Effectiveness, Safety May Cloud New Female Libido Booster Vyleesi

Alicia Ault

July 04, 2019

A self-injectable medication recently approved for treating low sexual desire in premenopausal women is raising many questions, including whether the therapy is effective in a real-world sense, and if it will be safe over the long-term.

The US Food and Drug Administration (FDA) approved bremelanotide (Vyleesi, AMAG Pharmaceuticals) on June 21, as reported by Medscape Medical News, making it the second therapy getting the agency's backing for hypoactive sexual desire disorder (HSDD) in premenopausal women. 

The approvals are aimed in part at boosting the FDA's track record on working with companies to develop treatments for female sexual dysfunction. The agency identified female sexual dysfunction as one of 20 high-priority disease areas in 2012.

Bremelanotide, a cyclic heptapeptide known to act as a melanocortin-4 receptor agonist, with what AMAG calls in an abstract "the potential to influence dopaminergic pathways involved in the sexual response," is a new molecular entity with a novel delivery method — subcutaneous injection by an autoinjector.

Its mechanism of action is unknown and it was not brought before an FDA advisory committee for review, unlike the first HSDD therapy approved by the agency, flibanserin (Addyi, Sprout Pharmaceuticals).

Soon after the approval, Cindy Pearson, executive director of the National Women's Health Network, issued a statement warning women to avoid using the drug until more is known about its safety and effectiveness. The question for Pearson is not what is known, but "what else don't we know," she told Medscape Medical News.

"The most positive thing is that the development of such therapies calls attention to the importance sexual pleasure plays in our overall well-being," Nan Wise, PhD, a licensed psychotherapist, certified sex therapist, cognitive neuroscience researcher, and part-time lecturer at Rutgers University, Newark, New Jersey, told Medscape Medical News.

But bremelanotide "does not address the psychosocial underpinnings of sexual desire issues," she said.

Pearson also gives kudos to drug companies for trying. "We're a generation of people who either lived through the sexual women's rights revolution or are the beneficiaries of it, so the idea that women have active sexual lives, have desire, enjoy sex — why wouldn't we want drugs to help us, if it wasn't as good as it used to have been and it might be as the result of medical problems," she said.

The "industry's interest is absolutely understandable," Pearson said, while noting that, so far, placebos have proven to be pretty effective.

Dropout Rate Raises Red Flags

Both Pearson and Wise said the number of women who did not complete the 6 months of the two pivotal trials was concerning.

AMAG and the FDA both say that 1247 premenopausal women enrolled in the two randomized, double-blind, placebo-controlled trials used to evaluate bremelanotide.

The company used a modified intent-to-treat methodology for its primary outcome analysis — which took the population down to 1202. Ultimately, 856 women completed what AMAG called the "core phase" of the study — completing an initial 1-month screening period, then a 1-month single blind placebo period, followed by 6 months on placebo or using the 1.75 milligram injection.

AMAG spokesperson Sarah Connors said the final 856 women in the study  should be viewed as an achievement, given the time commitment required of trial participants. "We believe the nearly 70% of women who completed this portion of the study is fairly robust," Connors told Medscape Medical News.

The company did not give all the reasons for why women dropped out. It said that 112 (18%) of 627 women in the bremelanotide safety population discontinued because of adverse events. "The most common adverse event resulting in discontinuation from the Vyleesi group was nausea (8%)," said Connors, noting that 12 (2%) of 620 placebo patients discontinued due to adverse events.

Of the bremelanotide dropouts, Pearson asks, "Why didn't more stay in?"

Small Effect, Lingering Safety Questions

The FDA said most patients used bremelanotide two or three times per month, and not more than once a week. About a quarter of the patients had an increase of 1.2 or more in their sexual desire score on the Female Sexual Function Index (FSFI), compared to 17% on placebo. Just over one third (35%) had a decrease of 1 point or more on the four-point Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO), compared with 31% of those taking placebo.

"Basically, it has a relatively modest effect," said Wise. "It can be statistically significant, they can call it clinically significant, but I'm not sure it's practically significant."

"People in clinical trials are usually highly motivated to find a treatment for their condition, often more so than the average person with the same symptoms," Pearson said. "If nearly 40% of the women randomized to bremelanotide dropped out before the trial ended, and only 4%-8% got any benefit over placebo, it looks like this drug is destined to be another failure."   

