FDA approves a new drug for increasing libido in premenopausal women

Courtesy: AMAG Pharmaceuticals

The US Food and Drug Administration (FDA) recently approved bremelanotide (Vyleesi, AMAG Pharmaceuticals), for the treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women.

Vyleesi, a melanocortin receptor agonist that comes as autoinjector, joins flibanserin(Addyi, Sprout Pharmaceuticals) as the class of drugs approved by the FDA for the treatment of acquired HSDD. Flibanserin is Serotonin 5-HT-Receptor Agonists and is taken orally.

HSDD is the most commonly prevalent female sexual dysfunction and is largely under-recognized and undertreated. It is believed that approximately 9% of all premenopausal women in the United States experience it but less than half of these patients seek help or initiate discussions with physicians.

 “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 from this condition have a choice of treatment options available to them,” quote Anita H. Clayton, M.D., Chair, Department of Psychiatry & Neurobehavioral Sciences, University of Virginia School of Medicine, VA in an AMAG Pharma news release.

The upside of bremelanotide is women need to use it as required as opposed to flibanserin which must be consumed daily.  The drug is dispensed as prefilled autoinjector pen which has to be self-administered by the woman into her abdomen or thigh at least 45 minutes before anticipated sexual activity and can be taken at any time of day.

Courtesy: AMAG Pharmaceuticals

Patients should not use more than one dose within 24 hours or more than eight doses per month. Patients should discontinue treatment after eight weeks if they do not report an improvement in sexual desire and associated distress.

While the exact mechanism of action is still unknown, the drug is believed to act on the melanocortin receptors in the central nervous system that are thought to be associated with sexual function.

The FDA approval of Vyleesi is based upon data from approximately 1,247 women in two pivotal (NCT02333071 and NCT02338960), replicate, double-blind placebo-controlled Phase 3 trials (RECONNECT). Most patients used the drug 2-3 times a month with no more than once a week.

Vyleesi does not enhance sexual performance, but there was a statistically significant increase in desire and decrease in distress at the time of intimacy. Women in both the trials didn’t experience any problem with the autoinjector.

The most common side effects of Vyleesi are nausea and vomiting, flushing, injection site reactions, and headache. An increase in blood pressure was also noted, which usually resolved in 12 hours. Hence, Vyleesi is contraindicated in patients at high risk of cardiovascular disease and those with high-blood pressure.

Vyleesi is not indicated for the treatment of HSDD in postmenopausal women or in men. AMAG is expected to make Vyleesi commercially available in September 2019 through select specialty pharmacies.

FDA press release

AMAG Pharmanews release

NAMS 2018 annual meeting kicks off in San Diego, California

The North American Menopause Society Annual Scientific Meeting kicks off today in San Diego, California. The agenda is packed with symposiums, lectures, research presentations, and debates over many challenging topics related to health and quality of life of women at midlife and beyond.

The conference theme is Innovation, Evidence, and Individualization: Moving Menopause Management Forward and begins Wednesday, October 3, from 8:00 AM to 1:00 PM with pre-Meeting organized by the 2018 Pre-Meeting Co-Chair, Sheryl Kingsberg, Ph.D. on female sexuality.

The presentation will address various aspects of the critical topics including the epidemiology and classification of hypoactive sexual desire disorder (HSDD).

The focus is to make the gynecologist comfortable about talking on the topic with patients.   The six speakers from different discipline of medicine will cover biopsychosocial approach to treating hypoactive sexual desire disorder (HSDD) in postmenopausal women, pharmacologic and nonpharmacologic options for arousal and orgasm issues, the role of the physical therapist in female sexual function and dysfunction, treatment options for sexual problems resulting from genitourinary syndrome of menopause, and testosterone for HSDD: clinical perspectives from sexual medicine and gynecology.

Elissa Epel, Ph.D., from the University of California, San Francisco will talk about Telomere lengths, their role in aging process and psychological aspects of aging in her keynote address “Healthy Longevity and Telomeres: what does sex have to do with it.”

