone, Reproductive and Urologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee voted 18-6 in favor of approval of flibanserin for the treatment of female hypoactive sexual desire disorder (HSDD) in premenopausal women. The disorder is characterized by the lack of desire for sexual activity Also see "Sprout's Flibanserin Gets Reluctant Nod From FDA Panel, But REMS Needed" - Pink Sheet, 5 June, 2015..

FDA highlighted concerns about cases of hypotension and syncope (fainting) – risks that were increased when the drug was used in combination with alcohol or moderate or strong CYP3A4 inhibitors. In briefing documents released prior to the meeting, the agency questioned whether it is possible to mitigate these risks Also see "Flibanserin Risk Management Challenges: Can A REMS Prevent Alcohol Interactions?" - Pink Sheet, 3 June, 2015..

Panel members expressed uncertainty about whether a REMS would be effective in limiting the population who gets the drug. According to Sprout, about 7% of premenopausal women have HSDD.

“I think it’s going to be tough sledding to try to avoid having this product used among women that drink,” given that 50% of women in this age population use alcohol, Committee Member Caleb Alexander, Johns Hopkins Bloomberg School of Public Health, said. As for whether alcohol should be contraindicated, he said he doesn’t have a strong opinion about that right now.

Other members noted that alcohol-drug interactions are fairly common with other drugs. For example, one panelist noted that her patients have taken metronidazole for infections and she has had no problem counseling them about the side effects of alcohol use. However, another committee member said the concern with flibanserin is that it would be used chronically.

Some panelists also questioned the feasibility of avoiding alcohol altogether.

Sprout conducted an alcohol interaction study in 25 people, only two of which were women. Panelists were critical of the lack of women in a study of a drug intended solely for women and recommended that another study be done in this population.

Not A Date Rape Drug, Panel Told

One of the most common side effects of flibanserin is sleepiness, and FDA expressed concern about the impact it might have on women. “Is sedation contributing to receptivity to sexual advances and or recall?” FDA’s Ashley Slagle, a member of the Clinical Outcomes Assessments Staff in the Office of New Drugs, asked during her presentation.

Diane Aronson, a patient representative on the committee, said she was concerned about the sleepiness side effect. “One thing I worry about is because of the indication of this drug, could it be thought of as [being] like a date rape drug,” she said.

An FDA representative responded, “I think that’s an excellent point and that is something certainly that we have thought about.”

Panelist Marianne Brandon, a clinical psychologist and sex therapist in Annapolis, Md., said it was “disrespectful to compare” flibanserin to a date rape drug. She said she has worked with multiple women who have received a date rape drug and been raped and that they told her they couldn’t move, were confused and lost their memories. “I’m hearing nothing on that level today about the side effects,” she said to cheers and applause from the audience, which was filled with individuals advocating approval of the drug.

A representative from Sprout noted that the company had looked at flibanserin’s potential use as a date rape drug. She said it does not have an immediate effect – by day 14 there was no effect on sexual desire – and did not cause hypersexuality, immobility or amnesia. She compared its sedative effect to products like the antihistamine Benadryl.

Breast Cancer Found In Mouse Study

During a report on flibanserin safety, FDA Medical Officer Olivia Easley mentioned the appearance of mammary gland carcinomas in mice given four times the human dose. Committee Member Michele Orza, Patient-Centered Outcomes Research Institute, said breast cancer risk “is kind of a show stopper” for her and asked what the panel should make of it.

An FDA representative noted that the longest exposure to the drug in the clinical programs was a year to 18 months, which is not enough to assess the risk for breast cancer development.

A toxicologist consultant for Sprout also responded to Orza’s concern about the data. “Based on the nature of the tumor findings in female mice there is a minimal biological probability that the mammary tumors were caused by flibanserin treatment and that the mouse tumors are clinically relevant,” she said.

However, she said there were no increases in mammary tumors in a two-year rat study in males or females or in the two-year mouse study in males and “the slight increase in mammary tumor incidence in field mice is not likely due to drug treatment since flibanserin is not genotoxic.” She added that there was no evidence of mammary gland hyperplasia in mice, rats or dogs treated chronically with flibanserin.

“Per the International Agency for Research on Cancer and Environmental Agency Protection guidelines on interpreting rodent carcinogenicity findings, if you only see increased tumor findings in a single sex of a single species, that finding is not considered predictive of a human cancer risk, and this was the case with the mammary tumors in flibanserin-treated mice,” she stated.

Another representative from Sprout said the company has offered to do a Phase IV epidemiological study following up on long-term exposure.

Panelists noted the need for long-term safety studies with flibanserin. They also recommended prescriber and pharmacy certification, a patient registry, prescriber education and checklists to document informed consent.

Sprout has also proposed a risk management program that includes a Medication Guide and a communication plan REMS, consisting of letters to prescribers, pharmacists and medical societies, a REMS website and tools for diagnosing HSDD and determining whether flibanserin use is appropriate for a specific patient. The company also intends to delay direct-to-consumer TV and radio ads for at least 18 months after launch.

‘Numerically Small’ Treatment Differences

The three pivotal trials supporting Sprout’s NDA included a total of 3,548 patients, with 2,310 randomized to 100 mg flibanserin and 1,238 to placebo for 24 weeks. The two co-primary endpoints were change in the number of satisfactory sexual events (SSEs) from the four-week baseline to the 28 days prior to a final clinic visit, and change in sexual desire as measured by questions in the Female Sexual Function Index (FSFI). Flibanserin showed a statistically significant improvement over placebo in increasing sexual desire in all three trials, although the treatment differences were numerically small.

FDA noted that the absolute difference in percentage of responders with flibanserin and the percentage of responders with placebo is about 9% to 15% and that the placebo response rates ranged from 29% to 49%.

FDA’s Christina Chang, clinical team leader in the Division of Bone and Reproductive Products, stated that depending on the analysis, satisfactory sexual events with flibanserin increased from 0.5 or 0.8, “so one event per month.”

For sexual desire measured by the FSFI Desire Index using 28-day recall, treatment with the drug resulted in an improvement in the score of slightly less than half a point on a scale of 1.2 to six. In two studies, sexual desire was assessed according to entries in an electronic diary, and no improvement was found over placebo.

A secondary endpoint was change in distress over the lack of sexual desire, measured by responses to questions in the Female Sexual Distress Scale. Chang said flibanserin consistently lowered distress score by about slightly less than half a point on a scale of zero to four.

Committee members expressed reluctance to vote for approval of the drug given its modest benefit. But they concluded that any improvement in sexual desire could make a difference for women, particularly since there is no approved treatment for HSDD.

Boehringer Ingelheim GMBH was the original sponsor for the product when an FDA advisory committee unanimously recommended against approval in 2010. Panelists said the company failed to demonstrate that flibanserin significantly improved sexual desire, as measured through a daily electronic diary, in the target population. They also raised concerns about the drug’s sedating and depressive effects and the lack of long-term safety data Also see "Flibanserin Fails To Improve Sexual Desire, FDA Advisory Committee Says" - Pink Sheet, 18 June, 2010..

FDA subsequently sent the company a “complete response” letter recommending that it conduct a new Phase III trial. Boehringer then passed the product to Sprout, which resubmitted the NDA in 2013. FDA sent a second “complete response” letter raising efficacy and safety concerns and Sprout conducted additional studies. It resubmitted the NDA on Feb. 18, giving it a user fee goal date of Aug. 18.

Based in Raleigh, N.C., Sprout was spun off from Slate Pharmaceuticals Inc. in 2011 and has focused solely on development of flibanserin.

In Recommending Flibanserin Approval, FDA Panelists Urge Alcohol Contraindication

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