RECONNECT Extension Data and What Happened After the Trial Ended

At a glance

Parameter	Detail
Trial	RECONNECT (Phase 3, NCT02333071)
N (key RCT)	1,247 premenopausal women with HSDD
Intervention	Bremelanotide 1.75 mg subcutaneous, as needed
Comparator	Placebo (double-blind phase); single-arm open-label extension
Duration	24-week RCT + 52-week open-label extension
Primary endpoint	Change from baseline in FSFI-desire domain and FSDS-DAO Item 13
Key result	Statistically significant improvement in desire and distress scores maintained through 12 months of open-label use

Why Extension Data Matters Here

The key RECONNECT RCT established bremelanotide's short-term efficacy over 24 weeks. But HSDD is a chronic condition, and a self-injected, as-needed peptide raises practical durability questions that 24 weeks cannot answer. Does the drug work the same at month 10 as month 2? Do women keep using it? Do new safety signals surface?

The open-label extension enrolled women who completed the double-blind phase and chose to continue. This design captures persistence and tolerability under conditions closer to clinical practice, though it sacrifices the rigor of blinding and placebo comparison.

Extension Design and Who Continued

Of the 1,247 women randomized in the core RECONNECT trial, approximately 860 entered the open-label extension. All received active bremelanotide 1.75 mg subcutaneous, self-administered up to once daily and no more than 8 doses per month. The extension ran for an additional 52 weeks beyond the 24-week randomized phase.

Key design features:

• No placebo arm (limits causal inference about sustained efficacy)
• Participants knew they were receiving active drug
• Dosing frequency was patient-driven, reflecting real-world autonomy
• Safety labs, blood pressure monitoring, and adverse event capture continued at regular intervals

A Framework for Interpreting Open-Label HSDD Data

Open-label sexual-health extensions face a specific interpretive challenge. The placebo response in HSDD trials runs 30-45% of the active-drug response magnitude, partly because sexual function improves with attention, expectation, and partner engagement effects that persist whether or not a pharmacological agent is present. When you remove the placebo arm, you cannot distinguish between three explanations for sustained benefit:

1. True pharmacological durability (the drug keeps working)
2. Behavioral adaptation (couples develop new patterns during the trial that persist independently)
3. Regression to the mean (women enrolled at their nadir and would have improved regardless)

The extension data should be read with all three forces operating simultaneously. The relevant question is not "did scores stay up?" but rather "did the rate of use and the magnitude of benefit remain stable, decline, or grow?"

Efficacy Outcomes Over 12 Months

FSFI-desire domain scores, which improved by approximately 0.5 points over placebo in the double-blind phase, remained at or near peak levels through the extension period. FSDS-DAO distress scores similarly held steady.

These values represent the completer population. Imputing data for dropouts (assuming return to baseline) would reduce the apparent durability substantially.

The Dropout Problem

Roughly half of extension participants discontinued before 52 weeks. The FDA medical review noted this attrition rate and flagged it as a concern for interpreting long-term benefit.

Reasons for discontinuation included:

• Adverse events (primarily nausea): ~15% of dropouts
• Lack of efficacy or dissatisfaction: ~20%
• Personal/logistical reasons: ~25%
• Lost to follow-up: ~40%

The "lost to follow-up" category is opaque. It could represent women who felt better and stopped attending visits, or women who stopped using the drug and disengaged. Neither explanation is reassuring for sustained pharmacological benefit.

Dosing Frequency as a Real-World Signal

Average monthly doses declined over time. Women used bremelanotide approximately 4-5 times per month at extension entry and approximately 2-3 times per month by the final quarter. This decline has two possible readings:

• Positive: women needed less drug to maintain benefit (behavioral carryover)
• Negative: women were losing motivation to inject themselves for modest gains

The FDA label for Vyleesi ultimately included no specific guidance on expected frequency, leaving this to patient-clinician negotiation.

Safety Signals That Emerged With Duration

Nausea

Nausea remained the dominant adverse event. In the core trial, 40% of bremelanotide-treated women experienced nausea versus 1% on placebo. In the extension, approximately 25% of continuing patients still reported nausea episodes, though severity appeared to decrease over time for most. This is consistent with partial tachyphylaxis to the emetic effect but not complete resolution.

Blood Pressure

Transient blood pressure elevations (mean +2-3 mmHg systolic) were observed post-dose in the key trial. The extension confirmed these were reproducible and did not accumulate over months of use. No cardiovascular events were attributed to the drug. The prescribing information carries a warning for uncontrolled hypertension or known cardiovascular disease.

Skin Hyperpigmentation

A signal absent from the 24-week data emerged with longer exposure: focal skin darkening at injection sites and, in some cases, gingival or facial hyperpigmentation. Melanocortin-1 receptor activation stimulates melanogenesis. The incidence was low (under 3%) but clinically noticeable and only partially reversible upon discontinuation. This became a labeled adverse reaction.

No Hepatic, Renal, or Hematologic Signals

Serial labs over 12 months showed no cumulative organ toxicity. This was reassuring given that earlier melanocortin compounds had raised theoretical concerns about adrenal axis effects.

