Rhythm Pharmaceuticals’ Phase 2 trial of setmelanotide in Prader-Willi syndrome shows six-month improvements in BMI, hyperphagia, body composition, and behavioral symptoms, supporting MC4R-targeted therapy as a potential disease-modifying approach.
Written By: Nalam Karthik, PharmD
Reviewed By: Pharmacally Editorial Team
Rhythm Pharmaceuticals reported six-month Phase 2 data (NCT06772597) showing that setmelanotide reduced BMI, improved hyperphagia and anxiety-related behaviors, and preserved lean mass in patients with Prader-Willi syndrome (PWS), supporting advancement into Phase 3 development. The findings were presented at ENDO 2026 in Chicago from an ongoing 52-week study evaluating the MC4R agonist in patients with genetically confirmed PWS and obesity.
The trial enrolled 18 patients aged 6 to 23 years, with 17 participants remaining on therapy as of June 12, 2026, reflecting sustained engagement throughout the study.
Scientific and Clinical Context
Prader-Willi syndrome is a rare genetic neurodevelopmental disorder characterized by severe hyperphagia, obesity, endocrine abnormalities, and behavioral challenges. Persistent hunger and reduced energy expenditure contribute substantially to disease burden and long-term health complications.
Setmelanotide is a melanocortin-4 receptor (MC4R) agonist that targets a key pathway involved in appetite regulation and energy balance. Impaired signaling through this pathway is believed to contribute to the excessive hunger and obesity observed in PWS, providing a strong biological rationale for MC4R-targeted therapy.
Weight and Body Composition Outcomes
Patients achieved a mean BMI reduction of approximately 3% after six months of treatment.
Among adults, mean BMI declined by 3.11%, with six of ten patients achieving reductions greater than 2.5% and four patients exceeding a 4% reduction. Pediatric participants experienced a mean BMI reduction of 3.00%, while BMI z-scores decreased by an average of 0.35. Five of seven children achieved clinically meaningful BMI z-score reductions greater than 0.2.
Dual-energy X-ray absorptiometry (DEXA) analyses demonstrated favorable changes in body composition across 16 evaluable patients. Fat mass decreased by 4.19%, while lean mass increased by 0.74%.
Six of nine adults achieved more than 5% fat mass reduction, and five of seven pediatric patients gained at least 2.95% lean mass, suggesting that weight reduction occurred while preserving or improving lean tissue.
Hyperphagia and Behavioral Improvements
Setmelanotide also showed meaningful effects on hunger-related symptoms.
Among ten patients with moderate-to-severe hyperphagia at baseline, defined by a Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score above 13, eight achieved clinically meaningful improvements of at least seven points.
Behavioral outcomes improved as well. Using the Prader-Willi Syndrome Anxiousness and Distress Behaviors Questionnaire (PADQ), ten of fifteen patients with elevated baseline scores achieved reductions of at least 11 points, indicating improvements in anxiety, emotional distress, and behavioral dysregulation.
Safety Profile
The safety profile remained consistent with previous experience with setmelanotide. Investigators reported no new safety signals during the study period.
Clinical Implications
Jennifer Miller, M.D., principal investigator and professor at the University of Florida, said the findings suggest MC4R agonism may affect multiple dimensions of PWS beyond weight management. Improvements in hunger-related symptoms and behavioral challenges could help reduce the daily burden experienced by patients and caregivers.
David Meeker, M.D., Chief Executive Officer of Rhythm Pharmaceuticals, said the results strengthen confidence in MC4R-targeted therapy and support progression into late-stage development.
Path Forward
The study remains ongoing, with final 52-week results expected to provide important insight into the durability of treatment effects. Based on the positive interim findings, Rhythm plans to advance setmelanotide into Phase 3 development for Prader-Willi syndrome.
If larger studies confirm these findings, setmelanotide could become one of the first targeted therapies to address both the metabolic and behavioral features of PWS, an area where effective treatment options remain limited.
Reference
About the Writer
Nalam Karthik (LinkedIn) is a healthcare writer and PharmD graduate with interests in pharmacovigilance, drug safety, clinical data analysis, and quality assurance. He is passionate about translating clinical and pharmaceutical knowledge into accessible healthcare content while staying engaged with advancements in drug development and patient safety initiatives.