Approval prospects for Boehringer Ingelheim's Girosa (flibanserin) as the first drug indicated for treating hypoactive sexual desire disorder could hinge on an FDA advisory committee's views regarding how improvements in sexual desire are best measured.

At a June 18 meeting, the Reproductive Health Drugs Advisory Committee will be asked whether flibanserin's impact on sexual desire is better evaluated using a 28-day recall assessment preferred by the sponsor, or a daily electronic diary - a measure for which the drug failed to show statistical significance in two North American trials.

Flibanserin is a post-synaptic 5-HT1a agonist and 5-HT2a antagonist. The drug was initially studied for major depressive disorder but failed to show efficacy in Phase II trials. However, flibanserin was not associated with the sexual dysfunction commonly seen with other antidepressants, and data suggesting it could improve sex drive led to further exploration as a treatment for HSDD in premenopausal women. The proposed dose is a 100 mg oral tablet daily at bedtime.

HSDD is defined as the persistent or recurrent deficiency or absence of sexual thoughts, fantasies, and/or desire for sexual activity, which causes marked distress or interpersonal difficulty. In briefing documents for the meeting, Boehringer estimates the condition affects as many as 8.6 million U.S. women ages 20-49 years.

There are no drugs specifically indicated for HSDD in the U.S., though FDA does have some experience evaluating drugs for the condition. Procter & Gamble withdrew its NDA for Intrinsa (testosterone patch) for female sexual dysfunction following a negative 2004 review by the Reproductive Health Drugs Advisory Committee, which found the long-term safety data available at that time to be inadequate. However, the drug is approved in Europe and marketed by Warner Chilcott (which acquired P&G's prescription pharmaceuticals business in 2009).

Efficacy Concerns Tied To Endpoint Issues

In a 2000 draft guidance, FDA's Division of Reproductive and Urologic Drug Products recommended that sponsors pursuing an HSDD indication demonstrate a change from baseline in satisfactory sexual events as the primary endpoint, with SSEs recorded daily by subjects. In practice, the division has typically advised sponsors that the change from baseline in sexual desire also should be a co-primary endpoint, with change from baseline in personal distress due to HSDD a key secondary endpoint, according to agency briefing documents for the flibanserin meeting.

In its review of flibanserin, the division focused on what it considered to be the two pivotal trials, both of which were randomized, double-blind, placebo-controlled studies conducted in North America and encompassing more than 2,400 subjects in total. The treatment period was 24 weeks.

The proposed flibanserin dose was associated with a statistically and clinically significant increase from baseline in the number of SSEs, as measured by subject responses in an electronic diary, with almost one additional SSE per month compared with placebo in both studies. However, the change from baseline in the prespecified co-primary endpoint of sexual desire as measured by the daily eDiary was not statistically significant.

Boehringer sought to modify the co-primary endpoint of sexual desire by using only two questions on sexual desire in the Female Sexual Function Index, which was a secondary endpoint in one of the pivotal studies. Using this measure, the change from baseline in desire was significant. However, the review division challenged the change in endpoints.

"The Division does not agree that the FSFI desire items should provide the primary support for efficacy on the co-primary endpoint of sexual desire," the agency's briefing documents state. "It is inappropriate to modify prespecified endpoints after results of the studies are known. In addition, the Division had expressed concern prior to NDA submission about the utility of the FSFI as an endpoint instrument."

FDA said it provided guidance in a 2005 meeting with the sponsor that the evaluation of change in sexual desire should not be based on a 28-day recall, as is the case with the FSFI sexual desire index, but rather on a more frequent recording of the endpoint, as reflected by the daily eDiary.

Furthermore, results from a randomized, double-blind, placebo-controlled study in Europe undercut Boehringer's arguments that the failure to show a treatment benefit on desire in the North American studies was because the eDiary was an inadequate endpoint instrument, the division said. In the European study, there was a statistically significant improvement in desire as measured by the eDiary, but not when assessed using the FSFI. The European trial failed to show a significant improvement in SSEs.

Safety Unknowns Could Prompt Post-Market Requirements

FDA is also asking the advisory committee to weigh flibanserin's risk/benefit profile in light of several safety concerns.

"An increased frequency of depression, syncope and accidental injury was observed among flibanserin-treated subjects when compared to placebo in the HSDD clinical trials database; syncope and depression appeared to be dose-proportional," the review division said.

The drug's tolerability was adversely affected when administered concomitantly with SSRIs, triptans and hormonal contraceptives, and coadministration with a potent CYP3A4 inhibitor led to at least a 4.5-fold increase in systemic exposure of flibanserin. These drug-drug interactions may increase the risk of accidental injury, syncope and depression, the review division said.

Furthermore, the population studied in the Phase II and III HSDD trials was generally healthy and taking few concomitant drugs. "The safety of flibanserin in the general population on concomitant prescription drugs or with significant medical or psychiatric histories is unknown. It is not clear if labeling alone will be sufficient to alert women to the numerous drug interactions that exist with flibanserin". The division's comments suggest that a Risk Evaluation and Mitigation Strategy may be needed.

Placebo-controlled data did not suggest a significant suicidality risk with flibanserin. However, given the drug's mechanism of action, it would be considered to have antidepressant properties, and a consult from FDA's Division of Psychiatric Products recommends that it carry the antidepressant class boxed warning on suicidality in labeling.

-Sue Sutter (s.sutter@elsevier.com)

Flibanserin Panel Review Will Pivot On Measurement Of Sexual Desire

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