All these bits of the “big picture” continue to complicate research in female sexual function.
It is imperative that we begin to understand the nuances of our patients’ sexual problems if we are to offer effective suggestions for treatment and management. Objectively determined genital arousal disorder very likely derives from neurovascular causes and is likely to respond to PDE5 inhibitors, but subjective arousal disorder with normal vulvar and vaginal engorgement and lubrication is not likely to respond to these agents.
This is the state of our basic science knowledge in 2010. What’s out there and on the horizon for us to offer our patients?
Flibanserin gets an unequivocal thumbs down
Phase-3 Trial 511.71. A twenty-four week, randomized, double-blind, placebo-controlled, safety and efficacy trial of flibanserin 50 milligrams every evening and flibanserin 100 mg every evening in women with hypoactive sexual desire disorder in North America. NCT00360529.
Phase-3 Trial 511.75. Best tolerability: 50 mg twice daily versus 100 mg in the evening versus 25 mg twice daily versus placebo in younger women in North America. NCT00360555.
Flibanserin is a 5HT 1A agonist, 2A antagonist, and weak dopamine agonist. It was originally studied as a treatment for major depressive disorder. In phase-2 trials, it was ineffective for management of depression but superior to placebo and an active comparator in improving sex drive (based on validated questionnaires). These results formed the basis for studying flibanserin as a treatment for HSDD. More than 5,000 women have been involved in phase-2 and phase-3 trials in the United States, Canada, and Europe.
Following FDA guidance for sponsors developing treatments for HSDD, drug maker Boehringer Ingelheim defined the primary endpoints for the pivotal trials as an increase in the number of sexually satisfying events (SSEs) and sexual desire, as measured by a daily diary. Sexual events included:
- genital touching by the partner
- masturbation
- oral sex
- intercourse
- orgasm.
Sexual desire was rated daily by the participants using an eDiary.
In North American phase-3 trials, 2,462 premenopausal women with acquired HSDD in stable, monogamous, functionally heterosexual, communicative relationships for at least 1 year were enrolled. Comorbid arousal and orgasmic disorders were allowed if they were secondary to decreased desire. Mean age of the participants was 35 to 36 years, and they were predominantly white, highly educated women in long-term relationships.
Two important exclusions worth noting:
- women who had depression, breast or other cancers (except skin cancer), or any major medical condition
- women who were taking any of the medications on a five-page list of excluded drugs (due to metabolism with the enzyme cytochrome P3A4).
Once they were screened, women completed a 4-week baseline assessment of sexual activity and desire, followed by a 24-week study period. They were randomized to receive 50 mg or 100 mg of flibanserin or placebo daily. Improvements in sexual function, compared with the 4-week baseline, had to be both statistically and clinically significant for the studies to be successful.
Flibanserin’s effects were clinically unimpressive
At a daily dosage of 100 mg, flibanserin was associated with a significant increase in the number of SSEs, compared with placebo. However, the co-primary endpoint of an increase in desire, as assessed by the eDiary, was not achieved in the active treatment group. Women who took flibanserin had a response rate of 30% to 40%, compared with 15% to 30% for women who took placebo. Although this difference was significant, it was clinically unimpressive, with fewer than 50% of participants experiencing significant improvement (TABLE 1).
TABLE 1
Flibanserin increased the mean number of sexually satisfying events—but improvement was modest
| Phase-3 trial | Measure | Placebo | Flibanserin | P value |
|---|---|---|---|---|
| 511.71 | Baseline | 2.7 | 3.0 | |
| 24 weeks | 3.5 | 4.6 | .005 | |
| 511.75 | Baseline | 2.7 | 2.6 | |
| 24 weeks | 2.6 | 4.4 | .024 |
Frequency of side effects is troubling
Among women who took the active drug, 34.6% discontinued the medication because of side effects, compared with 6.8% of women who took placebo. Most common side effects (and their incidence) were:
- nausea (12%)
- dizziness (11%)
- fatigue (11%)
- daytime somnolence (9.5%)
- anxiety (2%).
In the healthy study population, no major safety issues were associated with flibanserin. However, concomitant use of alcohol, a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI), or a triptan was associated with a marked increase in side effects.
In addition, women who were predisposed to depression or suicidal ideation were more likely to develop suicidal tendencies while taking flibanserin, compared with placebo.
Given the long list of prohibited medications (CYP3A4 promoters or inhibitors), many of which are in widespread use, and given the lack of pharmacodynamic assessment by the sponsor of circulating levels of active drug if used with any of these medications, FDA reviewers and advisory panel members grew concerned about the potential for major side effects if flibanserin were to be released for commercial use.