When the FDA approved flibanserin, sold as Addyi, the first libido drug for women in August 2015, the process and its aftermath were unusually dramatic. The drug and the FDA’s approval pitted women’s health advocates against one another on the question of whether women’s sexuality was being cynically manipulated for a drugmaker’s gain. The manufacturer, a small company called Sprout Pharmaceuticals, in Raleigh, N.C., recruited women’s health experts to endorse a gender-equity argument—that men have Viagra and women deserve a drug to help their sex lives, too. The opposition fired back that the drug was ineffective, had unacceptable side effects, and medicalized the experience of many women whose sexual desires are within the normal range.
But the evidence was strong enough for an FDA panel to support flibanserin by a vote of 18–6 and, potentially, open the floodgates for other drugs in development too, now that the government had officially recognized female sexual interest disorder (formerly known as hypoactive sexual desire disorder [HSDD]) as a condition that pharmaceuticals could treat. Low libido is one of several recognized sexual dysfunctions, such as vaginal pain or inability to orgasm, identified by the American Psychiatric Association (APA).
So far, though, that flood is little more than a trickle, given that flibanserin remains the only drug for female sexual dysfunction approved by the FDA. Even so, proponents see a huge market for drugs to treat women unhappy with their levels of desire for whom other solutions—such as talk therapy or hormones—haven’t worked, says Michael Krychman, MD, a gynecologist and sexual health specialist based in Newport Beach, Calif., who has been a vocal proponent for adding pharmaceuticals to the sexual dysfunction armamentarium. “There’s still a lot of interest and research in HSDD,” he says. A 2008 study published in JAMA Internal Medicine offers a sense of the possible market; it found that about a quarter of premenopausal women had low sexual desire and that just over half of those who had reached menopause felt that way. The study was based on phone interviews with 2,207 women, ages 30 to 70.
The female libido drug that seems to stand the best chance of being on the market next is bremelanotide, a synthetic peptide analog that mimics a naturally occurring hormone. Its maker, Palatin Technologies, in Cranbury, N.J., said in a November press release that phase 3 trials with 1,200 women found statistically significant improvement in HSDD over placebo. One drawback to bremelanotide is that it is injected.
Another product, branded as Lorexys, is a combination of bupropion, the antidepressant that is also prescribed for smoking cessation and as a treatment for seasonal affective disorder, and trazodone, an antidepressant that is also prescribed for insomnia. Recently reported results of phase 2a clinical trials showed that Lorexys worked better than bupropion.
Other pharmaceutical treatments in development include other antidepressants and several variations on testosterone. Krychman is still a fan of Addyi and thinks the data supporting it has been misinterpreted. “It works in about 60% of people and if it works in you it works really well,” he says.
But Addyi’s fate could also be a splash of cold water on drugmakers interested in this class. Sprout was purchased for $1 billion by Valeant soon after the drug’s approval. But Addyi sales have been pitifully low, expected to generate just $10 million in 2016, according to an investors’ lawsuit. Part of the problem may be that Addyi is limited to premenopausal women, though women past menopause report more issues with lost libido. Moreover, women must obtain Addyi from a prescriber and pharmacist who have undergone training in its risks and benefits and abstain from drinking alcohol while taking it. The daily pill costs up to $800 per month, and insurers have been slow to put it on formularies. The disappointing sales prompted former investors in Sprout to file a lawsuit in November, arguing that Valeant fired Sprout salespeople and reneged on marketing promises. Valeant already has reputation problems as one of the companies that has been ratcheting up drug prices. Even so, Valeant is likely to relaunch Addyi some time this year, predicts Krychman.
In the aftermath of a much-criticized process for Addyi, the FDA in October 2016 attempted to resolve some of the complaints by issuing a draft set of guidelines for all women’s libido drugs that may come before the agency in the future. The guidelines tighten some rules and clarify others. Among the issues addressed in the nonbinding draft guidance were testing developing female libido drugs on populations that are as representative as possible to those likely to use them, which include postmenopausal women and those taking antidepressants.
What remains unclear is whether the poor performance of the first libido drug for women was also due to a misunderstanding of women’s sexual health needs to begin with. Researchers in women’s sexual health fall into two distinct camps on how desire problems should be viewed, whether it is productive to think of women’s sexuality as the same as men’s, and whether a pharmaceutical response is appropriate. Lenore Tiefer, PhD, a sex therapist and associate clinical professor of psychiatry at the New York University School of Medicine, told the FDA in comments on its proposed guidelines that the APA tried to write a more nuanced description of women’s arousal and desire disorders in the DSM-5, but that some in the field preferred to keep HSDD as is because it better serves the interest of drugmakers who want an easy endpoint.
It was also unhelpful to describe Addyi as “Viagra for women,” given the different ways men and women experience and show arousal. Viagra is a vasodilator that can give a man an erection who has trouble getting one, an endpoint that is clearly defined and, in experimental settings, it is relatively easy to measure penile tumescence. In contrast, flibanserin is a mixed serotonin receptor agonist/antagonist targeting neurotransmitters, not the mechanics of blood flow. Researchers have devised a number of ways to measure female arousal, including tampon-shaped devices that measure engorgement of vaginal tissue. But in clinical and some research circumstances, a 19-question survey called the Female Sexual Function Index, is often used. Critics believe the survey is too vague a tool to use when prescribing a drug with potential side effects.
The FDA raised questions about the survey in its October draft guidelines, noting the lack of data to “adequately establish the validity of the instrument as a whole for regulatory purposes.”
Handing women a libido pill feels too reminiscent of the days when women were told it was all in their heads, says Cindy Pearson of the National Women’s Health Network.
Cindy Pearson, executive director of the National Women’s Health Network, is uncomfortable putting the range of women’s sexual response into a single box. Her organization has long advocated against knee-jerk pharmaceutical solutions to women’s health problems, such as treating menopause as a disease that is treated with hormone replacement. Pearson worries that the whole process of drug approval, and meeting the threshold of insurance company coverage, forces a nuanced question into shades of black and white. The danger is that perfectly normal women existing happily at one end of the libido spectrum—or whose experiences differ from “normal” in some other way—end up feeling inadequate or that they need to be treated when they are not unhappy with their sex lives. “Women have been hurt by being told their experience was a medical problem,” Pearson says. Handing women a pill feels too reminiscent of days gone by when women’s medical complaints were “all in their heads,” she says.
But Krychman argues that there remains plenty of room for women to have varied sexual response and not be medicalized. Just because there may be a pharmaceutical treatment for the women who are having problems doesn’t mean all women with tame libidos need to feel the need to take a drug, he argues. He cited the many women who come to his Sexual Health Center in Newport Beach, Calif., who are very distressed about the impact of their lack of desire on their relationships and sense of self. “I would invite people to my clinical office to see these women. It’s not just about having a low libido. These women have health concerns that are impactful and problematic. There’s a distress component to it as well.”
Another factor in the debate is whether women’s sexual response tends to be more spontaneous or responsive. Pearson says flibanserin was being evaluated on a “male model of spontaneous desire,” while women may more commonly be interested in sex in response to a sexual situation. “The sad truth is, we don’t have any kind of research that would give us an idea of what’s normal in the broad swath of women,” she says.
Meanwhile, the women’s health advocates who found themselves at odds over flibanserin have made up, Pearson says, noting that they are usually shoulder-to-shoulder on issues such as access to the abortion pill. “We were kind of mad at each other, but it’s over now,” she says. “In light of Donald Trump, we’re very unified.”