PT-141
Also known as: Bremelanotide, Bremelanotide acetate, Vyleesi, PT-141 acetate
Evidence: Clinical
Overview
Bremelanotide, a cyclic melanocortin receptor agonist and close analog of melanotan II; approved by the FDA in 2019 as Vyleesi (1.75 mg SC) for acquired HSDD in premenopausal women.
The approved product is Vyleesi, a single-dose 1.75 mg autoinjector; vendor PT-141 vials are not that product. Bremelanotide is a cyclic heptapeptide melanocortin agonist developed from melanotan II. Two 24-week phase 3 trials in 1,267 premenopausal women with acquired, generalized HSDD found more desire and less distress than placebo (Kingsberg 2019), and the FDA approved it in 2019 (NDA 210557); it remains marketed. The label excludes men, postmenopausal women and use to enhance sexual performance. Early trials in men with erectile dysfunction, including sildenafil non-responders, were small and development in men did not continue (Rosen 2004; Diamond 2005).
Benefits
Increased sexual desire and reduced distress in premenopausal women with acquired HSDD (two phase 3 RCTs, FDA-labeled), erectile response in men including sildenafil non-responders (small early trials, not an indication)
Dosing reference
- Research dose
- 1.75 mg SC per use (Vyleesi label)
- Range
- 1750 mcg, As needed
- Reconstitution
- 2 mL bacteriostatic water
- Common vial sizes
- 10 mg
Vyleesi label: 1.75 mg subcutaneously in the abdomen or thigh, as needed, at least 45 minutes before anticipated sexual activity; no more than one dose within 24 hours; more than 8 doses per month is not recommended; discontinue after 8 weeks if there is no improvement in desire. The phase 3 trials used this dose (Kingsberg 2019); the phase 2b trial also tested 0.75 and 1.25 mg (Clayton 2016).
Mechanism
Bremelanotide is a nonselective melanocortin receptor agonist with potency order MC1R, MC4R, MC3R, MC5R, MC2R; at therapeutic doses binding to MC1R and MC4R is most relevant (Vyleesi label). MC4R-expressing neurons are found throughout the CNS, but the label states that the mechanism by which it improves HSDD in women is unknown. MC1R on melanocytes drives melanin production, which explains the focal hyperpigmentation seen with repeated dosing. A transient rise in blood pressure with a small fall in heart rate follows each dose (Vyleesi label).
Evidence
Clinical: at least one published human trial or an approved drug
- Two identical 24-week phase 3 RCTs (RECONNECT) of 1.75 mg as needed in premenopausal women with HSDD improved desire and reduced distress versus placebo (Kingsberg et al., 2019)
- The 52-week open-label extension of the phase 3 trials reported continued effect and no new safety signal (Simon et al., 2019)
- Phase 2b dose-finding trial in premenopausal women with female sexual dysfunction tested 0.75, 1.25 and 1.75 mg SC (Clayton et al., 2016)
- Subcutaneous PT-141 produced erectile responses in healthy men and in men with an inadequate response to sildenafil (Rosen et al., 2004); low-dose intranasal PT-141 with sildenafil enhanced erection (Diamond et al., 2005)
- Human-trial status: approved by the FDA in 2019 as Vyleesi (NDA 210557) for acquired, generalized HSDD in premenopausal women and still marketed; not indicated in men or postmenopausal women
References
- Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized Phase 3 Trials. Kingsberg SA, Clayton AH, Portman D, et al., Obstetrics & Gynecology, 2019
- Bremelanotide for female sexual dysfunctions in premenopausal women: a randomized, placebo-controlled dose-finding trial. Clayton AH, Althof SE, Kingsberg S, et al., Women's Health, 2016
- Long-Term Safety and Efficacy of Bremelanotide for Hypoactive Sexual Desire Disorder. Simon JA, Kingsberg SA, Portman D, et al., Obstetrics & Gynecology, 2019
- Evaluation of the safety, pharmacokinetics and pharmacodynamic effects of subcutaneously administered PT-141, a melanocortin receptor agonist, in healthy male subjects and in patients with an inadequate response to Viagra. Rosen RC, Diamond LE, Earle DC, et al., International Journal of Impotence Research, 2004
- Co-administration of low doses of intranasal PT-141, a melanocortin receptor agonist, and sildenafil to men with erectile dysfunction results in an enhanced erectile response. Diamond LE, Earle DC, Garcia WD, Spana C, Urology, 2005
Side effects
Vyleesi label, phase 3 (n=627): nausea 40% versus 1.3% on placebo, mostly after the first dose, flushing 20%, injection-site reactions 13%, headache 11%, vomiting 5%; 18% stopped for adverse reactions versus 2% on placebo. Each dose raises blood pressure by up to 6/3 mmHg, peaking 2 to 4 h, with a small fall in heart rate. Focal hyperpigmentation of the face, gums or breasts in 1%, more with daily dosing and darker skin, not always resolved after stopping.
Storage
- Storage
- Refrigerated (2-8°C)
- Lyophilized
- 24+ months at room temperature
- Reconstituted
- 28-30 days refrigerated
Pharmacology
- Half-life
- Terminal half-life about 2.7 h (range 1.9 to 4.0 h) after 1.75 mg SC in humans; Tmax about 1 h (Vyleesi label)
- Bioavailability
- SC absolute bioavailability about 100% (human, Vyleesi label); 21% protein bound; exposure rises less than dose-proportionally from 0.3 to 10 mg
- Molecular weight
- 1025.18 Da
- Sequence
- Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH