Bremelanotide [PT-141]

[Michael Scally MD]

[OA] Bremelanotide for Female Sexual Dysfunctions in Premenopausal Women: A Randomized, Placebo-Controlled Dose-Finding Trial

AIM: Evaluate efficacy/safety of bremelanotide (BMT), a melanocortin-receptor-4 agonist, to treat female sexual dysfunctions in premenopausal women.

METHODS: Patients randomized to receive placebo or BMT 0.75, 1.25 or 1.75 mg self-administered subcutaneously, as desired, over 12 weeks. Primary end point was change in satisfying sexual events/month. Secondary end points included total score changes on female sexual function index and female sexual distress scale-desire/arousal/orgasm.

RESULTS: Efficacy data, n = 327. For 1.25/1.75-mg pooled versus placebo, mean changes from baseline to study end were +0.7 versus +0.2 satisfying sexual events/month (p = 0.0180), +3.6 versus +1.9 female sexual function index total score (p = 0.0017), -11.1 versus -6.8 female sexual distress scale-desire/arousal/orgasm total score (p = 0.0014). Adverse events: nausea, flushing, headache.

CONCLUSION: In premenopausal women with female sexual dysfunctions, self-administered, as desired, subcutaneous BMT was safe, effective, and well tolerated (NCT01382719).

Clayton AH, Althof SE, Kingsberg S, et al. Bremelanotide for female sexual dysfunctions in premenopausal women: a randomized, placebo-controlled dose-finding trial. Womens Health (Lond Engl). http://www.futuremedicine.com/doi/full/10.2217/whe-2016-0018

 

[Michael Scally MD]

AMAG Pharmaceuticals and Palatin Technologies Enter Into Exclusive Licensing Agreement for North American Rights to Rekyndatm (bremelanotide), a Potential Treatment for a Common Female Sexual Disorder
http://finance.yahoo.com/news/amag-pharmaceuticals-palatin-technologies-enter-130000216.html

AMAG Pharmaceuticals, Inc. (Nasdaq:AMAG) together with Palatin Technologies, Inc. (NYSE MKTTN) today announced they have entered into an agreement for exclusive North American rights to develop and commercialize RekyndaTM (bremelanotide), an investigational product designed for on-demand treatment of hypoactive sexual desire disorder (HSDD) in pre-menopausal women, that has successfully completed two Phase 3 trials. The anticipated filing date in the U.S. for a new drug application (NDA) for Rekynda is in early 2018, with an anticipated approval and launch by early 2019.


Rekynda (bremelanotide), an investigational product, is thought to possess a novel mechanism of action, activating endogenous melanocortin pathways involved in sexual desire and response.

The two Phase 3 studies for HSDD in pre-menopausal women consisted of double-blind placebo-controlled, randomized parallel group studies comparing a subcutaneous dose of 1.75 mg Rekynda delivered via an auto-injector pen to placebo.

Each trial consisted of more than 600 patients randomized in a 1:1 ratio to either the treatment arm or placebo with a 24 week evaluation period. In both clinical trials, Rekynda met the pre-specified co-primary efficacy endpoints of improvement in desire and decrease in distress associated with low sexual desire as measured using validated patient-reported outcome instruments.

Women in the trials had the option, after completion of the trial, to continue in an ongoing open-label safety extension study for an additional 12 months. Nearly 80% of patients elected to remain in the open-label portion of the study, and all of these patients will continue to receive Rekynda.

 

[Michael Scally MD]

Licenses for Vyleesi™ (bremelanotide)
https://www.palatin.com/research-focus/female-sexual-dysfunction/bremelanotide-license/

Palatin exclusively licensed North American rights to develop and commercialize Vyleesi™, the trade name for bremelanotide, to AMAG Pharmaceuticals, Inc. (Nasdaq:AMAG). A New Drug Application for Vyleesi, an on-demand treatment for hypoactive sexual desire disorder (HSDD) in premenopausal women, was filed in the first quarter of 2018, with anticipated completion of Food and Drug Administration (FDA) review by June 23, 2019.

 

[Michael Scally MD]

In the coming days, the Food and Drug Administration will decide whether to approve an injection meant to increase women’s drive for sex. Its demonstrated effects are modest, but some doctors say the drug would meet a real need for thousands of women. Others, however, argue it is simply pharmaceutical overreach, another effort that reduces the complexity of human sexuality to a set of measurable dots on a chart.

“It’s a mismatch of models,” said Leonore Tiefer, a sex therapist who previously ran the sex and gender clinic at New York’s Montefiore Medical Center. “They want the car repair model: ‘Hello, doctor, I’ve got this carburetor that doesn’t work in my car. Could you fix it for me without talking to me?’ It’s laughable.”

The drug, bremelanotide, is an on-demand therapy for women with hypoactive sexual desire disorder, or HSDD, which is defined as a distressing loss of interest in sex. And its Massachusetts-based manufacturer, AMAG Pharmaceuticals, hopes the drug can do for sexual desire what Viagra did for erectile dysfunction. It could win FDA approval as early as Friday.

