Rhythm Pharmaceuticals Reports Positive Phase 3 Data for Setmelanotide in Hypothalamic Obesity

Rhythm Pharmaceuticals announced additional positive data from its global Phase 3 TRANSCEND trial of setmelanotide in patients with acquired hypothalamic obesity. Setmelanotide delivered an 18.8% placebo-adjusted difference in BMI reduction at 52 weeks in the expanded dataset (N=142), which added 12 patients from a Japanese cohort and 10 supplemental patients to the original pivotal population.

Across all treated patients, mean BMI fell 16.4% from baseline on setmelanotide (n=94) versus a 2.4% increase on placebo (n=48), achieving statistical significance (95% CI; P<0.0001). Among patients aged 12 and older (n=98), weekly average most-hunger scores declined by 2.5 points on setmelanotide (n=66) compared with 1.3 points on placebo (n=32), also statistically significant (P=0.0015).

Rhythm has submitted the final 52-week dataset to FDA ahead of schedule for its supplemental NDA seeking a label expansion to acquired hypothalamic obesity, with a PDUFA goal date of March 20, 2026. The company will submit the full data package to the FDA on March 2, 2026 ahead of the previously agreed upon submission date for the supplemental data. In Europe, a Type II variation to the existing marketing authorization is under CHMP review, with an opinion expected in the second quarter of 2026 and potential marketing authorization in the second half. The company also plans to file in Japan, leveraging the newly reported local cohort.

The new data follow April 2025 topline results from the pre-specified 120-patient pivotal cohort, reinforcing the primary and key secondary endpoints in a broader, more globally representative population.

Acquired hypothalamic obesity is a rare disease characterized by accelerated and sustained weight gain caused by an injury to the hypothalamus. Hypothalamic injury may lead to decreased alpha-melanocyte-stimulating hormone (α-MSH) production and impairment of MC4R pathway signaling. The MC4R pathway is responsible for regulating energy balance and body weight. Acquired hypothalamic obesity most frequently follows the growth or treatment of craniopharyngioma, astrocytoma or other hypothalamic-pituitary tumors. Additional causes of injury may include traumatic brain injury, stroke or inflammation. Due to impairment of the MC4R pathway, patients experience accelerated and sustained weight gain, often accompanied by hyperphagia and/or decreased energy expenditure. Acquired hypothalamic obesity can occur as early as six months following hypothalamic injury. Rhythm estimates 10,000 patients living with acquired HO in the United States, approximately 10,000 patients in Europe and between 5,000 to 8,000 people living with acquired hypothalamic obesity in Japan.

Rhythm is a commercial-stage biopharmaceutical company committed to transforming the lives of patients and their families living with rare neuroendocrine diseases. Rhythm's lead asset, IMCIVREE (setmelanotide), an MC4R agonist designed to treat hyperphagia and severe obesity, is approved by the FDA to reduce excess body weight and maintain weight reduction long term in adult and pediatric patients 6 years of age and older with syndromic or monogenic obesity due to Bardet-Biedl syndrome (BBS) or genetically confirmed pro-opiomelanocortin (POMC), including proprotein convertase subtilisin/kexin type 1 (PCSK1), deficiency.