PT-141 FDA Approval Studies Breakdown
On June 21, 2019, the FDA approved bremelanotide -- marketed as Vyleesi -- for the treatment of hypoactive sexual desire disorder in premenopausal women.
On June 21, 2019, the FDA approved bremelanotide -- marketed as Vyleesi -- for the treatment of hypoactive sexual desire disorder in premenopausal women. It was only the second drug ever approved for this indication, and the first to work through a completely different mechanism than its predecessor, flibanserin (Addyi). This article breaks down every clinical study that led to that approval, from early-phase erectile dysfunction research in men to the pivotal RECONNECT trials in women.
Table of Contents
- What Is PT-141 (Bremelanotide)?
- From Melanotan II to PT-141: The Discovery Path
- Mechanism of Action: How PT-141 Differs From Other Drugs
- Early Clinical Studies: Erectile Dysfunction in Men
- Phase II Trials: Pivoting to Female Sexual Dysfunction
- The RECONNECT Phase III Trials
- Long-Term Safety and Efficacy Data
- Safety Profile Across the Clinical Program
- Blood Pressure and Cardiovascular Findings
- FDA Review and Approval Decision
- How PT-141 Compares to Flibanserin (Addyi)
- Post-Approval Research and Ongoing Questions
- FAQ
- The Bottom Line
- References
What Is PT-141 (Bremelanotide)?
PT-141 (bremelanotide) is a synthetic melanocortin receptor agonist. It is a cyclic heptapeptide that activates multiple melanocortin receptors, with its therapeutic effects on sexual function primarily mediated through MC3R and MC4R in the central nervous system.
PT-141 is the active metabolite of Melanotan II, the tanning peptide developed at the University of Arizona. During early tanning trials, researchers noticed that Melanotan II produced unexpected sexual side effects -- spontaneous erections and increased desire -- in study participants. This observation sent the research in an entirely new direction.
The approved formulation (Vyleesi) is administered as a 1.75 mg subcutaneous injection via auto-injector, given at least 45 minutes before anticipated sexual activity. It is approved for use no more than once per 24 hours and no more than 8 times per month.
From Melanotan II to PT-141: The Discovery Path
The story of PT-141 begins with an accident. In the mid-1990s, a researcher at the University of Arizona accidentally injected himself with a high dose of Melanotan II and experienced an eight-hour erection. The anecdote, widely cited in the pharmacology literature, sparked interest in the melanocortin system as a target for sexual dysfunction.
Palatin Technologies acquired the rights to develop melanocortin-based therapeutics and identified bremelanotide (PT-141) as a more targeted compound. While structurally related to Melanotan II, PT-141 was specifically developed and tested for sexual function applications rather than tanning.
Key distinction: PT-141 was initially studied as an intranasal spray for both male and female sexual dysfunction. However, the intranasal formulation was abandoned after Phase IIb trials showed it caused unacceptable blood pressure increases. The subcutaneous injection route used in the approved product largely resolved this problem, producing smaller and more transient hemodynamic changes.
Mechanism of Action: How PT-141 Differs From Other Drugs
PT-141 acts through a mechanism that is fundamentally different from every other approved sexual dysfunction treatment.
Traditional erectile dysfunction drugs (sildenafil, tadalafil, vardenafil) are phosphodiesterase type 5 (PDE5) inhibitors. They work in the periphery by increasing blood flow to erectile tissue. They address the mechanical side of sexual function -- the physical ability to achieve and maintain an erection -- but do not affect desire or arousal in the brain.
Flibanserin (Addyi), the only other drug approved for HSDD, works on serotonin receptors (5-HT1A agonist / 5-HT2A antagonist). It is taken daily and requires 4-8 weeks to produce effects.
PT-141 acts on melanocortin receptors (MC3R and MC4R) in the hypothalamus and limbic system. These brain regions regulate sexual motivation and arousal. As described by Pfaus et al. (2022) in CNS Spectrums, bremelanotide "targets neurobiologic components of female sexual function" by modulating pathways that influence desire itself -- not just the physical response.
This is what makes PT-141 conceptually different: it works on the "wanting" part of sexual function rather than the "doing" part. It is also on-demand (used before sexual activity) rather than a daily medication, which distinguishes it from flibanserin.
Early Clinical Studies: Erectile Dysfunction in Men
Before PT-141 was studied for female sexual dysfunction, the earliest clinical work focused on erectile dysfunction in men.
