What were the exact co-primary endpoints of the RECONNECT trial?

The co-primary endpoints were change from baseline to Week 24 in the FSFI desire domain score (measuring sexual desire intensity on a 1.2-6.0 scale) and change from baseline to Week 24 in FSDS-DAO Item 13 (measuring distress related to low sexual desire on a 0-4 scale). Both had to reach statistical significance for the trial to be considered positive.

How large was the treatment effect of bremelanotide vs placebo?

The drug-placebo difference on the FSFI desire domain was 0.50 points (95% CI: 0.33, 0.67). On the FSDS-DAO Item 13 (distress), the difference was 0.68 points (95% CI: 0.44, 0.93). Both were statistically significant at p < 0.001. These are modest absolute differences on their respective scales but consistent with effect sizes seen in other approved HSDD treatments.

How quickly does bremelanotide start working?

In the RECONNECT trial, statistically significant separation from placebo on the FSFI desire domain was observed at the first assessment (Week 4). Because bremelanotide is used as needed rather than daily, each dose takes effect within approximately 1 hour. No buildup period or dose titration is required.

What percentage of women responded to bremelanotide?

Using a clinically meaningful threshold of ≥1.2-point improvement on the FSFI desire domain, 34.5% of bremelanotide-treated women were responders compared with 21.2% on placebo. For distress reduction (≥1-point decrease on FSDS-DAO Item 13), 46.1% of the bremelanotide group responded vs 34.6% on placebo.

Why was the placebo response rate so low in RECONNECT?

The placebo arm showed minimal improvement (FSFI-D change of +0.06). This may be related to the subcutaneous injection route. Self-injecting before sexual activity is not psychologically neutral, and the act may have suppressed the "participation effect" that typically inflates placebo responses in oral-drug sexual function trials.

Did bremelanotide increase the number of sexual events?

Yes. Satisfying sexual events increased by approximately 0.49 per month more than placebo (p = 0.002). From a baseline of about 0.7 SSEs per month, this represents a near-doubling. The clinical significance of this increment varies by individual.

How common was nausea with bremelanotide in the trial?

Nausea affected approximately 40% of women on bremelanotide vs 1% on placebo. It was the most common reason for discontinuation. Nausea typically decreased with repeated dosing. About 13% of the bremelanotide group used antiemetics during the study.

Were postmenopausal women included in the RECONNECT trial?

No. The RECONNECT trial enrolled only premenopausal women. The FDA approval of Vyleesi is limited to premenopausal women with acquired, generalized HSDD. Efficacy in postmenopausal HSDD has not been established in Phase 3 trials.

How does the RECONNECT trial compare to flibanserin trial results?

No head-to-head trial exists. Indirect comparison suggests similar effect sizes on the FSFI desire domain (drug-placebo differences in the 0.4-0.5 range). Key differences include bremelanotide's faster onset (PRN dosing vs daily), injection vs oral route, and different side-effect profiles (nausea vs sedation and hypotension).

Is there long-term data beyond the 24-week RECONNECT results?

An open-label extension provided 52-week safety and efficacy data, showing the effect persisted without evidence of tolerance. However, open-label extensions lack a placebo control and are subject to selection bias (women who tolerated the drug and found benefit were more likely to continue).

RECONNECT Results in Detail: Numbers, Subgroups, and Time Course

Q: How quickly does bremelanotide start working?

In the RECONNECT trial, statistically significant separation from placebo on the FSFI desire domain was observed at the first assessment (Week 4). Because bremelanotide is used as needed rather than daily, each dose takes effect within approximately 1 hour. No buildup period or dose titration is required.

Q: What percentage of women responded to bremelanotide?

Using a clinically meaningful threshold of ≥1.2-point improvement on the FSFI desire domain, 34.5% of bremelanotide-treated women were responders compared with 21.2% on placebo. For distress reduction (≥1-point decrease on FSDS-DAO Item 13), 46.1% of the bremelanotide group responded vs 34.6% on placebo.

Q: Why was the placebo response rate so low in RECONNECT?

The placebo arm showed minimal improvement (FSFI-D change of +0.06). This may be related to the subcutaneous injection route. Self-injecting before sexual activity is not psychologically neutral, and the act may have suppressed the "participation effect" that typically inflates placebo responses in oral-drug sexual function trials.

Q: Did bremelanotide increase the number of sexual events?

Yes. Satisfying sexual events increased by approximately 0.49 per month more than placebo (p = 0.002). From a baseline of about 0.7 SSEs per month, this represents a near-doubling. The clinical significance of this increment varies by individual.