Symposiums are scheduled throughout the conference to discuss critical midlife topics like the role of stress in cardiovascular health of women, breast health, bone health, osteoporosis and increasing rate of hip fractures, and obesity and weight loss.

The Friday morning breakfast is reserved for ‘Trauma-informed care’ including the #MeToo discussion to help physician deal effectively with women who have suffered adverse sexual event, rape or abuse.

Looking forward to some very interesting abstracts presented at the conference.

Meeting page
Scientific Program
Ob/Gyn Updated Facebook page

Another novel drug for female hypoactive sexual desire shows promising results in phase III trials.

Women who are distressed because of hypoactive sexual desire could soon find relief because of a new drug, Bremelanotide (BMT).

Female Sexual Dysfunctions (FSD) encompasses multifactorial entities affecting about 10% of the population. Few treatment options exist to treat this condition.

auto-injector for Bremelanotide, Palatine Technologies

Bremelanotide, is a novel cyclic 7-amino acid melanocortin-receptor agonist with a high affinity for the type-4 receptor. It increases levels of dopamine and norepinephrine in medial preoptic area, thereby,  modulating the  brain pathways involved in sexual response.

The results of two phase III trials were presented as a poster at the American Society of Clinical Psychopharmacology (ASCP) annual meeting, Florida May 29 – June 2, 2017.

The RECONNECT study comprises 2 Phase 3, multicenter trials involving 1,247 premenopausal women with low sexual desire. The women were in stable, monogamous relationship.

In this intent to treat study, the women underwent a month screening period and a month of treatment with a placebo so that the investigators could have an idea about various baseline scores.

Women were randomized to nearly 6 months of treatment with either self-administered BMT (1.75 mg) or placebo subcutaneously using an auto-injector, as-desired, prior to sexual activity. This was followed by an open label 52 weeks extension.

The control and cases were assessed on various indices like the desire domain of the Female Sexual Function Index (FSFI-D) and the Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO) score for feeling bothered by low sexual desire; FSDS total and bother scores; Women’s Index of Treatment Satisfaction (WITS-9) score; self-assessment of benefit, and satisfying sexual event (SSE) items of the Female Sexual Encounter Profile-Revised (FSEP-R).

Besides significantly improving the scores of all the indices, the women on BMT showed a significant improvement in number of satisfying sexual events, arousal, lubrication and orgasm. The women also reported feeling less distressed and more satisfied with their sexual relations.

Most common side effects encountered were nausea, vomiting, flushing, or headaches resulting in 18% of women to discontinue the drug as compared to 2% in placebo group.

The average age of the study participants was 39 years, more than 80% were white with a mean BMI of 28.7 kg/m2 and most of them were suffering from hypoactive sexual desire disorder (HSDD) with decreased arousal.

In 2015, FDA approved the little pink pill or flibanserin (Addyi) a serotonin 1A receptor agonist and a serotonin 2A receptor antagonist, as the first treatment for hypoactive sexual desire disorder in premenopausal women.

The authors concluded, “Treatment with BMT is associated with clinically meaningful and statistically significant improvement in desire and a decrease in distress; both hallmark characteristics of HSDD. BMT is an efficacious treatment for key aspects of sexual function — desire, arousal, lubrication, and orgasm, in premenopausal women.”

All the poster abstracts at the conference can be accessed here.

A new review hype the controversy associated with the ‘pink pill’ commonly dubbed as ‘Female Viagra’.

 

Image Courtesy: L.A. Times

The little pink pill or Flibanserin (Addyi, Sprout Pharmaceuticals)  also dubbed  as the "Female Viagra" was approved by the US Food and Drug Administration (FDA) for the treatment of  hypoactive sexual desire disorder (HSDD) in premenopausal women,  in August 2015, despite  being unsure  about suboptimal risk-benefit trade-offs.