Phase I Studies in Healthy Volunteers
Uckert et al. (2014), reviewing early clinical data in Expert Opinion on Investigational Drugs, summarized the results from Phase I studies:
- PT-141 administered intranasally produced dose-dependent erectile responses in healthy men
- At doses of 7.5-20 mg intranasal, subjects showed measurable increases in penile rigidity using RigiScan monitoring
- The erectogenic effect occurred without visual sexual stimulation, suggesting a central rather than peripheral mechanism
Phase II Erectile Dysfunction Studies
Shadiack et al. (2007) in Current Topics in Medicinal Chemistry reviewed the clinical development program for melanocortin agonists in sexual dysfunction:
- Phase II trials in men with mild-to-moderate erectile dysfunction showed statistically significant improvements in erectile response
- The intranasal formulation produced blood pressure elevations that raised safety concerns
- These blood pressure findings ultimately led to the clinical hold placed on the intranasal program by the FDA in 2007
The clinical hold on intranasal PT-141 was a pivotal moment. Rather than abandoning the compound, Palatin Technologies reformulated it for subcutaneous injection and shifted the primary indication from male ED to female HSDD -- a condition with a far greater unmet medical need at the time, as there were no approved treatments for it.
Phase II Trials: Pivoting to Female Sexual Dysfunction
Diamond et al. (2006): First Female Study
The first published clinical study of bremelanotide in women appeared in The Journal of Sexual Medicine in 2006 (Diamond et al.). This was a proof-of-concept study in premenopausal women with female sexual arousal disorder (FSAD).
| Parameter | Detail |
|---|---|
| Design | Randomized, double-blind, placebo-controlled |
| Subjects | Premenopausal women with FSAD |
| Route | Intranasal |
| Key finding | Statistically significant increase in subjective sexual arousal compared to placebo |
| Citation count | 147 (as of 2026) |
This study was notable because it demonstrated that a melanocortin agonist could affect subjective sexual response in women -- something PDE5 inhibitors had repeatedly failed to do in female trials.
Clayton et al. (2016): Phase IIb Dose-Finding
The critical Phase IIb trial was published by Clayton et al. (2016) in Women's Health. This was a randomized, placebo-controlled dose-finding study specifically designed to identify the optimal subcutaneous dose for the Phase III program.
Study design:
- Premenopausal women with HSDD (with or without decreased arousal)
- Subcutaneous injection (the new route, replacing intranasal)
- Multiple dose levels tested
- Co-primary endpoints: FSFI desire domain score and FSDS-DAO Item 13 (distress related to low desire)
Results:
The 1.75 mg subcutaneous dose emerged as the optimal balance of efficacy and tolerability:
- Statistically significant improvements in desire and reduction in distress
- Nausea was the most common side effect but was manageable
- Blood pressure changes were smaller and more transient than with the intranasal route
- This dose was selected for the pivotal Phase III RECONNECT trials
The RECONNECT Phase III Trials
The RECONNECT program consisted of two identically designed Phase III trials -- Study 301 and Study 302 -- that formed the basis for the FDA approval application.
Study Design
| Parameter | Detail |
|---|---|
| Study names | RECONNECT Study 301 and Study 302 |
| ClinicalTrials.gov | NCT02333071 (301) and NCT02338960 (302) |
| Design | Randomized, double-blind, placebo-controlled |
| Duration | 24 weeks |
| Population | Premenopausal women (ages 21+) diagnosed with HSDD |
| Total randomized | 1,267 women (safety population: 1,247) |
| Dose | 1.75 mg subcutaneous injection, used as needed before sexual activity |
| Maximum frequency | No more than once per 24 hours; up to 8 doses per month |
| Study dates | Study 301: January 2015 - July 2016; Study 302: January 2015 - August 2016 |
| Sponsor | Palatin Technologies / AMAG Pharmaceuticals |
Co-Primary Endpoints
The FDA agreed to two co-primary endpoints for the RECONNECT trials:
- FSFI Desire Domain (FSFI-D): A validated questionnaire measuring sexual desire on a 1.2-6.0 scale
- FSDS-DAO Item 13: A measure of personal distress specifically related to low sexual desire, scored on a 0-4 scale (higher = more distress)
Both endpoints needed to show statistically significant separation from placebo for the trial to succeed.