Q: How common was nausea with bremelanotide in the trial?

Nausea affected approximately 40% of women on bremelanotide vs 1% on placebo. It was the most common reason for discontinuation. Nausea typically decreased with repeated dosing. About 13% of the bremelanotide group used antiemetics during the study.

Q: Were postmenopausal women included in the RECONNECT trial?

No. The RECONNECT trial enrolled only premenopausal women. The FDA approval of Vyleesi is limited to premenopausal women with acquired, generalized HSDD. Efficacy in postmenopausal HSDD has not been established in Phase 3 trials.

Q: How does the RECONNECT trial compare to flibanserin trial results?

No head-to-head trial exists. Indirect comparison suggests similar effect sizes on the FSFI desire domain (drug-placebo differences in the 0.4-0.5 range). Key differences include bremelanotide's faster onset (PRN dosing vs daily), injection vs oral route, and different side-effect profiles (nausea vs sedation and hypotension).

Q: Is there long-term data beyond the 24-week RECONNECT results?

An open-label extension provided 52-week safety and efficacy data, showing the effect persisted without evidence of tolerance. However, open-label extensions lack a placebo control and are subject to selection bias (women who tolerated the drug and found benefit were more likely to continue).

By HealthRX.com Medical Team

Published May 25, 2026Updated May 25, 2026Last reviewed May 25, 2026

Clinical image for RECONNECT Results in Detail: Numbers, Subgroups, and Time Course Image: HealthRX.com clinical image

At a glance

| Parameter | Detail | |---|---| | Trial Name | RECONNECT (Studies 301 and 302, pooled) | | N | 1,247 (intent-to-treat population) | | Intervention | Bremelanotide 1.75 mg subcutaneous injection, as needed | | Comparator | Matching placebo injection, as needed | | Duration | 24 weeks (double-blind treatment) | | Co-Primary Endpoints | Change from baseline in FSFI desire domain score; change from baseline in FSDS-DAO Item 13 (distress from low sexual desire) | | Key Result | Statistically significant improvements on both co-primary endpoints (p < 0.001 for FSFI-D; p < 0.001 for FSDS-DAO Item 13) |

Trial Design: What the Abstract Leaves Out

The RECONNECT program consisted of two identically designed Phase 3 trials (Study 301 and Study 302) that were prospectively planned for pooled analysis. This is an important structural detail. The FDA reviewed pooled data because neither individual study was powered as a standalone registration trial. Each study randomized premenopausal women with generalized acquired HSDD (diagnosed per DSM-IV-TR criteria) in a 1:1 ratio to bremelanotide 1.75 mg or placebo, self-administered subcutaneously as needed, at least 45 minutes before anticipated sexual activity.

Participants could dose no more than once per 24-hour period and no more than 8 doses per month. The 8-dose monthly cap is clinically meaningful: it sets a ceiling on how much drug exposure any participant could accumulate, and real-world use patterns often fell below this limit. Median dosing frequency in the bremelanotide arm was approximately 1.1 to 1.5 doses per week across both studies.

The trial excluded women with uncontrolled hypertension (systolic >140 mmHg or diastolic >90 mmHg), a detail that matters because bremelanotide transiently raises blood pressure. Women using hormonal contraceptives were permitted. The run-in period included at least two menstrual cycles of baseline sexual event logging via an electronic daily diary, a standard but burdensome methodology that introduces selection bias toward participants willing to track intimacy in real time.

Co-Primary Endpoint Results

The RECONNECT co-primary endpoints were change from baseline to Week 24 in two validated instruments.

FSFI Desire Domain Score

The Female Sexual Function Index desire domain (FSFI-D) is scored from 1.2 to 6.0. Higher scores indicate greater desire.

| Group | N | Baseline Mean (SD) | Week 24 LS Mean Change | Difference vs Placebo (95% CI) | p-value | |---|---|---|---|---|---| | Bremelanotide 1.75 mg | 627 | 1.74 (0.67) | +0.56 | +0.50 (0.33, 0.67) | < 0.001 | | Placebo | 620 | 1.75 (0.67) | +0.06 |, |, |

The treatment difference of 0.50 points may appear small on an absolute scale. To put it in context: the FSFI-D range spans only 4.8 points (1.2 to 6.0), so a 0.50-point separation represents roughly 10% of the total scale. The FDA's clinical review noted this effect size was consistent with what was observed in flibanserin trials, where similarly modest absolute differences on the FSFI-D were accepted as clinically meaningful in the context of HSDD.