 

[GymRaccoon]

The quote from the sex therapist is funny. Definitely triggered there. Worried about being put out of business lol.

 

[Michael Scally MD]

New Sex Drug for Women to Improve Low Libido Is Approved
New Sex Drug for Women to Improve Low Libido Is Approved by the F.D.A.

The Food and Drug Administration has approved a new drug to treat low sexual drive in women, the only one besides Addyi, which entered the market in 2015.

The drug, to be called Vyleesi, will be sold by AMAG Pharmaceuticals and is intended to be used 45 minutes before sex, via an auto-injector pen that is administered in the thigh or abdomen.

 

[Michael Scally MD]

FDA approves new treatment for hypoactive sexual desire disorder in premenopausal women
FDA approves new treatment for hypoactive sexual desire disorder in premenopausal women

Vyleesi activates melanocortin receptors, but the mechanism by which it improves sexual desire and related distress is unknown. Patients inject Vyleesi under the skin of the abdomen or thigh at least 45 minutes before anticipated sexual activity and may decide the optimal time to use Vyleesi based on how they experience the duration of benefit and any side effects, such as nausea.

…The most common side effects of Vyleesi are nausea and vomiting, flushing, injection site reactions and headache. About 40% of patients in the clinical trials experienced nausea, most commonly with the first Vyleesi injection, and 13% needed medications for the treatment of nausea.

 

[Michael Scally MD]

Available in Specialty Pharmacies [September]

[Package Insert] VYLEESI (Bremelanotide injection), for Subcutaneous Use
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210557s000lbl.pdf

VYLEESI is a melanocortin receptor agonist indicated for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD) as characterized by low sexual desire that causes marked distress or interpersonal difficulty.

The recommended dosage of VYLEESI is 1.75 mg administered subcutaneously in the abdomen or thigh, as needed, at least 45 minutes before anticipated sexual activity. The duration of efficacy after each dose is unknown and the optimal window for VYLEESI administration has not been fully characterized.

Patients may decide the optimal time for VYLEESI administration based on how they experience the duration of effect on desire and any adverse reactions such as nausea. Patients should not administer more than one dose within 24 hours. The efficacy of consecutive doses within 24 hours has not been established and administering doses close together may increase the risk of additive effects on blood pressure.

Administering more than 8 doses per month is not recommended. Few patients in the phase 3 program received more than 8 doses per month. Also, more frequent dosing increases the risk for focal hyperpigmentation and the length of time per month when blood pressure is increased.

In the phase 3 placebo-controlled trials, focal hyperpigmentation, including involvement of the face, gingiva, and breasts, was reported in 1% of patients who received up to 8 doses per month of VYLEESI compared to no placebo-treated patients.

In another clinical study, 38% of patients developed focal hyperpigmentation after receiving VYLEESI daily for 8 days; among patients who continued VYLEESI for 8 more consecutive days, an additional 14% developed new focal pigmentary changes.

Patients with dark skin were more likely to develop focal hyperpigmentation. Resolution of the focal hyperpigmentation was not confirmed in all patients after discontinuation of VYLEESI. More than 8 monthly doses of VYLEESI is not recommended. Consider discontinuing VYLEESI if hyperpigmentation develops.

In the phase 3 placebo-controlled trials, nausea was the most commonly reported adverse reaction, reported in 40% of VYLEESI-treated patients, requiring anti-emetic therapy in 13% of VYLEESI-treated patients and leading to premature discontinuation from the trials for 8% of VYLEESI-treated patients.

Nausea improves for most patients with the second dose. Consider discontinuing VYLEESI for persistent or severe nausea or initiating anti-emetic therapy for those patients who are bothered by nausea but wish to continue with VYLEESI treatment.

 

[Michael Scally MD]

[OA] Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder

Objective: To evaluate the safety and efficacy of bremelanotide for the treatment of premenopausal women with hypoactive sexual desire disorder.

Methods: Two identical phase 3, randomized, double-blind, placebo-controlled, multicenter clinical trials (RECONNECT) evaluated the safety and efficacy of bremelanotide 1.75 mg administered subcutaneously as needed in premenopausal women with hypoactive sexual desire disorder. Patients were randomized 1:1 to 24 weeks of treatment with bremelanotide or placebo.

Sample size was estimated based on simulations from key endpoints in patients with hypoactive sexual desire disorder from a prior trial. Coprimary efficacy endpoints were change from baseline to end-of-study in the Female Sexual Function Index-desire domain score and Female Sexual Distress Scale-Desire/Arousal/Orgasm item 13.

Results: Study 301 began on January 7, 2015, and concluded on July 26, 2016. Study 302 began on January 28, 2015, and concluded on August 4, 2016. Of the 1,267 women randomized, 1,247 and 1,202 were in the safety and efficacy (modified intent-to-treat) populations, respectively. Most participants were white (85.6%), from U.S. sites (96.6%), and had a mean age of 39 years.