Efficacy Results
Both RECONNECT studies met both co-primary endpoints:
| Endpoint | Study 301 (vs. placebo) | Study 302 (vs. placebo) | Integrated (vs. placebo) |
|---|---|---|---|
| FSFI-D change | +0.30 (p < 0.001) | +0.42 (p < 0.001) | +0.35 (p < 0.001) |
| FSDS-DAO Item 13 change | -0.37 (p < 0.001) | -0.29 (p = 0.005) | -0.33 (p < 0.001) |
What these numbers mean:
- FSFI-D improvement of 0.35 points represents a clinically meaningful increase in sexual desire scores. Bremelanotide-treated women reported more frequent sexual thoughts and greater desire for sexual activity.
- FSDS-DAO reduction of 0.33 points means women experienced less personal distress about their low sexual desire.
Satisfying sexual events (SSE): While SSE was a secondary endpoint, bremelanotide-treated women showed numerical increases in the number of satisfying sexual events per month. The primary efficacy analysis focused on desire and distress rather than frequency of events -- an important distinction, as HSDD is fundamentally a disorder of desire, not performance.
Interpretation
Kingsberg et al. (2019), publishing the results in Obstetrics & Gynecology, concluded: "Both studies demonstrated that bremelanotide significantly improved sexual desire and related distress in premenopausal women with hypoactive sexual desire disorder."
The effect sizes were described as "moderate" by independent analysts. A re-analysis published by Jaspers et al. (2021) in the Journal of Sexual Medicine examined the Phase III data and noted that while statistically significant, the absolute improvements were modest on the measurement scales used. This observation has been part of the ongoing clinical discussion about bremelanotide's place in therapy.
Long-Term Safety and Efficacy Data
Beyond the 24-week RECONNECT trials, a 52-week open-label extension study evaluated the long-term safety and durability of bremelanotide's effects.
Simon et al. (2019): Open-Label Extension
Published in Obstetrics & Gynecology alongside the primary RECONNECT results, this study followed women who continued bremelanotide treatment for up to one year total.
Key findings:
- Efficacy was maintained over the 52-week period -- desire improvements and distress reductions persisted
- No new safety signals emerged with extended use
- The most common reason for discontinuation was nausea (consistent with acute tolerability rather than cumulative toxicity)
- No evidence of tachyphylaxis (loss of drug effect over time)
Safety Profile Across the Clinical Program
Clayton et al. (2022) published a comprehensive safety analysis across the entire bremelanotide clinical development program in the Journal of Women's Health. This pooled analysis included all Phase II and Phase III studies plus the long-term extension.
Adverse Event Rates
| Adverse Event | Bremelanotide | Placebo |
|---|---|---|
| Nausea | 40.0% | 1.3% |
| Flushing | 20.3% | 1.3% |
| Headache | 11.3% | 1.9% |
| Injection site reactions | 5.4% | 0.9% |
| Vomiting | >4% (specific % not reported) | <1% |
Nausea Profile
Nausea was the most common adverse event and the most common reason for discontinuation. However, the pattern showed clear adaptation:
| Dose Number | Nausea Incidence |
|---|---|
| First dose | 21% |
| Second dose | 3% |
| Third dose | 2% |
This rapid decline in nausea from 21% at first dose to 2-3% at subsequent doses suggests receptor desensitization and indicates that patients who tolerate the first few doses are likely to tolerate continued use.
Focal Hyperpigmentation
Skin darkening was monitored throughout the clinical program given bremelanotide's melanocortin mechanism:
- With recommended dosing (up to 8 times/month): 1% of patients developed focal hyperpigmentation
- With daily dosing for 8 days (above recommended frequency): 38% developed hyperpigmentation
- Resolution was not confirmed in all patients after stopping the drug
- Higher rates were observed in women with darker skin tones
Blood Pressure and Cardiovascular Findings
The blood pressure story was central to bremelanotide's development. The intranasal formulation was put on clinical hold specifically because of hypertensive effects. The subcutaneous formulation was designed to produce slower absorption and more controlled hemodynamic changes.
Hemodynamic data from the subcutaneous formulation:
| Parameter | Change | Timing |
|---|---|---|
| Systolic BP increase | Up to 6 mmHg (mean) | Peak at 2-4 hours post-dose |
| Diastolic BP increase | Up to 3 mmHg (mean) | Peak at 2-4 hours post-dose |
| Heart rate | Decrease of up to 5 bpm | Same timeframe |
| Return to baseline | Within 12 hours | -- |
Alcohol Co-Administration Study
Clayton et al. (2017) published a dedicated Phase I study in Clinical Therapeutics examining the safety of bremelanotide when taken with alcohol -- a practical consideration given the drug's on-demand use pattern.