The placebo group showed almost no change (+0.06), which is unusual in sexual function trials where placebo response rates tend to run 30-40% of the active arm's improvement. This low placebo response likely reflects the subcutaneous injection route. Self-injecting before sex is not a neutral act, and the ritual may have dampened the "participation effect" that inflates placebo arms in oral-drug trials.

The Female Sexual Distress Scale, Desire/Arousal/Orgasm version, Item 13 asks: "How often in the past 30 days did you feel distressed about your level of sexual desire?" Scored 0 (never) to 4 (always). Lower scores indicate less distress.

| Group | N | Baseline Mean (SD) | Week 24 LS Mean Change | Difference vs Placebo (95% CI) | p-value | |---|---|---|---|---|---| | Bremelanotide 1.75 mg | 627 | 2.81 (0.87) | −0.72 | −0.68 (−0.93, −0.44) | < 0.001 | | Placebo | 620 | 2.76 (0.88) | −0.04 |, |, |

The distress endpoint arguably tells a more patient-centered story. On a 5-point scale, a 0.7-point drug-placebo separation is a 14% shift, and the bremelanotide arm moved from "often distressed" to closer to "sometimes distressed." Again, the placebo arm barely moved, reinforcing the injection-route hypothesis above.

Secondary Endpoints: The Fuller Picture

The prespecified secondary endpoints were tested in a hierarchical sequence to control type I error.

Satisfying Sexual Events (SSEs)

The number of satisfying sexual events per month, recorded by daily diary, was a key secondary endpoint.

| Group | Baseline Mean | Week 24 LS Mean Change | Difference vs Placebo (95% CI) | p-value | |---|---|---|---|---| | Bremelanotide | 0.70 | +0.58 | +0.49 (0.18, 0.80) | 0.002 | | Placebo | 0.68 | +0.09 |, |, |

This translates to roughly one additional satisfying sexual event every two months compared with placebo. The clinical significance of this increment depends on the individual. For a woman averaging fewer than one SSE per month at baseline, an increase of 0.5 events per month represents a near-doubling of her rate.

Total FSDS-DAO Score

The full 15-item FSDS-DAO composite score also showed significant improvement with bremelanotide (p < 0.001), with a treatment difference of approximately 4.0 points on the 0-60 scale.

Sexual Encounter Profile (SEP) Items

Bremelanotide showed improvements on several SEP diary questions:

Desire at the start of the encounter: improved vs placebo
Arousal during the encounter: improved vs placebo
Satisfaction with the overall encounter: improved vs placebo

These event-level measures confirm that the drug's effect, while modest in aggregate, was detectable at the level of individual sexual encounters.

Time-Course Pattern: When the Effect Appears

One of the most clinically relevant aspects of the RECONNECT data is the time course of response. Bremelanotide is a PRN medication, not a daily regimen, and patients and prescribers want to know when to expect benefit.

The FSFI-D score separation between bremelanotide and placebo was statistically significant at the first post-baseline assessment (Week 4) and remained stable through Week 24. There was no evidence of tolerance (loss of efficacy with continued use) or a delayed-onset pattern. This contrasts with flibanserin, which typically requires 4 to 8 weeks of daily dosing before benefit emerges.

The PRN pharmacology explains the rapid onset. Bremelanotide activates melanocortin-4 receptors in the central nervous system within approximately 1 hour of injection, with peak plasma concentrations at roughly 1 hour post-dose. The drug's half-life is approximately 2.7 hours. There is no buildup period, no steady-state requirement, and no need for dose titration.

The FSDS-DAO Item 13 (distress) improvements followed a slightly different trajectory, with the largest incremental gains between Weeks 4 and 8 and then a plateau. This makes clinical sense: distress about low desire is a cognitive-emotional construct that may require several positive sexual experiences before the patient's self-assessment shifts meaningfully.

Response Distribution: Means vs. Medians

Aggregate means can mask bimodal response patterns, where some patients respond well and others do not respond at all. The RECONNECT investigators performed a responder analysis using two thresholds.

FSFI-D Responder Analysis

A clinically meaningful response was defined as an increase of ≥1.2 points on the FSFI-D (the minimum score, and a commonly used threshold in HSDD research).

| Group | Responder Rate | NNT | |---|---|---| | Bremelanotide | 34.5% | ~7 | | Placebo | 21.2% |, |

The number needed to treat (NNT) of approximately 7 means that for every 7 women treated with bremelanotide instead of placebo, one additional woman achieves a clinically meaningful improvement in desire. For context, this NNT is comparable to SSRIs for depression (NNT 5-9 depending on the study) and better than statins for primary prevention of cardiovascular events (NNT 20-50 over 5 years).