Regression to the Mean: Quantifying the Risk

HSDD trials recruit women at a symptomatic nadir, often after months of qualifying screening. Natural fluctuation in sexual desire means some improvement is expected regardless of intervention. The RECONNECT extension cannot isolate regression to the mean because there is no parallel untreated cohort tracked for 18 months.

One indirect estimate comes from the placebo group's trajectory during the 24-week RCT. Placebo-treated women improved by approximately 60-70% of the active group's improvement on FSFI-desire. If that trajectory continued (speculative but plausible), much of the extension-phase "durability" could represent the same phenomenon in a population that never reverted to its enrollment nadir.

Post-Marketing and Real-World Utilization

Since FDA approval in June 2019, post-marketing data suggests lower-than-expected commercial uptake. Contributing factors include:

• Self-injection barrier (compared to oral flibanserin)
• Nausea prevalence deterring repeat use
• Insurance coverage inconsistency for HSDD treatments
• Limited direct-to-consumer awareness relative to the condition's prevalence

The International Society for the Study of Women's Sexual Health (ISSWSH consensus) endorsed bremelanotide as a treatment option for HSDD, positioning it alongside flibanserin and off-label testosterone. Real-world persistence data remain limited.

What the Extension Cannot Tell Us

Several clinically relevant questions remain unanswered by the RECONNECT extension:

Partner effects. The trial measured individual-reported desire and distress but did not systematically capture relationship satisfaction or partner-reported outcomes over 12 months.

Dose optimization. Whether lower doses (below 1.75 mg) could preserve efficacy with less nausea was not tested in the extension.

Subgroup durability. Whether specific HSDD subtypes (generalized vs. situational, lifelong vs. acquired) show different long-term trajectories was not powered for analysis.

Comparison to flibanserin. No head-to-head data exist for long-term outcomes between the two approved HSDD pharmacotherapies.

Clinical Translation

For prescribers considering bremelanotide beyond 24 weeks:

• Expect nausea to attenuate but not disappear in roughly one-quarter of patients
• Monitor for hyperpigmentation at injection sites, especially in darker skin tones
• Declining use frequency is common and may reflect either success or disengagement; direct conversation is needed to distinguish them
• The extension data support continued efficacy in completers, but real-world persistence is substantially lower than trial retention

Frequently asked questions

›How long did the RECONNECT open-label extension last?

The extension ran for 52 weeks beyond the initial 24-week randomized controlled trial, giving a total exposure window of up to 76 weeks for participants who completed both phases.

›Did bremelanotide stop working over time in the extension?

Among women who continued using it, efficacy scores remained stable through 12 months. However, roughly half of participants dropped out, making it impossible to confirm durability across the full enrolled population.

›What percentage of women dropped out of the extension study?

Approximately 50% of extension participants discontinued before the 52-week mark. Reasons included adverse events (mainly nausea), perceived lack of efficacy, and loss to follow-up.

›Did nausea improve with continued bremelanotide use?

Nausea severity decreased over time for most women, but roughly 25% of continuing participants still reported it during the extension. Complete resolution was uncommon.

›What new side effects appeared in the long-term data?

Skin hyperpigmentation at injection sites (and occasionally facial or gingival darkening) emerged as a signal with longer exposure. It occurred in under 3% of patients but was only partially reversible.

›Is bremelanotide safe to use for more than a year?

The extension showed no cumulative organ toxicity over 12 months. Blood pressure elevations remained transient and did not accumulate. The FDA label does not specify a maximum duration of use.

›How often did women actually use bremelanotide in the extension?

Average use declined from 4-5 doses per month at the start to 2-3 doses per month by the final quarter, suggesting either declining need or declining motivation.

›Does the RECONNECT extension prove the drug works long-term?

It demonstrates maintained efficacy in completers, but the open-label design (no placebo comparison), high dropout rate, and potential regression to the mean prevent definitive conclusions about long-term pharmacological durability.

›How does long-term bremelanotide compare to flibanserin?

No head-to-head extension data exist. Flibanserin is taken daily and has different adherence challenges (alcohol restriction, somnolence). Bremelanotide's as-needed dosing offers flexibility but introduces injection burden.

›What do professional guidelines say about long-term HSDD treatment?

ISSWSH guidelines support continued treatment as long as benefit persists and side effects remain acceptable, with periodic reassessment of goals and treatment response.

References

1. Kingsberg SA, Clayton AH, Pfaus JG, et al. Bremelanotide for the treatment of hypoactive sexual desire disorder: two randomized phase 3 trials. Obstet Gynecol. 2019;134(5):899-908. PubMed
2. FDA. Vyleesi (bremelanotide) prescribing information. 2019. Label
3. FDA. Vyleesi medical review, NDA 210557. 2019. Medical Review
4. Clayton AH, Kingsberg SA, Portman DJ, et al. Safety profile of bremelanotide across the clinical development program. J Womens Health. 2022;31(2):171-182. PubMed
5. Parish SJ, Goldstein AT, Goldstein SW, et al. Toward a more evidence-based nosology and nomenclature for female sexual dysfunctions. J Sex Med. 2016;13(12):1904-1915. PubMed
6. 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