WASHINGTON - Boehringer Ingelheim GmbH's experimental drug flibanserin, a postsynaptic 5-HT1A agonist and 5-HT2A antagonist, failed to significantly improve a woman's sexual desire in Phase III testing, FDA drug reviewers said.
The studies, however, had demonstrated a statistically significant improvement over placebo in sexually satisfying experiences in women taking the investigational medicine, which has been called "female Viagra."
Nonetheless, regulators said the trials failed to meet the agreed-on criteria for success in establishing the efficacy of flibanserin as a treatment for hypoactive sexual desire disorder (HSDD), a condition in which women experience a persistent or recurrent deficiency or absence of sexual thoughts, fantasies or desire for sexual activity.
In briefing documents posted ahead of Friday's meeting of the FDA's Reproductive Health Drugs Advisory Committee, drug reviewers also said trial data suggested that flibanserin may be associated with a dose-proportional increase in depression-related adverse events.
Ingelheim, Germany-based Boehringer Ingelheim is seeking to have the first product on the U.S. market to treat HSDD, a condition the firm called "clinically relevant and consequential," for which there is an "unmet medical need."
Sex therapy is "neither widely available from accredited providers nor has been shown to be consistently effective" for the condition, the company said in separate documents posted Wednesday on the FDA's website.
Because there is no approved pharmacologic therapy for the treatment of HSDD, many women are exposed to off-label treatments, such as bupropion and testosterone, "whose safety and efficacy have not been prospectively assessed in adequate and well-controlled trials in women with HSDD and whose risks may not be well understood," Boehringer Ingelheim insisted.
Flibanserin, which the German drugmaker is proposing to sell under the trade name Girosa for HSDD, was originally developed to treat depression, based on antidepressant-like effects in preclinical models.
But the drug's Phase IIa depression trials failed to show efficacy on the primary endpoint.
A retrospective assessment, however, noted virtually no occurrence of sexual dysfunction. In one of the four trials, flibanserin was superior in women to the positive comparator and placebo on the Arizona Sexual Experiences Scale scale, mainly on the item "How strong is your sex drive?" Based on that data, the firm began pursuing HSDD in women as an indication.
Even though Boehringer Ingelheim's two North American trials of flibanserin 100 mg at bedtime showed a statistically significant difference between flibanserin and placebo for the endpoint of satisfactory sexual events, regulators said both studies failed to demonstrate a statistically significant improvement on the co-primary endpoint of sexual desire.
In addition, regulators said depression, anxiety, irritability and dizziness occurred with slightly greater frequency in the four weeks following discontinuation of flibanserin 100 mg taken at bedtime - adverse events drug reviewers recommended should be included in the drug's labeling, if approved.
The only serious adverse event that occurred more commonly among flibanserin-treated patients compared with placebo was appendicitis, the FDA said.
Regulators also noted that the tolerability of flibanserin was only moderate, with nearly 15 percent of women who received 100 mg at bedtime discontinuing treatment prematurely due to an adverse event, compared with 6.8 percent in the placebo group.
Tolerability of flibanserin was adversely affected when it was administered with commonly used prescription drugs, including selective serotonin-reuptake inhibitors (SSRIs), triptans and hormonal contraceptives, or when taken with alcohol.
Concomitant administration of potent CYP3A4 inhibitors, such as clarithromycin, ritonavir or ketoconazole, with flibanserin at 50 mg at bedtime led to a nearly fivefold increase in systemic exposure to flibanserin.
In addition, the frequency of adverse events of dizziness, nausea and vomiting increased significantly with concomitant administration of flibanserin and a CYP3A4 inhibitor.
The FDA noted, however, that the population studied in the Phase II and III HSDD trials was generally healthy and taking few, if any, concomitant medications.
Reviewers added that 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," regulators said.