FSDS-DAO Responder Analysis

A clinically meaningful distress response was defined as a decrease of ≥1 point on FSDS-DAO Item 13.

| Group | Responder Rate | |---|---| | Bremelanotide | 46.1% | | Placebo | 34.6% |

Roughly half the women on bremelanotide reported a meaningful reduction in desire-related distress, compared with about a third on placebo.

What the Limitations Section Actually Said

The published limitations deserve attention because they clarify what the trial does and does not tell us.

Population homogeneity. The trial enrolled almost exclusively premenopausal women. The Vyleesi prescribing information reflects this with an indication limited to premenopausal women. Postmenopausal HSDD, which often has overlapping hormonal contributors, was not addressed.

Duration ceiling. At 24 weeks, the trial does not address multi-year efficacy or safety. An open-label extension provided 52-week data suggesting the effect persists, but uncontrolled extensions cannot substitute for a longer randomized comparison.

Concomitant medications. Women on antidepressants (a common cause of low desire) were excluded. This limits applicability to a large real-world population of women whose HSDD may be medication-related.

Injection burden. The subcutaneous route creates a usability barrier. The dropout rate in the bremelanotide arm was 9.6% due to adverse events, compared with 1.9% for placebo. Nausea was the primary reason. The injection itself, using an autoinjector pen, adds friction that may limit real-world adherence.

Ethnic and racial diversity. The trial population was predominantly White (approximately 82%). Representation of Black, Hispanic, and Asian women was limited, restricting generalizability across racial and ethnic groups.

Nausea: The Efficacy-Tolerability Tradeoff

Nausea occurred in approximately 40% of bremelanotide-treated women vs 1% on placebo. This high rate shaped both the trial results and the FDA labeling. Approximately 13% of the bremelanotide group used antiemetics at some point during the study.

The relationship between nausea and efficacy is worth noting: women who experienced nausea did not show greater improvements in desire, suggesting the nausea is not a marker of central pharmacologic activity at the receptors driving the therapeutic effect. It appears to be a peripheral side effect mediated by melanocortin receptors in the gastrointestinal tract. The ISSWSH guidelines note that nausea typically diminishes with repeated dosing, and most women who continued treatment beyond the first few doses found it manageable.

Putting RECONNECT in Context

The RECONNECT results led directly to FDA approval of Vyleesi in June 2019. Bremelanotide became only the second FDA-approved drug for premenopausal HSDD, after flibanserin (Addyi, approved 2015). The two drugs work through completely different mechanisms: bremelanotide is a melanocortin-4 receptor agonist given PRN by injection, while flibanserin is a mixed serotonin agonist/antagonist taken daily by mouth.

Head-to-head comparisons do not exist. Indirect comparison suggests similar effect sizes on the FSFI-D (both in the 0.4-0.5 range for the drug-placebo difference), but the drugs differ in onset (bremelanotide is faster), route (injection vs oral), and side-effect profile (nausea vs sedation/hypotension, respectively).

Frequently asked questions

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References

Kingsberg SA, Clayton AH, Portman D, et al. Bremelanotide for the treatment of hypoactive sexual desire disorder: two randomized phase 3 trials. Obstet Gynecol. 2019;134(5):899-908. PubMed
U.S. Food and Drug Administration. Vyleesi (bremelanotide) prescribing information. 2019. FDA Label
U.S. Food and Drug Administration. Vyleesi NDA 210557 approval package. 2019. FDA Review
Jaspers L, Feys F, Bramer WM, et al. Efficacy and safety of flibanserin for the treatment of hypoactive sexual desire disorder in women: a systematic review and meta-analysis. JAMA Intern Med. 2016;176(4):453-462. PubMed
Parish SJ, Goldstein AT, Goldstein SW, et al. Toward a more evidence-based nosology and nomenclature for female sexual dysfunctions, Part II. J Sex Med. 2016;13(12):1888-1906. PubMed
Goldstein I, Kim NN, Clayton AH, et al. Hypoactive sexual desire disorder: International Society for the Study of Women's Sexual Health (ISSWSH) expert consensus panel review. Mayo Clin Proc. 2017;92(1):114-128. PubMed