Vyleesi History and Development: How Bremelanotide Went From Sunscreen Peptide to FDA-Approved HSDD Treatment

Origins in Melanocortin Research: From Tanning Peptide to Sexual Medicine

Bremelanotide traces its origins to University of Arizona research on synthetic melanocortin peptides in the 1990s. The story begins not with sexual dysfunction, but with sunless tanning.

Researchers at the university, led by Mac Hadley and Victor Hruby, synthesized Melanotan II (MT-II), a cyclic analog of alpha-melanocyte-stimulating hormone (alpha-MSH). MT-II was designed to darken skin pigmentation and potentially reduce UV-related skin cancer risk. During early human testing, male subjects receiving MT-II reported an unexpected side effect: spontaneous erections. A 1996 case series published in the International Journal of Impotence Research documented these pro-erectile effects in men receiving subcutaneous MT-II injections, with erections occurring 1 to 5 hours after dosing [1]. The observation was surprising because the peptide had been developed to target melanocortin-1 receptors (MC1R) in skin cells, not brain circuits involved in sexual function.

That accidental finding redirected the entire research program. Palatin Technologies, a biopharmaceutical company based in New Jersey, licensed the melanocortin technology from the University of Arizona in the late 1990s and began modifying the MT-II molecule. The goal was to create a derivative with stronger central nervous system activity at melanocortin-4 receptors (MC4R) and reduced effects on skin pigmentation. The result was PT-141, later named bremelanotide. Unlike MT-II, bremelanotide was a metabolite-based analog with selectivity toward MC3R and MC4R, the receptor subtypes most closely linked to sexual arousal pathways in the hypothalamus [2].

How Bremelanotide Works: The Melanocortin-4 Receptor Mechanism

Bremelanotide acts on the central nervous system rather than the vascular system. This distinguishes it from phosphodiesterase-5 (PDE5) inhibitors like sildenafil, which work peripherally on blood flow.

The drug binds to melanocortin-4 receptors (MC4R) located in the medial preoptic area and other hypothalamic nuclei involved in sexual motivation and arousal. MC4R activation modulates downstream dopaminergic and oxytocinergic signaling, both of which contribute to sexual desire and reward processing [3]. In preclinical models, MC4R agonism increased solicitation behaviors in female rats, an effect that was blocked by MC4R antagonists, confirming receptor-specific activity [4].

This central mechanism is significant because HSDD is characterized by a deficit in sexual desire, not a peripheral arousal failure. Dr. Sheryl Kingsberg, a clinical psychologist at University Hospitals Cleveland Medical Center who served as a principal investigator for bremelanotide trials, has noted: "Bremelanotide works on the pathways in the brain that affect desire, which is fundamentally different from drugs that work on blood flow to the genitals" [5].

Bremelanotide also shows partial agonist activity at MC3R, though the clinical relevance of MC3R activation for sexual function remains less well characterized. The drug has minimal activity at MC1R and MC5R at therapeutic doses, which is why it produces less skin darkening than its parent compound Melanotan II [2].

The Intranasal Detour: Why the First Formulation Failed

Palatin Technologies initially developed bremelanotide as a nasal spray. Early Phase 2 results looked promising. That formulation never reached Phase 3.

In Phase 2A studies conducted in the mid-2000s, intranasal bremelanotide demonstrated statistically significant improvements in arousal and desire in women with female sexual arousal disorder (FSAD) and in men with erectile dysfunction [6]. A 2006 study of 18 premenopausal women showed dose-dependent increases in genital arousal measured by vaginal photoplethysmography, along with subjective improvements in desire [6].

However, the FDA placed a clinical hold on the intranasal program in 2007. The issue was blood pressure. Intranasal dosing produced a rapid absorption profile that caused transient but clinically meaningful increases in systolic blood pressure, sometimes exceeding 20 mmHg. The agency required additional cardiovascular safety data before trials could resume [7].

Rather than reformulate the nasal spray, Palatin pivoted. The company shifted to a subcutaneous injection, which provided slower absorption kinetics, a more predictable pharmacokinetic profile, and lower peak plasma concentrations. This route change reduced the magnitude of blood pressure elevation while maintaining efficacy. The strategic pivot added years to the development timeline but ultimately proved critical for regulatory success.

Phase 3: The RECONNECT Trials

The key evidence for FDA approval came from RECONNECT, a pair of randomized, placebo-controlled, Phase 3 trials enrolling premenopausal women with HSDD.

The RECONNECT program included Study 301 and Study 302, with a combined enrollment of 1,247 women. Participants self-administered bremelanotide 1.75 mg or placebo subcutaneously on an as-needed basis, at least 45 minutes before anticipated sexual activity, over a 24-week treatment period [5]. The co-primary endpoints were change from baseline in the Female Sexual Distress Scale, Desire/Arousal/Orgasm item (FSDS-DAO) score and the Female Sexual Function Index desire domain (FSFI-D) score.

Results published in Obstetrics & Gynecology in 2019 showed significant improvements on both co-primary endpoints. Women receiving bremelanotide had a mean FSDS-DAO score reduction of -1.7 points compared to -1.0 for placebo (P<0.001). The FSFI-D score increased by 0.6 points versus 0.2 for placebo (P<0.001) [5]. Treatment effects were observed as early as 4 weeks, and approximately 50% of bremelanotide-treated patients showed a clinically meaningful response on the FSDS-DAO, compared with 36% on placebo.

The most common adverse event was nausea, reported in 40% of bremelanotide-treated patients versus 1% on placebo. Nausea was typically mild, occurred within the first few doses, and often diminished with continued use. Transient increases in blood pressure were observed (mean change of 2 to 3 mmHg systolic), but no serious cardiovascular events were reported in the trials [5].

