PT-141 (bremelanotide), what the published trial data and Vyleesi label actually show

Key takeaways

• Vyleesi (bremelanotide injection 1.75 mg subcutaneous, on-demand) was FDA-approved in June 2019 for hypoactive sexual desire disorder (HSDD) in premenopausal women. It is not approved for men or for postmenopausal women.
• Bremelanotide is a non-selective melanocortin receptor agonist with affinity for MC1R, MC3R, MC4R, and MC5R. The pro-sexual effects are believed to be mediated centrally, primarily through MC4R.
• The pivotal RECONNECT trials (24 weeks each, total ~1,200 women) demonstrated improvements in desire and distress scores; treatment effect sizes were small but statistically significant on the FSDS-DAO Q13 distress item.
• The Vyleesi label includes a warning on transient blood pressure increase (mean 6 mmHg systolic, 3 mmHg diastolic) for up to 12 hours post-dose. Use is limited to once per 24 hours and no more than 8 doses per month.
• Off-label use of compounded PT-141 in men (for erectile function or arousal) and in postmenopausal women is not supported by FDA-approved labeling and has limited published trial evidence at the doses commonly used.

What bremelanotide is

Bremelanotide is a synthetic cyclic heptapeptide developed from melanotan II by removal of the C-terminal amide group. It binds the melanocortin receptor family with affinities approximately MC1R > MC4R > MC3R > MC5R. The MC4R action in the central nervous system is the basis for the pro-sexual mechanism; the MC1R action in skin is the basis for the temporary darkening of nevi reported by some users (and the basis for the related compound melanotan II, which has not been approved for any indication anywhere). The pharmacology and PubChem entry document the receptor profile .

The mechanism for pro-sexual effects is believed to be primarily central, acting on hypothalamic MC4R-expressing neurons that modulate sexual desire and arousal pathways. The peripheral autonomic effects (transient blood pressure increase, flushing, nausea) are also receptor-mediated and well characterized in the labeled product profile .

FDA approval and the Vyleesi label

Vyleesi (bremelanotide injection 1.75 mg, on-demand subcutaneous) was approved by the FDA on June 21, 2019 for hypoactive sexual desire disorder (HSDD) in premenopausal women. The labeled indication is narrow: HSDD in premenopausal women, defined as decreased sexual desire causing marked distress or interpersonal difficulty, not better explained by another medical or psychiatric condition, relationship issue, or medication side effect. The label is not approved in men or in postmenopausal women .

The label limits use to one dose per 24 hours and no more than 8 doses per month. The recommended administration is at least 45 minutes before anticipated sexual activity. The label also restricts use in patients with uncontrolled hypertension or established cardiovascular disease because of the transient blood pressure increase post-dose .

RECONNECT-1 and RECONNECT-2 evidence

The RECONNECT-1 and RECONNECT-2 phase 3 trials randomized a total of approximately 1,200 premenopausal women with HSDD to bremelanotide 1.75 mg subcutaneous on-demand or placebo, for 24 weeks each. The two co-primary endpoints were the change from baseline in the Female Sexual Function Index desire domain (FSFI-D) and the change in the FSDS-DAO Item 13 (distress over low sexual desire). Both endpoints favored bremelanotide with statistical significance, though absolute effect sizes were modest .

Approximately 25 percent of bremelanotide subjects met responder criteria on the desire endpoint vs. 17 percent on placebo. Sexual events (encounters) and orgasm frequency were not statistically improved over placebo. The clinical question of whether the magnitude of effect justifies the label profile is one of the reasons Vyleesi has had a smaller commercial uptake than its sponsors anticipated.

Blood pressure and cardiovascular considerations

The most clinically important side effect of bremelanotide is a transient blood pressure increase post-dose. The Vyleesi label reports a mean increase of approximately 6 mmHg systolic and 3 mmHg diastolic peaking 2 to 4 hours after the dose and returning to baseline within 8 to 12 hours. Heart rate decreases slightly. The label includes a warning that bremelanotide should not be used in patients with uncontrolled hypertension or known cardiovascular disease .

Other common adverse events include nausea (about 40 percent of users), flushing (about 20 percent), injection-site reactions, headache, and vomiting. Hyperpigmentation (focal or generalized darkening) was reported by approximately 1 percent of subjects in the pivotal trials and was not always reversible after discontinuation .

Off-label and compounded PT-141 use

Compounded PT-141 is widely sold as a research peptide and is sometimes prescribed off-label by telehealth services for men (for erectile function or libido) and for postmenopausal women. Neither use is on the Vyleesi label. The published clinical trial evidence for bremelanotide in men is limited to early-phase development data; bremelanotide was studied in male erectile dysfunction in earlier trials by the original sponsor before development pivoted to the female HSDD indication. The published evidence does not support equivalence to PDE5 inhibitors for erectile function, and the cardiovascular labeling restrictions apply equally to off-label use .

Compounded peptide quality, sterility, identity confirmation, and dose accuracy depend entirely on the compounding pharmacy and are not directly comparable to the FDA-approved injection. The FDA has issued general cautions on compounded products that do not necessarily inherit the safety profile of the labeled drug .

What the evidence does not show

• Bremelanotide is not a treatment for any organic cause of sexual dysfunction (vascular erectile dysfunction, hormonal hypogonadism, postmenopausal genitourinary syndrome).
• There is no published trial evidence of long-term safety beyond the 52-week open-label extensions of the RECONNECT trials.
• There is no evidence that bremelanotide treats, cures, or prevents any disease. The Vyleesi indication is for distress associated with HSDD, not for disease management .
• Combined use of bremelanotide with naltrexone (an investigational use to address opioid receptor cross-talk) is not supported by approved labeling.