Setmelanotide shows interim phase 2 signals in Prader-Willi syndrome

Rhythm Pharmaceuticals reported 6-month interim data from an ongoing phase 2 trial of setmelanotide in children, adolescents, and young adults with Prader-Willi syndrome (PWS), with observed reductions in BMI measures, fat mass, hyperphagia scores, and anxiety-related behaviors, according to data presented at ENDO 2026.¹

“Patients and families living with PWS face severe hyperphagia and obesity due to underlying MC4R pathway dysfunction and have limited effective treatment options,” Jennifer Miller, MD, of the University of Florida Division of Endocrinology, Department of Pediatrics, and principal investigator of the trial, said in the company announcement. Miller added that reductions in hyperphagia, anxiety, and weight “have the potential to ease the burden not only on patients, but also on their caregivers.”

The findings support continued development of melanocortin-4 receptor (MC4R) agonism in PWS, but the results remain preliminary. The trial is ongoing, has a small sample size, and the company announcement did not describe a placebo comparator or provide detailed adverse event rates specific to the PWS cohort.

Rhythm enrolled 18 patients aged 6 to 23 years with PWS. Adults were required to have a BMI of at least 30 kg/m², and pediatric participants were required to have a BMI at or above the 95th percentile for age and sex. The study is planned for 52 weeks, and 17 participants remained on active therapy as of June 12, 2026. The interim analysis used a May 7, 2026, data cutoff.

At month 6, the company reported a mean BMI reduction of 3.06% among 17 treated participants. Adult participants had a mean BMI reduction of 3.11%; 6 of 10 adults achieved a BMI reduction greater than 2.5%, and 4 achieved a reduction greater than 4%. Pediatric participants had a mean BMI reduction of 3.00% and a mean BMI z-score reduction of 0.35; 5 of 7 children achieved a BMI z-score reduction greater than 0.2.

Body composition data were available for 16 participants by dual-energy x-ray absorptiometry. Mean lean mass increased by 0.74%, while mean fat mass decreased by 4.19%. Among adults with available scans, 6 of 9 had more than a 5% reduction in fat mass. Among pediatric participants, 5 of 7 gained at least 2.95% in lean mass.

Hyperphagia was assessed with the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Among 10 participants who entered the study with moderate to severe hyperphagia, defined by the company as an HQ-CT score greater than 13, 8 achieved at least a 7-point reduction, which Rhythm characterized as clinically meaningful. Anxiety and behavioral dysregulation were assessed with the PWS Anxiousness and Distress Behaviors Questionnaire; among 15 participants with baseline scores greater than 11, 10 achieved an improvement of at least 11 points.

PWS is a rare genetic disorder involving hypotonia, developmental and cognitive impairment, endocrine abnormalities, hyperphagia, and obesity risk. Hyperphagia often emerges in early childhood and can create substantial caregiver burden because of persistent food-seeking behavior and the need for environmental controls around food access.² Rhythm estimated in its announcement that PWS affects approximately 400,000 people worldwide, including 12,500 to 16,000 patients in the United States, but those figures were company estimates rather than trial-derived prevalence data.¹

Setmelanotide is an MC4R agonist intended to activate signaling in the leptin-melanocortin pathway, a pathway involved in appetite regulation and energy homeostasis. The drug has previously been evaluated in rare genetic obesity disorders, including phase 3 studies in POMC, PCSK1, and LEPR deficiency and in Bardet-Biedl syndrome.^3,4 According to Rhythm, setmelanotide is currently approved in the United States for several rare obesity indications, including acquired hypothalamic obesity and obesity due to Bardet-Biedl syndrome or POMC, PCSK1, or LEPR deficiency; it is not approved for PWS.¹

Safety findings in the interim PWS analysis were described by the company as consistent with the established setmelanotide profile. The announcement did not provide PWS-specific rates of adverse events. In approved uses, warnings and precautions for setmelanotide include hypersensitivity reactions, depression and suicidal ideation, spontaneous penile erections, skin hyperpigmentation and changes in nevi, and indication-specific risks in acquired hypothalamic obesity, including adrenal insufficiency and sodium imbalance.

The next key step will be confirmation in a larger phase 3 program with prespecified endpoints, adequate duration, and a comparator group. Clinically, the most important unanswered questions include the durability of BMI and hyperphagia changes, whether body composition improvements translate into functional or metabolic benefit, and how tolerability compares with the risks of long-term treatment in children and adolescents with PWS.

References

1. Rhythm Pharmaceuticals. Rhythm Pharmaceuticals presents positive interim six-month data from phase 2 trial of setmelanotide in patients with Prader-Willi syndrome (PWS) at ENDO 2026. GlobeNewswire. June 13, 2026. Accessed June 15, 2026. https://www.globenewswire.com/news-release/2026/06/13/3311380/0/en/rhythm-pharmaceuticals-presents-positive-interim-six-month-data-from-phase-2-trial-of-setmelanotide-in-patients-with-Prader-Willi-syndrome-pws-at-endo-2026.html

2. Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader-Willi syndrome. Genet Med. 2012;14(1):10-26. doi:10.1038/gim.0b013e31822bead0

3. Clément K, van den Akker E, Argente J, et al. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol. 2020;8(12):960-970. doi:10.1016/S2213-8587(20)30364-8

4. Haqq AM, Chung WK, Dollfus H, et al. Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alström syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period. Lancet Diabetes Endocrinol. 2022;10(12):859-868. doi:10.1016/S2213-8587(22)00277-7