PT-141

1) Clinical Overview

PT-141, the generic name bremelanotide, is a cyclic heptapeptide melanocortin receptor agonist developed for on-demand treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women. It non-selectively activates melanocortin receptor subtypes with the following order of potency: MC1R > MC4R > MC3R > MC5R > MC2R. Therapeutic effects are thought to arise largely through MC4R signaling within central sexual-motivation circuits, although the precise linkage between receptor activation and clinical benefit has not been fully defined. The U.S. FDA approved subcutaneous bremelanotide (brand name Vyleesi) in 2019 for acquired, generalized HSDD in premenopausal women; it is not indicated for use in men or postmenopausal women and is not approved to enhance sexual performance. 

2) Human Clinical Findings

Pivotal phase 3 trials in premenopausal women with HSDD.

Two large, identically designed, randomized, double-blind, placebo-controlled trials (24-week core periods) tested bremelanotide 1.75 mg SC as needed. Co-primary endpoints were the FSFI-Desire domain (increase = improvement) and FSDS-DAO Item 13 (decrease = less distress). Across studies, bremelanotide produced statistically significant improvements vs placebo in both sexual desire (e.g., +0.30 and +0.42 in the two trials; integrated +0.35) and distress (e.g., −0.37 and −0.29; integrated −0.33). Nausea, flushing, and headache were the most frequent adverse events. 

Dose and administration used clinically.

The approved regimen is 1.75 mg subcutaneously at least 45 minutes before anticipated sexual activity, with no more than one dose in 24 hours and no more than eight doses per month; patients who do not experience meaningful benefit after 8 weeks are advised to discontinue. 

Earlier/other populations.

Prior clinical work evaluated intranasal bremelanotide for male erectile dysfunction (ED), including a randomized, double-blind trial in men considered sildenafil “non-responders,” which reported higher response rates than placebo but also more adverse effects; the journal has since posted an expression of concern for that paper. These ED studies did not lead to approval, and bremelanotide is not indicated for men. 

3) Mechanism & Effects

Bremelanotide activates melanocortin receptors, with clinically relevant signaling attributed primarily to MC4R within hypothalamic and limbic pathways that govern sexual motivation and reward. Preclinical and translational work suggests MC4R agonism may enhance sexual-cue processing and dopaminergic tone in regions such as the medial preoptic area; in women with HSDD, MC4R agonism has been associated with modulation of brain responses to erotic stimuli, supporting a central (rather than peripheral vasodilatory) mechanism. While the label documents nonselective receptor activation, the mechanistic translation from receptor binding to improved desire is still being refined. 

4) Safety & Considerations

Cardiovascular effects and contraindications.

Bremelanotide transiently increases blood pressure (mean maximal ↑ ~6 mmHg systolic and ~3 mmHg diastolic, peaking 2–4 hours post-dose) and reduces heart rate (up to ~5 bpm), typically resolving within 12 hours. It is contraindicated in patients with uncontrolled hypertension or known cardiovascular disease and not recommended for patients at high CV risk. Doses must not be repeated within 24 hours, and >8 doses/month is discouraged partly to limit cumulative BP exposure. 

Common adverse reactions and discontinuation.

Across phase 3 trials, nausea occurred in ~40% of treated patients (antiemetic use ~13%; discontinuation ~8%), often improving by the second dose; flushing, injection-site reactions, headache, and vomiting occurred in ≥4%. Focal hyperpigmentation (face, gingiva, breasts) was reported in ~1% with up to 8 doses/month but rose with daily dosing; in some patients, resolution after discontinuation was not confirmed. 

Drug–drug considerations.

Bremelanotide can delay gastric emptying, potentially affecting absorption of oral medications. It can significantly decrease systemic exposure to oral naltrexone; avoid co-administration with oral naltrexone-containing products used for opioid or alcohol dependence. 

Population and labeling boundaries.

Per FDA labeling, bremelanotide is approved only for premenopausal women with acquired, generalized HSDD and is not indicated for postmenopausal women, men, or to enhance performance. 

References

1. U.S. Prescribing Information (Vyleesi, bremelanotide injection). Full label including indication, dosing, contraindications, warnings (BP/HR), adverse reactions (nausea, hyperpigmentation), and drug interactions (gastric emptying; naltrexone). U.S. FDA, 2019. 
2. Kingsberg SA, Clayton AH, et al. Bremelanotide for the treatment of HSDD: Two randomized phase 3 trials (RECONNECT). Obstet Gynecol. 2019. (Significant improvements in FSFI-Desire and FSDS-DAO Item 13; 24-week core). 
3. Pfaus JG, et al. Neurobiology of bremelanotide in HSDD. Sex Med Rev / Curr Opin (mechanistic review: MC4R and hypothalamic dopamine signaling in sexual motivation). 
4. Safarinejad MR, Hosseini SY. Intranasal bremelanotide in men with sildenafil-refractory ED: randomized, double-blind, placebo-controlled trial. J Urol. 2008. (Efficacy signal reported; note 2023 expression of concern by the journal).