Vyleesi Mechanism of Action: The Full Bremelanotide Pathway Explained

What receptors does bremelanotide activate?

The label describes bremelanotide as a melanocortin receptor agonist that nonselectively activates several subtypes, in this order of potency: MC1R, MC4R, MC3R, MC5R and MC2R [1]. At therapeutic doses, binding at MC1R and MC4R is the most relevant [1]. The molecule itself is a cyclic peptide of seven amino acids [1].

MC1R is first in that potency order and MC4R is second [1]. MC1R binding can increase pigmentation, and in the placebo-controlled trials focal hyperpigmentation was reported in 1% of patients using up to eight doses per month [1].

MC4R neurons are present in many areas of the central nervous system [1]. A 1994 mapping study in rat brain found MC4R messenger RNA in virtually every brain region examined, including cortex, thalamus, hypothalamus, brainstem and spinal cord, and in both parvicellular and magnocellular neurons of the hypothalamic paraventricular nucleus [2]. MC4R also has a role in appetite and energy control, and MC4R defects cause lack of satiety and early-onset severe obesity [3]. Whether its activation explains Vyleesi's effect on desire is unknown [1].

How did desire scores change in clinical trials?

The RECONNECT program was two identical randomized, double-blind, placebo-controlled 24-week trials: 1,267 women were randomized, 1,247 were in the safety population and 1,202 in the efficacy analysis, with a mean age of 39 [4]. Sexual desire on the FSFI-desire domain improved by 0.30 points in study 301 and 0.42 in study 302 versus placebo, and by 0.35 across the integrated studies (all P<0.001) [4]. Distress related to low desire fell by 0.37, 0.29 and 0.33 points on item 13 (P<0.001, P=0.005, P<0.001) [4]. The label reports desire change from baseline as 0.5 versus 0.2 in study 1 and 0.6 versus 0.2 in study 2 [1]. The FSFI desire domain runs from 1.2 to 6.0, so these are fractions of a point on that range [1].

Desire scores improved, but the trials found no significant difference in the number of satisfying sexual events [4].

What animal studies add

In a 2004 study in female rats, PT-141 — a peptide analog of alpha-melanocyte-stimulating hormone that binds central melanocortin receptors — selectively stimulated solicitational behaviors without affecting lordosis, pacing or other sexual behaviors, produced no generalized motor activation, and did not affect the perception of sexual reward [5]. The authors concluded that central melanocortin systems are important in the regulation of female sexual desire [5]. It is one rat study, and it identifies a behavioral target rather than a human pathway.

A 2007 review of melanocortin agents in sexual dysfunction noted that their erectogenic properties were thought to come from binding melanocortin receptors in the central nervous system, particularly the hypothalamus, and that the bremelanotide clinical work at that time used a nasal formulation [6]. Vyleesi is subcutaneous [1]; an intranasal 20 mg dose appears in the label only in pharmacology studies, including one that achieved a 2.5-fold higher mean peak concentration than Vyleesi [1].

Pigmentation and MC1R

MC1R is expressed on melanocytes, and binding there leads to melanin expression and increased pigmentation [1]. Focal hyperpigmentation, including the face, gums and breasts, was reported by 1% of patients taking up to 8 doses a month versus none on placebo; in another study, 38% of patients developed it after daily dosing for 8 days, and a further 14% after 8 more consecutive days [1]. Risk is higher in darker skin, resolution was not confirmed in all patients after stopping, and the label says to consider discontinuing Vyleesi if hyperpigmentation develops [1].

Blood pressure and heart rate

Each dose transiently raises blood pressure and lowers heart rate [1]. The maximal increases were 6 mmHg systolic and 3 mmHg diastolic, peaking 2 to 4 hours after the dose, with a heart rate reduction of up to 5 beats per minute; values usually returned to baseline within 12 hours, and no additive effect appeared with repeat daily dosing 24 hours apart for up to 16 days [1]. Those are maximal, not average, figures. In an open-label ambulatory study of 127 premenopausal women dosed once daily for 8 days, mean daytime blood pressure rose 1.9 mmHg systolic (95% CI 1.0 to 2.7) and 1.7 mmHg diastolic (95% CI 0.9 to 2.4), with a mean heart rate decrease of 0.5 beats per minute [1].

The label lists uncontrolled hypertension or known cardiovascular disease as contraindications and does not recommend Vyleesi in patients at high risk for cardiovascular disease [1].

Nausea: the most common effect

Nausea was reported by 40% of Vyleesi-treated patients versus 1.3% on placebo; 13% needed anti-nausea medicine and 8% stopped the trials because of it [1]. Incidence was highest after the first dose, at 21%, then fell to about 3% after later doses, with median onset within one hour and a duration of about two hours [1]. In a phase 4 single-dose study of 228 healthy women, 8 mg of oral ondansetron taken 30 minutes before a 1.75 mg subcutaneous dose did not reduce the incidence of nausea, and the label does not recommend pre-treatment; ondansetron given after the dose or after nausea starts has not been formally studied [1].

Pharmacokinetics

After a 1.75 mg subcutaneous dose, mean peak plasma concentration is 72.8 ng/mL, AUC is 276 hr*ng/mL, median time to peak is about 1.0 hour, absolute bioavailability is about 100%, and mean terminal half-life is about 2.7 hours (range 1.9 to 4.0) [1]. Bremelanotide is metabolized by hydrolysis of amide bonds, with 64.8% of radioactivity recovered in urine and 22.8% in feces [1]. Exposure rises 1.5-fold in moderate and 2-fold in severe renal impairment, and 1.2-fold (mild) to 1.7-fold (moderate) in hepatic impairment [1].

What the label says about timing and the 8-dose cap

The dose is 1.75 mg subcutaneously into the abdomen or thigh, at least 45 minutes before anticipated sexual activity, and no more than one dose in 24 hours. The label recommends no more than eight doses per month, and it recommends discontinuing Vyleesi after 8 weeks if symptoms have not improved [1]. Duration of efficacy after a dose is unknown and the optimal window for administration has not been fully characterized [1].

The monthly cap has two stated reasons: more frequent dosing increases the risk of focal hyperpigmentation and lengthens the time each month during which blood pressure is raised, and few patients in the phase 3 program used more than 8 doses a month [1].

Slowed gastric emptying and oral medicines

The label says Vyleesi may slow gastric emptying and reduce the rate and extent of absorption of oral medicines. It instructs patients to avoid Vyleesi with oral drugs that depend on threshold blood concentrations, such as antibiotics, and says to consider discontinuing Vyleesi if an oral medicine has a delayed effect when a quick effect is needed, such as with indomethacin [1]. The label says to avoid Vyleesi with oral naltrexone products used for alcohol or opioid addiction because Vyleesi may lower naltrexone exposure and treatment failure could have severe consequences [1].

PT-141 and Vyleesi are not the same product

Bremelanotide is FDA-approved as Vyleesi (NDA 210557, approved June 21, 2019) for premenopausal women with acquired, generalized HSDD, and it is not indicated for HSDD in postmenopausal women or in men, or to enhance sexual performance [1][7]. PT-141 products sold as compounded or research-use peptides are not Vyleesi and are not FDA-approved drugs, and compounded drugs are not reviewed by FDA for safety, effectiveness or quality before marketing [8].