Setmelanotide Shows Promising Early Results in Prader-Willi Syndrome: Phase 2 Data Signal Efficacy and Support Advancement
Preliminary Data Show Reduction in BMI and Hunger—Majority of Patients Respond by Month 3
Rhythm Pharmaceuticals has unveiled early data from its exploratory Phase 2 study investigating setmelanotide in patients with Prader-Willi syndrome (PWS). These results highlight positive efficacy signals, especially for the two central challenges faced by people with PWS: excessive body weight (as measured by BMI) and uncontrollable hunger, or hyperphagia.
Among 18 enrolled patients, most showed reductions in both BMI and hyperphagia at interim points. Specifically, six of eight patients who completed three months of therapy achieved reductions in BMI, and six of seven showed improvement on the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). At the six-month checkpoint, three out of five had further reductions in BMI—with two experiencing greater benefit versus their Month 3 results.
| Checkpoint | Patients Assessed | BMI Reduction Observed | Hyperphagia Reduction Observed |
|---|---|---|---|
| Month 3 | 8 | 6 | 6 (of 7 evaluable) |
| Month 6 | 5 | 3 | Not specified |
Phase 2 Safety Profile Remains Consistent and Patient Retention High
Setmelanotide's safety profile continues to align with prior clinical experiences, showing no unexpected adverse reactions and consistent tolerability. Notably, 17 out of the 18 enrolled participants remain on active treatment as of the latest update, reflecting robust patient retention—a sign that tolerability issues are not forcing withdrawals in the short to mid-term.
Next Steps: Moving Into Phase 3 and Expanding the Program
Given the positive preliminary findings, Rhythm will advance setmelanotide into a pivotal Phase 3 registrational trial in PWS once the current trial concludes. In parallel, the company has launched a Part D arm of its Phase 1 trial for another MC4R agonist, RM-718, which is now screening up to 20 PWS patients for a 26-week study. These next steps are intended to broaden the potential treatment toolkit for a disorder that currently lacks highly effective therapies.
Why This Matters: Addressing Critical Needs in PWS With Few Options
PWS is a rare genetic disorder that profoundly disrupts hunger control and metabolic regulation, impacting roughly 20,000 individuals in the United States alone. The absence of robust, FDA-approved options for PWS-related obesity and hyperphagia has been a longstanding challenge for patients and caregivers. The promising results from setmelanotide, and the company’s pipeline focus on MC4R agonists, mark meaningful steps toward closing this treatment gap.
Key Safety Considerations for Setmelanotide
As setmelanotide advances through trials, its safety profile is closely monitored. The most common side effects (incidence =20%) include skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, and abdominal pain, with other serious adverse events flagged for ongoing vigilance. The drug’s full prescribing information includes detailed guidance on these risks and limitations for certain populations (including neonates, low birth weight infants, and breastfeeding individuals).
Takeaway: New Hope Emerges, but Ongoing Research Will Determine the Scope of Impact
While it’s too soon to declare setmelanotide a breakthrough for all with PWS, these early Phase 2 results present meaningful progress and support Rhythm’s expansion into Phase 3 studies. Investors, patients, and the clinical community will be watching closely for updated data in 2026 and beyond. For those tracking innovation in rare endocrine and genetic obesity syndromes, Rhythm’s momentum with setmelanotide and RM-718 may warrant a closer look as pivotal trials unfold.
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