Regulatory Path and FDA Approval

Bremelanotide's road to regulatory approval was neither quick nor simple. Two decades passed between the initial pro-sexual observations and the final FDA decision.

The FDA accepted Palatin's New Drug Application (NDA) for bremelanotide in February 2018, with priority review designation. The application was filed under Section 505(b)(1), requiring a full package of safety and efficacy data. An FDA advisory committee meeting in June 2018 reviewed the data and voted favorably, though panelists raised questions about the modest effect sizes and the 40% nausea rate.

On June 21, 2019, the FDA approved bremelanotide injection (Vyleesi) for acquired, generalized HSDD in premenopausal women [8]. The approval came with several label restrictions. Patients may not use more than one dose in 24 hours or more than 8 doses per month. The drug is contraindicated in patients with uncontrolled hypertension or known cardiovascular disease. Bremelanotide also carries a precaution about potential for focal hyperpigmentation, a residual effect from its melanocortin-1 receptor activity, particularly in patients with darker skin tones [8].

The approval made bremelanotide only the second FDA-approved pharmacotherapy for HSDD in premenopausal women, following flibanserin (Addyi), which had been approved in 2015. Unlike flibanserin, which requires daily oral dosing, bremelanotide offers on-demand use, a distinction that many clinicians and patients consider a practical advantage.

Commercialization and Post-Approval Trajectory

AMAG Pharmaceuticals acquired North American commercial rights to Vyleesi through a license agreement with Palatin Technologies and launched the product in September 2019.

Initial uptake was modest. Multiple factors contributed to slow commercial traction. The self-injection format presented a barrier for some patients. The 40% nausea rate deterred others. Insurance coverage for HSDD treatments remained inconsistent, with many plans requiring prior authorization or refusing coverage entirely. AMAG reported approximately $2 million in net Vyleesi revenue for the fourth quarter of 2019, falling well below initial projections [9].

In November 2020, Covis Pharma Group acquired AMAG Pharmaceuticals, including the Vyleesi franchise. The acquisition shifted commercialization strategy, and Covis has maintained the product's availability while adjusting marketing approach. Palatin Technologies retained certain milestone and royalty rights and has continued to explore bremelanotide's potential in additional indications, including hemorrhagic shock and obesity-related conditions.

Despite commercial challenges, the drug's approval represented a milestone in sexual medicine. Dr. Anita Clayton, Professor of Psychiatry and Neurobehavioral Sciences at the University of Virginia and a RECONNECT investigator, stated: "The approval of bremelanotide validated that low sexual desire in women is a medical condition with neurobiological underpinnings that can be treated pharmacologically" [5].

Bremelanotide in the Broader HSDD Treatment Context

HSDD affects an estimated 6% to 10% of premenopausal women in the United States, making it the most common female sexual dysfunction [10]. Before flibanserin's 2015 approval, no pharmacotherapy had been approved for this condition.

Bremelanotide and flibanserin differ in their mechanisms, dosing regimens, and adverse effect profiles. Flibanserin is a daily oral 5-HT1A agonist / 5-HT2A antagonist that requires 4 to 8 weeks to reach full effect and carries a boxed warning about severe hypotension and syncope when combined with alcohol [11]. Bremelanotide is an on-demand subcutaneous injection with effects beginning within hours but carries a high nausea rate. Head-to-head trials comparing the two agents have not been conducted.

The International Society for the Study of Women's Sexual Health (ISSWSH) process of care guidelines for HSDD recommend a biopsychosocial assessment before initiating pharmacotherapy and note that both flibanserin and bremelanotide are treatment options for premenopausal women meeting diagnostic criteria [12]. The guidelines emphasize that HSDD is a diagnosis of exclusion, requiring clinicians to rule out relationship factors, medication effects (particularly SSRIs), hormonal deficiencies, and psychiatric comorbidities before prescribing.

Current clinical practice patterns suggest that many providers prescribe bremelanotide to women who prefer on-demand dosing, who have not responded to flibanserin, or who cannot tolerate flibanserin's alcohol restriction. The choice between the two agents often depends on patient preference regarding route of administration and willingness to accept nausea versus daily dosing commitments.

What Ongoing Research May Reveal

Palatin Technologies has explored bremelanotide beyond HSDD. The compound's melanocortin receptor activity has generated interest in several preclinical and early clinical settings.

Investigational work has examined bremelanotide for hemorrhagic shock, where MC4R agonism may help maintain cardiovascular function during severe blood loss through modulation of autonomic outflow [13]. Palatin has also studied a related melanocortin compound (PL-8177) for inflammatory bowel disease, leveraging the anti-inflammatory properties of melanocortin signaling through MC1R.

In sexual medicine, research questions remain. Post-marketing studies continue to examine long-term safety, including the clinical significance of focal hyperpigmentation with repeated dosing. Investigators have also explored whether bremelanotide might benefit postmenopausal women with HSDD, a population excluded from the RECONNECT trials that represents a large unmet need. A Phase 3 study in postmenopausal women was initiated but has not yet produced published results.

The melanocortin system itself remains an active area of pharmacological research. Setmelanotide, another MC4R agonist, received FDA approval in 2020 for rare genetic obesity conditions, demonstrating the therapeutic breadth of this receptor family [14]. Whether additional melanocortin-based drugs will emerge for sexual dysfunction, metabolic disease, or inflammatory conditions depends on ongoing trial results.

Bremelanotide 1.75 mg is administered subcutaneously at least 45 minutes before anticipated sexual activity, with a maximum frequency of one dose per 24 hours and 8 doses per month, and patients should be counseled that nausea affects approximately 40% of users but typically attenuates after the first several doses [5][8].