The FDA noted that there was no difference in the number of satisfying sexual events. Wise said the difference was about 0.7 more satisfying events per month. If women were truly experiencing an increase in desire, it would probably translate to "more than less than one time a month," she said.

Adverse events were also an issue: 40% percent of women using bremelanotide reported nausea, with 13% needing medication. 1% had skin darkening — on the gums, face, and breasts — which did not go away for half of them. The drug is contraindicated for those with uncontrolled hypertension or at high risk for cardiovascular disease and in women taking oral naltrexone.

Wise brought up another potential long-term concern — the drug acts through the central nervous system. "To me that is like using a sledgehammer to drive a thumbtack," she said.

AMAG said it is planning two postmarketing studies: a pregnancy registry and a lactating women's study.

Finally, the FDA said women should discontinue the medication after 8 weeks if they have not improved. Connors said the same language is in the flibanserin label; it's a way of ensuring that the risk is "focused on patients who are getting the benefit," she said.

How Many Have HSDD?

In 2017, the International Society for the Study of Women's Sexual Health (ISSWSH) Expert Consensus Panel updated its previous guidelines on HSDD.

"Some think it is a manufactured diagnosis," said Wise, but she noted that it is known in the DSM-5 manual as female sexual interest/arousal disorder (FSIAD). However, she said, the nature of female desire is more complex than male desire.

"You can have low interest but still intact arousal — such that once things get jump-started the systems work," Wise said. "Some women with low interest still have satisfying sex once they get into it."

Women tend to lose active spontaneous desire in long-term relationships; receptive desire may also dissipate, but it can be accessed "by those who understand how to kick-start it," she said.

Overall, said Wise, there's evidence that American men and women are having less sex, pointing to a 2017 study that concluded it was partially because of a lack of a steady partner and a decline in frequency with existing partners.

It's a symptom of something bigger, she said. "People appear to be suffering in general from anhedonia — inability to experience pleasure both in and out of the bedroom."

Pearson said she's not sure what to think of HSDD, in part because of the dearth of research on female sexuality. "I don't think we know enough to really understand what's in the range of normal for women and what's out of the range of normal," she said.

The ISSWSH said HSDD affects 10% of adult women. AMAG's chief medical officer, Julie Krop, MD, said in a statement the company believes it affects nearly 6 million premenopausal women. Connors, the company spokesperson, said 1 in 10 American women have the condition.

"HSDD has been recognized as a medical condition since the 1970s, yet it has been widely underdiagnosed and undertreated," said Anita H. Clayton, MD, chair of the department of psychiatry and neurobehavioral sciences, University of Virginia School of Medicine, Charlottesville, in the company statement. "Women with HSDD often avoid situations that could lead to intimacy, the impact of which goes far beyond the bedroom and can often result in anxiety, loss of vitality, self-esteem issues, and relationship stress. It is important that women suffering with this condition have a choice of treatment options available to them."

Will Insurers Bite?

It remains to be seen whether insurers will cover bremelanotide.

Connors said that AMAG anticipates launching the therapy in September, coinciding with National Sexual Health Month. "We are still determining specific pricing, and reimbursement information," she said, adding that the company would ensure that women have access.

"We believe that once they are aware of its value, insurers will cover Vyleesi at a comparable level to other sexual dysfunction medications for both men and women," said Connors.

Flibanserin — which was also seen as not very effective and has some alcohol-related restrictions — has had a difficult path with insurers. The Associated Press reported last month that it was prescribed 6000 times in 2018. The once-daily medication was initially priced at $800 per month, but has since been reduced to $400, said the AP.

Sprout Pharmaceuticals claims that flibanserin is covered by most commercial insurers. However, it is essentially giving the drug away.

Patients can receive their first 8 weeks free, regardless of insurance coverage — and the FDA and the company recommend stopping the drug if it has not worked within 2 months. Sprout promises that subsequent refills will be no more than $25/month; cash-paying customers will pay no more than $99/month out of pocket.

Wise said she believes that older women would not be likely to use bremelanotide off-label but that younger women may look to it as an option because a loss of desire is more difficult for them.

But she says, "I wouldn't recommend this to anybody."

Said Pearson, "Hopefully, not too many women will be left with darkened skin and disappointed hopes."

Pearson has disclosed no relevant financial relationships. Wise is the author of the forthcoming book, "Why Good Sex Matters: Understanding the Neuroscience of Pleasure for a Smarter, Happier, and More Purpose-Filled Life."

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