- Healthy male and female volunteers received bremelanotide with and without ethanol
- Alcohol did not meaningfully increase the blood pressure effects
- No significant pharmacokinetic interaction was observed
- The combination was well tolerated
Contraindications
Based on the blood pressure data, the FDA label contraindicates Vyleesi in patients with:
- Uncontrolled hypertension
- Known cardiovascular disease
The label also warns that bremelanotide may slow gastric emptying, which could affect absorption of concomitant oral medications.
FDA Review and Approval Decision
The FDA approved bremelanotide (Vyleesi) on June 21, 2019, making it the second drug approved for HSDD in premenopausal women.
Key aspects of the FDA's evaluation:
- Efficacy: Both RECONNECT trials met both co-primary endpoints with statistical significance, satisfying the FDA's standard of two adequate and well-controlled studies
- Safety: The transient blood pressure increases were considered manageable with appropriate labeling and contraindications
- Risk mitigation: The FDA required the label to include dosing limits (maximum once daily, 8 times monthly) and contraindications for cardiovascular disease
- Abuse potential: A dedicated assessment found no evidence that bremelanotide produces subjective responses predictive of abuse
- No REMS required: Unlike flibanserin, which required a Risk Evaluation and Mitigation Strategy due to alcohol interactions, bremelanotide was approved without a REMS
The approval was not without debate. Some reviewers questioned whether the magnitude of improvement on the FSFI desire domain scale was clinically meaningful for individual patients, even if statistically significant across the population. This is a recurring theme in sexual dysfunction drug development, where measurement instruments may not fully capture subjective experiences.
How PT-141 Compares to Flibanserin (Addyi)
| Feature | Bremelanotide (Vyleesi) | Flibanserin (Addyi) |
|---|---|---|
| Mechanism | MC3R/MC4R agonist (melanocortin) | 5-HT1A agonist / 5-HT2A antagonist (serotonin) |
| Route | Subcutaneous injection | Oral tablet |
| Dosing | On-demand (before sexual activity) | Daily (at bedtime) |
| Time to effect | Within 45 minutes | 4-8 weeks of daily use |
| Alcohol restriction | None | Cannot use with alcohol (boxed warning) |
| REMS required | No | Yes |
| Most common side effect | Nausea (40% at first dose) | Dizziness, sleepiness, nausea |
| Approval date | June 2019 | August 2015 |
| Population | Premenopausal women with HSDD | Premenopausal women with HSDD |
The two drugs offer genuinely different therapeutic profiles. Bremelanotide's on-demand use and lack of alcohol interaction make it more practical for many patients. Flibanserin's oral route avoids injection but requires daily commitment regardless of sexual activity. For more on these options, see our guide on best peptides for sexual health.
Post-Approval Research and Ongoing Questions
Since the 2019 approval, several additional studies have expanded the understanding of bremelanotide:
Subgroup analyses (2022): Pre-specified and integrated subgroup analyses from the RECONNECT trials (published in Journal of Women's Health) showed consistent efficacy across age groups, weight categories, and BMI quartiles. The safety profile was also similar across these subgroups.
Neurobiology review (Pfaus et al., 2022): Published in CNS Spectrums, this paper provided the most detailed analysis of bremelanotide's central mechanism of action, mapping the neural circuits through which MC3R/MC4R activation influences sexual motivation and desire.
Pharmacovigilance review (Cipriani et al., 2023): Published in Expert Opinion on Pharmacotherapy, this evaluation of bremelanotide's post-market safety and clinical performance confirmed the safety profile seen in trials and noted no unexpected adverse events in clinical practice.
Ongoing questions include:
- Efficacy in postmenopausal women (the current approval is limited to premenopausal women)
- Potential applications in male sexual dysfunction (early-phase data was promising but never pursued to Phase III)
- Long-term safety beyond one year of use
- Real-world effectiveness outside the controlled trial setting
- Potential role in combination therapy with other HSDD treatments
FAQ
What is PT-141 and how does it work?
PT-141 (bremelanotide) is a melanocortin receptor agonist that activates MC3R and MC4R receptors in the brain. It works on the neural circuits that regulate sexual desire and motivation, acting on the "wanting" rather than the physical mechanics of sexual function.
