SAT-713 - Setmelanotide, a Melanocortin-4 Receptor Agonist, in Prader-Willi Syndrome: Initial Phase 2 Results

Background: Patients with Prader-Willi syndrome (PWS) often lack expression of genes involved with the development and function of the hypothalamic melanocortin-4 receptor (MC4R) pathway. This may result in decreased alpha-melanocyte-stimulating hormone (α-MSH) levels and disrupted pathway signaling, leading to hyperphagia (insatiable hunger and abnormal food-seeking behaviors) and obesity. There are no approved treatments for weight reduction in PWS. Setmelanotide, an MC4R agonist, has been associated with weight reduction in several other MC4R pathway diseases, and was previously evaluated in a small, short-term, Phase 2 PWS trial. Here, we report the initial results from an ongoing Phase 2 trial of setmelanotide in PWS (NCT06772597) with higher doses and an extended duration of treatment compared with the previous study.

Methods: This is an exploratory, Phase 2, open-label trial of setmelanotide in participants with PWS, aged 6 to 65 years old, with body mass index (BMI) ≥95th percentile (adjusted for age and sex) for < 18 years old and BMI ≥30 kg/m2 for ≥18 years old. Open-label setmelanotide was given subcutaneously once daily and escalated to doses of up to 4-5 mg/day in participants ≥12 years old per investigator discretion, for 52 weeks. Primary endpoints assess safety and tolerability; secondary endpoints included change in BMI, hyperphagia as evaluated by the Hyperphagia Questionnaire for Clinical Trials (HQ-CT), and body composition via Dual-Energy X-ray Absorptiometry.

Results: At data snapshot (November 14, 2025), 18 participants were enrolled; 17 were ongoing; one had discontinued by family decision. At baseline, the mean (SD) age of all participants was 17.1 (5.6) years; 8 (44.4%) were female, 15 (83.3%) were White, and the mean (SD) BMI was 39.1 (9.5) kg/m2. The most commonly reported adverse events were skin hyperpigmentation (27.8%) and injection site reactions (22.2%). Eight participants received ≥3 months of treatment. At Month 3, BMI reductions from baseline ranged from 1.3% to 4.8% in 6 participants; 2 participants – one with poorly controlled diabetes and one who stopped then restarted setmelanotide at a low dose – exhibited BMI increases of ~2%. Six of 7 evaluable participants had HQ-CT reductions at Month 3. Five participants had 6 months of treatment; 2 had deepening BMI reductions from baseline (-5.6 and -5.9%), 1 was unchanged (-2.6%), and 2 increased (+0.5 and +4.2%, the latter being the participant with diabetes). Three of 4 evaluable participants had body composition improvements, with greater fat than lean mass loss, at Month 6.

Conclusions: Encouraging preliminary results were seen following setmelanotide in participants with PWS and obesity, including improvements in BMI, body composition, and hyperphagia. Additional 6+ month data from this trial will be presented, and a Phase 3 trial is planned.

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