Rhythm reports positive Phase 2 setmelanotide data in PWS
Rhythm Pharmaceuticals has presented six-month interim data from its ongoing Phase 2 trial of setmelanotide in Prader-Willi syndrome (PWS), reporting clinically meaningful reductions in BMI, fat mass, and hyperphagia across a cohort of 17 patients. The data were presented at the Endocrine Society's Annual Meeting (ENDO 2026) in Chicago on 13 June.
The 52-week trial enrolled 18 patients aged 6 to 23 years with obesity-range BMI. Of the 17 remaining on active therapy at the data cut-off date of 7 May 2026, the mean BMI reduction at six months was 3.06%. Adult patients (n=10) recorded a mean reduction of 3.11%, with six achieving greater than 2.5% BMI reduction; paediatric patients (n=7) saw a mean reduction of 3.00%, with five achieving a clinically meaningful BMI z-score reduction of more than 0.2.
Body composition and behavioural endpoints
Body composition analysis, available for 16 patients via DEXA scan, showed a mean lean mass gain of 0.74% alongside a mean fat mass reduction of 4.19%. Six of nine adult patients achieved more than 5% fat mass reduction, and five of seven paediatric patients gained at least 2.95% in lean mass. The preservation of lean mass alongside fat loss is a clinically relevant distinction in an obese paediatric population, where muscle preservation during weight reduction is a recognised treatment objective.
Hyperphagia, a defining and often debilitating feature of PWS, also improved. Eight of ten patients who entered the trial with moderate to severe hyperphagia scores achieved at least a seven-point reduction on the Hyperphagia Questionnaire for Clinical Trials (HQ-CT), the threshold defined as clinically meaningful. In the anxiety and behaviour domain, ten of fifteen patients with elevated baseline scores on the PWS Anxiousness and Distress Behaviours Questionnaire (PADQ) achieved clinically meaningful improvement of eleven points or more.
Jennifer Miller, principal investigator and endocrinologist at the University of Florida College of Medicine, said the reductions in hyperphagia and anxiety scores "have the potential to ease the burden not only on patients, but also on their caregivers who manage the daily challenges of this disease."
Safety findings were described as consistent with setmelanotide's established profile across its existing approved indications.
Regulatory path and competitive context
Rhythm's chief executive David Meeker said the results increased the company's confidence to advance into Phase 3 development for PWS. Setmelanotide is already approved by the FDA, European Commission, and the UK's MHRA for several other MC4R pathway-related obesity indications, including Bardet-Biedl syndrome and POMC deficiency, which provides a meaningful regulatory foundation for a PWS filing.
PWS affects an estimated 400,000 people globally, with Rhythm estimating a US patient population of between 12,500 and 16,000. The company calculates that 80% to 90% of those patients live with hyperphagia and obesity, representing a target population of roughly 8,500 to 12,750 individuals in the United States alone. Effective pharmacological options for hyperphagia in PWS remain scarce; growth hormone therapy addresses some aspects of the syndrome but does not target the hunger dysregulation central to morbidity and caregiver burden.
The MC4R agonism approach is not without competition in the rare obesity space. A number of academic groups and smaller biotechs are exploring GLP-1 receptor agonists and other metabolic pathways in PWS, though none has yet reached late-stage development with a primary hyperphagia endpoint. Full 52-week data from the Rhythm trial will be needed to assess durability and the longer-term safety signal before a Phase 3 design can be finalised.