Image Courtesy:  Chicago Tribune

Flibanserin, a 5-HT1A agonist, a 5-HT2A antagonist, and a very weak partial agonist on dopamine D4 receptors, increases levels of dopamine and norepinephrine and decreases serotonin in animal brain areas. Therefore, since dopamine and norepinephrine are thought to promote and serotonin is thought to inhibit sexual desire and arousal, it was suggested that flibanserin enhances sexual desire in HSDD,

A recent systematic review and meta-analysis of randomized clinical trials was published on line on February, 2016 in Journal of American Medical Association (JAMA10.1001/jamainternmed.2015.8565) which assessed efficacy and safety of flibanserin for the treatment of HSDD in women.

The approval of Flibanserin by FDA (a failed antidepressant) has always been shrouded in mystery. It was rejected by FDA twice before it was approved by FDA in August 2015; its clinical review team which voted against it advocating that the benefit-harm balance was unfavorable was overruled by the Clinical Pharmacology and Clinical Division Director. He acknowledged ‘the limited efficacy and worrisome harms, but emphasized the unmet need in women for whom other treatments failed.’

In the recent review by Jaspers L et al from the Erasmus University Medical Center, Rotterdam, the Netherlands, Included five published and 3 unpublished studies constituting a total of   5914 women. The Primary efficacy outcomes were number of satisfying sexual events (SSEs), eDiary sexual desire, and Female Sexual Function Index (FSFI) desire. Safety outcomes were 4 common adverse events (AEs): dizziness, somnolence, nausea, and fatigue and many others. The inclusion of studies focusing on postmenopausal women took into account the potential off-label use.

The study found minimal benefit by the use of Addyi, specifically the pooled mean difference for a Sexually Satisfying Event (SSE) between 100 mg of Flibanserin and placebo was .49%, 1.63 for ediary desire and .27% for Female Sexual Function Index (FSFI) desire domain.

This means that the drug only added .5 additional satisfying sexual experiences per month, while the incidence of adverse effects increased four fold said the study coauthor Ellen T. M. Laan, PhD, from the Department of Sexology and Psychosomatic Obstetrics and Gynecology, Academic Medical Center, University of Amsterdam, the Netherlands, said in a recorded interview with JAMA Internal Medicine.

The risk ratio for study discontinuation due to adverse events was 2.19. The most bothersome was syncope and hypotension that occurred with concurrent alcohol use or CYP3A4 inhibitors, including oral contraceptives and fluconazole.

Meanwhile, many physicians have questioned the results of the study and have reported favorable results with many of the patients using it. They also believe that  the women should be allowed to make an informed decision to choose the ‘pink pill’ as the men are allowed to make an informed decision about ‘Viagra’.

On the basis of the study findings the authors concluded that “The findings of this review suggest that the benefits of flibanserin treatment are marginal, particularly when taking into account the concurrent occurrence of AEs.”

More robust evidence on its safety profile and efficacy is needed before a recommendation can be made in guidelines and clinical practice regarding its use, as majority of American physician indicated that they would prefer an approved HSDD pharmacological product over available non-pharmacological treatments. Further, it is known that an integrative approach involving psychological interventions play a crucial role in treatment of HSDD.

The authors acknowledge the limitation of the study and recommend that future studies should include women from more diverse ethnicity, with a history of somatic and psychological co-morbidities, medication use, and surgical menopause.

References:

http://www.jsm.jsexmed.org/article/S1743-6095%2815%2931530-7/abstract

http://link.springer.com/article/10.1007%2Fs10508-012-0062-0

http://www.cnn.com/2016/02/29/health/female-viagra-gets-mixed-reviews/index.html

http://archinte.jamanetwork.com/article.aspx?articleid=2497781#ioi150116r17

http://archinte.jamanetwork.com/article.aspx?articleid=2497781

http://www.jsm.jsexmed.org/article/S1743-6095%2815%2932579-0/pdf