What it is
PT-141 (generic name bremelanotide, approved as Vyleesi) is a synthetic peptide analogue of alpha-melanocyte-stimulating hormone (α-MSH) developed by Palatin Technologies as an analogue of melanotan II (Hadley and Dorr 2006). It was first tested as an intranasal spray in men with erectile dysfunction in the early 2000s, then reformulated as a subcutaneous injection and studied in premenopausal women with low sexual desire, the population for which it was approved in 2019.
Mechanism of action
Bremelanotide is an agonist at melanocortin receptors, a family of five receptors (MC1R to MC5R) that respond to α-MSH and related hormones. Dhillon and Keam (2019) describe it as a synthetic α-MSH analogue with high affinity for the melanocortin 4 receptor (MC4R); other descriptions call it a nonselective agonist across MC1R to MC5R. Melanocortin receptors in the brain are involved in appetite and sexual behavior, and bremelanotide's effects on sexual desire are thought to be central rather than a direct effect on genital tissue. How receptor activation translates into the changes in desire scores seen in trials is not well understood. Activity at other melanocortin receptors may explain some side effects: MC1R regulates pigment production in skin cells and is a plausible route for the focal hyperpigmentation noted in the labeling. Nausea and flushing were the most frequent adverse events across studies, and the labeling also describes small, transient increases in blood pressure after each dose.
What it’s most studied for
PT-141 is most studied for hypoactive sexual desire disorder in premenopausal women, a diagnosis of persistent low sexual desire that causes distress. A 12-week dose-finding trial (Clayton et al. 2016) led to the two 24-week RECONNECT phase 3 trials (Kingsberg et al. 2019) and a 52-week open-label extension (Simon et al. 2019), which together supported approval. Earlier work by Diamond et al. (2004) examined intranasal PT-141 for erectile response in men, a use that was not carried forward to approval.
Notable findings
Each finding carries the species or population it was observed in and the dose that study used. Doses are reported as research context, exactly as published. They are not guidance.
Desire and distress in two phase 3 trials (RECONNECT)
Kingsberg et al. (2019) randomized 1,267 premenopausal women with HSDD 1:1 to bremelanotide or placebo for 24 weeks; 1,202 formed the efficacy population. Compared with placebo, the Female Sexual Function Index desire domain improved by 0.30 points in Study 301 and 0.42 points in Study 302 (0.35 in the integrated analysis, all P<.001), and the co-primary measure of distress about low desire also improved significantly. Most adverse events were mild or moderate and related to tolerability; in trial reports, nausea occurred in about 40% versus 1% on placebo, flushing in about 20% versus 0.3%, and headache in about 11% versus 2%.
- Dose studied
- Bremelanotide 1.75 mg subcutaneously, self-administered as needed before anticipated sexual activity, premenopausal women, 24 weeks
[3] Kingsberg SA et al. · 2019 · PMID 31599840 ↗
52-week open-label extension
Simon et al. (2019) offered open-label bremelanotide to women who had completed the RECONNECT core phase; of 856 eligible, 684 entered and 272 completed the 52-week extension. Desire scores continued to improve among women who had received bremelanotide from the start, and women who switched from placebo also improved. Nausea, flushing and headache were the most common treatment-related adverse events, and the authors reported no new safety signals.
- Dose studied
- Bremelanotide 1.75 mg subcutaneously as needed, premenopausal women, 52 weeks (after the 24-week core phase)
[4] Simon JA et al. · 2019 · PMID 31599847 ↗
Phase 2b dose-finding trial in women
Clayton et al. (2016) randomized premenopausal women with female sexual dysfunction to placebo or one of three bremelanotide doses for 12 weeks. Comparing the pooled 1.25 mg and 1.75 mg groups with placebo, satisfying sexual events rose by 0.7 versus 0.2 per month (p = 0.018) and the Female Sexual Function Index total score rose by 3.6 versus 1.9 points (p = 0.0017). Nausea, flushing and headache were the main adverse events, and the 1.75 mg dose went forward into phase 3.
- Dose studied
- Bremelanotide 0.75, 1.25 or 1.75 mg subcutaneously, self-administered as desired, premenopausal women, 12 weeks
[2] Clayton AH et al. · 2016 · PMID 27181790 ↗
Intranasal PT-141 and erectile response in men
Diamond et al. (2004) gave intranasal PT-141 or placebo to healthy men and to men with mild-to-moderate erectile dysfunction and measured erections with RigiScan monitoring. Plasma exposure rose with dose, and erectile responses were statistically significant versus placebo at doses above 7 mg, with the first erection at about 30 minutes. Flushing and nausea were the most common adverse events, with no clinically significant changes reported in vital signs, laboratory tests or ECGs.
- Dose studied
- Intranasal PT-141, with responses differing from placebo at doses above 7 mg, healthy men and men with mild-to-moderate erectile dysfunction
[5] Diamond LE et al. · 2004 · PMID 14963471 ↗
Study quality
The evidence for PT-141 in its approved use is strong in design: two randomized, double-blind, placebo-controlled phase 3 trials in 1,267 premenopausal women, a dose-finding trial, a 52-week extension, and FDA approval. The size of the benefit is modest. At approval, FDA reported that about 25% on bremelanotide improved their desire score by 1.2 points or more versus 17% on placebo, distress decreased in 35% versus 31%, and there was no increase in sexual satisfaction. Fewer than half of extension participants completed it. Per the label, nausea led 8% to stop treatment; blood pressure rose transiently by up to 6 mmHg systolic and 3 mmHg diastolic, peaking 2 to 4 hours after dosing, with heart rate falling by up to 5 beats per minute; and focal hyperpigmentation of the face, gums or breasts was reported, more often in people with darker skin. It is contraindicated in uncontrolled hypertension or known cardiovascular disease. The male studies were early-phase only.
References
- 1Bremelanotide: First Approval. Drugs. DOI 10.1007/s40265-019-01187-w
- 2Bremelanotide for female sexual dysfunctions in premenopausal women: a randomized, placebo-controlled dose-finding trial. Women's Health (London). PMID 27181790
- 3Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized Phase 3 Trials. Obstetrics & Gynecology. PMID 31599840
- 4Long-Term Safety and Efficacy of Bremelanotide for Hypoactive Sexual Desire Disorder. Obstetrics & Gynecology. PMID 31599847
- 5Double-blind, placebo-controlled evaluation of the safety, pharmacokinetic properties and pharmacodynamic effects of intranasal PT-141, a melanocortin receptor agonist, in healthy males and patients with mild-to-moderate erectile dysfunction. International Journal of Impotence Research. PMID 14963471
- 6Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization. Peptides. PMID 16412534
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