What were the Phase III RECONNECT trial results?
Two identical Phase III trials enrolled 1,247 premenopausal women with HSDD. Both trials met both co-primary endpoints: bremelanotide significantly increased sexual desire scores (FSFI-D: +0.35 vs. placebo, p < 0.001) and reduced distress related to low desire (FSDS-DAO: -0.33 vs. placebo, p < 0.001).
What are the most common side effects of bremelanotide?
Nausea (40% with first dose, dropping to 2-3% by third dose), flushing (20.3%), headache (11.3%), and injection site reactions (5.4%). Nausea is the most common reason patients stop taking the drug.
Is PT-141 approved for men?
No. Early clinical studies showed PT-141 produced erectile responses in men, but the clinical development was redirected toward female HSDD. The current FDA approval is exclusively for premenopausal women. There is no approved melanocortin-based treatment for male sexual dysfunction.
How does PT-141 differ from Viagra or Cialis?
PDE5 inhibitors like sildenafil (Viagra) and tadalafil (Cialis) increase blood flow to erectile tissue. They address the physical mechanism of erection but do not affect desire. PT-141 acts on brain receptors that influence sexual desire itself. They work through completely different pathways.
Can PT-141 be used with other peptides?
The FDA-approved prescribing information does not address combination with other peptides. PT-141 may slow gastric emptying, which could affect oral drug absorption. See our peptide stacking guide for general considerations on combining peptides.
Is PT-141 the same as Melanotan II?
No. PT-141 (bremelanotide) is a metabolite of Melanotan II that was separately developed, tested in controlled clinical trials, and approved by the FDA. Melanotan II has never been approved for any use and carries different and less well-characterized risks. For more on the parent compound, see our Melanotan II profile.
The Bottom Line
The clinical development of PT-141 followed a genuinely unusual path. It started as a tanning drug. It accidentally revealed sexual side effects. The nasal spray got put on hold for blood pressure problems. The program pivoted to subcutaneous injection and shifted from male erectile dysfunction to female desire disorder. Along the way, it became the first drug to demonstrate that targeting melanocortin receptors in the brain could treat a sexual dysfunction condition.
The RECONNECT trials were well-designed, adequately powered, and met their endpoints. The effect sizes were statistically significant and, in the FDA's assessment, clinically meaningful. The safety profile is dominated by first-dose nausea that resolves quickly and transient blood pressure changes that are manageable with proper patient selection.
What bremelanotide represents for the broader field is perhaps as important as the drug itself. It validated an entirely new biological pathway for treating sexual dysfunction -- one that works on desire rather than mechanics, and one that traces its origins to the melanocortin system first explored through Melanotan II.
References
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Kingsberg SA, Clayton AH, Portman D, et al. Bremelanotide for the treatment of hypoactive sexual desire disorder: two randomized phase 3 trials. Obstetrics & Gynecology. 2019;134(5):899-908. LWW
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Simon JA, Kingsberg SA, Portman D, et al. Long-term safety and efficacy of bremelanotide for hypoactive sexual desire disorder. Obstetrics & Gynecology. 2019;134(5):909-917. LWW
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Clayton AH, Kingsberg SA, Portman D, et al. Safety profile of bremelanotide across the clinical development program. Journal of Women's Health. 2022;31(2):171-182. SAGE
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Clayton AH, Althof SE, Kingsberg S, et al. Bremelanotide for female sexual dysfunctions in premenopausal women: a randomized, placebo-controlled dose-finding trial. Women's Health. 2016;12(3):325-337. SAGE
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Pfaus JG, Sadiq A, Spana C, Clayton AH. The neurobiology of bremelanotide for the treatment of hypoactive sexual desire disorder in premenopausal women. CNS Spectrums. 2022;27(1):61-74. Cambridge
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Cipriani S, Alfaroli C, Maseroli E, et al. An evaluation of bremelanotide injection for the treatment of hypoactive sexual desire disorder. Expert Opinion on Pharmacotherapy. 2023;24(2):181-190. Taylor & Francis
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Uckert S, Bannowsky A, Albrecht K, et al. Melanocortin receptor agonists in the treatment of male and female sexual dysfunctions: results from basic research and clinical studies. Expert Opinion on Investigational Drugs. 2014;23(11):1477-1483. Taylor & Francis
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U.S. Food and Drug Administration. VYLEESI (bremelanotide injection) prescribing information. Approved June 2019. FDA