Announcement • Jul 09

Rhythm Pharmaceuticals Publishes Phase 3 TRANSCEND Trial Results for Setmelanotide in Acquired Hypothalamic Obesity

Rhythm Pharmaceuticals announced that results from its pivotal Phase 3 TRANSCEND trial evaluating setmelanotide, a melanocortin-4 receptor (MC4R) agonist, in patients with acquired hypothalamic obesity have been published in The New England Journal of Medicine. The TRANSCEND study is the largest and longest placebo-controlled clinical trial ever conducted in patients with acquired hypothalamic obesity. The publication highlights robust improvements in weight and hunger achieved with setmelanotide therapy in adult and pediatric patients aged four years and older. In this 52-week, randomized, double blind, placebo-controlled Phase 3 study, the first 120 patients who reached 52 weeks on therapeutic regimen were evaluated as the primary analysis cohort. Patients treated with setmelanotide achieved: -19.8% placebo-adjusted difference in body mass index (BMI) reduction (n=120); Primary endpoint of mean BMI reduction of -16.5% from baseline for all patients on setmelanotide therapy (n=81) compared with +3.3% BMI change for patients on placebo (n=39) at 52 weeks. Setmelanotide was generally well tolerated. No new safety signals were observed, and adverse events leading to treatment discontinuation were comparable between treatment and placebo groups. In March 2026, the U.S. Food and Drug Administration (FDA) approved setmelanotide (IMCIVREE) as the first and only therapy for acquired hypothalamic obesity in adults and children aged 4 years and older. Also in March 2026, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) recommended marketing authorization for IMCIVREE to include the treatment of obesity and the control of hunger in adults and children 4 years of age and above with acquired hypothalamic obesity due to hypothalamic injury or impairment. The global, randomized, double blind, placebo-controlled Phase 3 TRANSCEND trial evaluated the efficacy and safety of setmelanotide in patients aged 4 years and older with acquired hypothalamic obesity. A total of 120 participants were randomized 2:1 to once daily subcutaneous setmelanotide or placebo for 52 weeks. The primary endpoint was mean percent change in BMI after 52 weeks of treatment. Full topline results were previously announced in April 2025. 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 (a-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. In the United States, setmelanotide is indicated to reduce excess body weight and maintain weight reduction long term in adults and pediatric patients aged 4 years and older with acquired hypothalamic obesity, in adult and pediatric patients aged 2 years and older with syndromic or monogenic obesity due to Bardet-Biedl syndrome (BBS) or Pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS). In the European Union and the United Kingdom, setmelanotide is indicated for the treatment of obesity and the control of hunger associated with genetically confirmed BBS or loss-of-function biallelic POMC, including PCSK1, deficiency or biallelic LEPR deficiency in adults and children 2 years of age and above. In the European Union and the United Kingdom, setmelanotide should be prescribed and supervised by a physician with expertise in obesity with underlying genetic etiology. Setmelanotide is not indicated for the treatment of patients with the following conditions as setmelanotide would not be expected to be effective: Obesity due to suspected POMC, PCSK1, or LEPR deficiency with POMC, PCSK1, or LEPR variants classified as benign or likely benign; Other types of obesity not related to acquired HO, BBS, or POMC, PCSK1 or LEPR deficiency, including obesity associated with other genetic syndromes and general (polygenic) obesity.

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