From baseline to end-of-study, women taking bremelanotide had statistically significant increases in sexual desire (study 301: 0.30, P<.001; study 302: 0.42, P<.001; integrated studies 0.35, P<.001) and statistically significant reductions in distress related to low sexual desire (study 301: -0.37, P<.001; study 302: -0.29, P=.005; integrated studies -0.33, P<.001) compared with placebo. Patients taking bremelanotide experienced more nausea, flushing, and headache (10% or more in both studies) compared with placebo.

Conclusions: Both studies demonstrated that bremelanotide significantly improved sexual desire and related distress in premenopausal women with hypoactive sexual desire disorder. The safety profile was favorable. Most treatment-emergent adverse events were related to tolerability and the majority were mild or moderate in intensity.

Kingsberg SA, Clayton AH, Portman D, Williams LA, Krop J, Jordan R, Lucas J, Simon JA. Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized Phase 3 Trials. Obstet Gynecol. 2019 Nov;134(5):899-908. doi: 10.1097/AOG.0000000000003500. PMID: 31599840; PMCID: PMC6819021. Bremelanotide for the Treatment of Hypoactive Sexual Desire ... : Obstetrics & Gynecology

 

[Michael Scally MD]

[OA] Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder

Objective: To evaluate the safety and efficacy of bremelanotide for the treatment of premenopausal women with hypoactive sexual desire disorder.

Methods: Two identical phase 3, randomized, double-blind, placebo-controlled, multicenter clinical trials (RECONNECT) evaluated the safety and efficacy of bremelanotide 1.75 mg administered subcutaneously as needed in premenopausal women with hypoactive sexual desire disorder. Patients were randomized 1:1 to 24 weeks of treatment with bremelanotide or placebo.

Sample size was estimated based on simulations from key endpoints in patients with hypoactive sexual desire disorder from a prior trial. Coprimary efficacy endpoints were change from baseline to end-of-study in the Female Sexual Function Index-desire domain score and Female Sexual Distress Scale-Desire/Arousal/Orgasm item 13.

Results: Study 301 began on January 7, 2015, and concluded on July 26, 2016. Study 302 began on January 28, 2015, and concluded on August 4, 2016. Of the 1,267 women randomized, 1,247 and 1,202 were in the safety and efficacy (modified intent-to-treat) populations, respectively. Most participants were white (85.6%), from U.S. sites (96.6%), and had a mean age of 39 years.

From baseline to end-of-study, women taking bremelanotide had statistically significant increases in sexual desire (study 301: 0.30, P<.001; study 302: 0.42, P<.001; integrated studies 0.35, P<.001) and statistically significant reductions in distress related to low sexual desire (study 301: -0.37, P<.001; study 302: -0.29, P=.005; integrated studies -0.33, P<.001) compared with placebo. Patients taking bremelanotide experienced more nausea, flushing, and headache (10% or more in both studies) compared with placebo.

Conclusions: Both studies demonstrated that bremelanotide significantly improved sexual desire and related distress in premenopausal women with hypoactive sexual desire disorder. The safety profile was favorable. Most treatment-emergent adverse events were related to tolerability and the majority were mild or moderate in intensity.

Kingsberg SA, Clayton AH, Portman D, Williams LA, Krop J, Jordan R, Lucas J, Simon JA. Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized Phase 3 Trials. Obstet Gynecol. 2019 Nov;134(5):899-908. doi: 10.1097/AOG.0000000000003500. PMID: 31599840; PMCID: PMC6819021. Bremelanotide for the Treatment of Hypoactive Sexual Desire ... : Obstetrics & Gynecology

[OA] Re-Analyzing Phase III Bremelanotide Trials for "Hypoactive Sexual Desire Disorder" in Women

Kingsberg et al. described results from two 24-week Phase III trials of bremelanotide for treating hypoactive sexual desire disorder (HSDD) in women. 72.72% of protocol-listed outcomes were not reported by Kingsberg et al., who provided results of 15 secondary measures which were not listed in the study protocols. None of their efficacy outcomes were reported in line with CONSORT data reporting standards and no secondary outcome had a stated rationale or cited evidence of validity.

My meta-analysis of the trials' data, based on the FDA New Drug Application, found similar results to Kingsberg et al. However, Kingsberg et al. did not report that

a) adverse event-induced study discontinuation was substantially higher on bremelanotide: OR = 11.98, 95% CI = 3.74-38.37, NNH: 6 or

b) participants preferred placebo, measured by the combination of both

1) completing a clinical trial and

2) electing to participate in the follow-up open-label study (OR = 0.30, 95% CI = .24-.38, NNH: 4).

Bremelanotide's modest benefits on incompletely reported post-hoc measures of questionable validity in combination with participants substantially preferring to take placebo suggest that the drug is generally not useful. Kingsberg et al.'s data reporting and measurement practices were incomplete and lacked transparency.

Spielmans GI. Re-Analyzing Phase III Bremelanotide Trials for "Hypoactive Sexual Desire Disorder" in Women. J Sex Res. 2021 Mar 7:1-20. doi: 10.1080/00224499.2021.1885601. Epub ahead of print. PMID: 33678061. https://www.tandfonline.com/doi/full/10.1080/00224499.2021.1885601