PT-141

In two 24-week phase 3 randomised, double-blind, placebo-controlled trials in premenopausal women with hypoactive sexual desire disorder (RECONNECT; 1,202 analysed), bremelanotide 1.75 mg improved the Female Sexual Function Index desire domain by 0.30 points more than placebo in study 301 and 0.42 in study 302, and reduced desire-related distress on Female Sexual Distress Scale item 13 by 0.37 and 0.29 points more than placebo respectively (all P less than or equal to .005).¹¹

An independent meta-analysis of the same two phase 3 trials, reconstructed from the FDA New Drug Application rather than the published reports, reproduced the efficacy estimates but found discontinuation for adverse events far more common on bremelanotide than placebo (odds ratio 11.98, 95% CI 3.74-38.37; number needed to harm 6), and that 72.72% of protocol-listed outcomes went unreported in the primary publication.¹²

In the uncontrolled 52-week open-label extension of RECONNECT, 684 of 856 eligible women enrolled and 272 completed. Female Sexual Function Index desire rose 1.25-1.30 points from baseline in women who had received bremelanotide during the double-blind phase and 0.70-0.77 points in those who had received placebo, with distress falling 1.4-1.7 and 0.9 points; these are within-group changes, not placebo-controlled differences.¹³

In an independent systematic review and meta-analysis of 36 trials in women with sexual desire, arousal or orgasmic dysfunction without sexual pain, which pooled the bremelanotide, flibanserin and mindfulness-based cognitive behavioural therapy trials separately, bremelanotide improved total Female Sexual Function Index score and its desire and arousal subscales, flibanserin improved total score and desire only, and all three reduced sexual distress; no study compared drug against therapy directly.¹⁴

In healthy men given subcutaneous PT-141 across 0.3-10 mg arms without visual sexual stimulation, RigiScan-measured erectile responses were statistically significant above 1.0 mg; in men with erectile dysfunction who reported an adequate erection on 100 mg sildenafil no more than half the time, the 4 mg and 6 mg arms both produced statistically significant responses versus placebo in a crossover design with visual sexual stimulation.²

In a randomised crossover study in 19 men with erectile dysfunction responsive to a phosphodiesterase type 5 inhibitor, the combined subtherapeutic arm — 7.5 mg intranasal PT-141 with 25 mg sildenafil — produced a significantly greater RigiScan erectile response over the six hours post-dose than 25 mg sildenafil with placebo spray, with no new adverse events and no increase in their frequency or severity over either agent alone.¹⁵

In female rats, PT-141 selectively increased solicitational behaviours toward males while leaving lordosis, pacing and other sexual behaviours unchanged, and produced neither generalised motor activation nor any shift in the perception of sexual reward — the first pharmacological effect reported in this model that is confined to appetitive rather than reflexive sexual behaviour.¹⁶

In two phase 1 randomised, double-blind, placebo-controlled trials in premenopausal women with a body mass index above 30 kg/m2, the bremelanotide arm of Study A lost 1.3 kg more weight than placebo over 16 days (95% CI 0.8-1.9 kg, P less than .0001) while eating about 400 kcal/day less (P less than .01); in the crossover Study B twice-daily bremelanotide reduced mean body weight by 1.7 kg versus 0.9 kg on placebo (P less than .001).¹⁷

Four cryo-electron microscopy structures of full-length human melanocortin 4 receptor bound to heterotrimeric Gs — with alpha-MSH, afamelanotide, bremelanotide and the small molecule THIQ — showed bremelanotide in the orthosteric pocket in the binding mode shared by the peptide agonists; the authors linked subtype selectivity to small-molecule rather than peptide recognition, and cited low agonist selectivity across the family as a reason MC4R-selective obesity drugs have been hard to develop.⁸