SAT-711 Efficacy And Safety Of Once-daily Oral Bivamelagon In Acquired Hypothalamic Obesity: Results From A Double-blind, Multicenter, Placebo-controlled, Randomized Phase 2 Trial

Abstract Disclosure: V. Thaker: Rhythm Pharmaceuticals. E. Kaizer Grishman: Rhythm Pharmaceuticals. F. Erenler: Rhythm Pharmaceuticals. M.M. Kelsey: Rhythm Pharmaceuticals. R. Morgan: Rhythm Pharmaceuticals. E.H. Harris: Rhythm Pharmaceuticals. H. Gan: Rhythm Pharmaceuticals. J. Oosterom: Rhythm Pharmaceuticals. H. Lee: Rhythm Pharmaceuticals. Z. Mohamed: Rhythm Pharmaceuticals. I.S. Farooqi: Rhythm Pharmaceuticals. Background: Melanocortin-4 receptor (MC4R) signaling in the hypothalamus plays a critical role in the regulation of hunger, satiety, and body weight. Damage to the hypothalamus—due to injury, benign or malignant lesion, radiation, surgery, or inflammation—can disrupt signaling through the MC4R pathway, resulting in accelerated weight gain and acquired hypothalamic obesity (aHO). aHO is also characterized by hyperphagia (insatiable hunger and abnormal food-seeking behaviors), reduced resting energy expenditure, decreased quality of life, higher risk of developing cardiovascular and endocrine dysfunction–related comorbidities, and higher mortality risk. There are currently no approved treatments for aHO. The favorable results from the Phase 3 trial of the injectable MC4R agonist setmelanotide suggest that this mechanism of action has therapeutic utility in aHO. Bivamelagon (LB54640), a once-daily next-generation oral MC4R agonist, demonstrated dose-dependent weight reduction and safety in a Phase 1 first-in-human trial in healthy participants with overweight or obesity. We will present results of the 14-week, multicenter, international, randomized, double-blind, placebo-controlled Phase 2 trial of bivamelagon in participants with aHO (NCT06046443). Methods: A total of 28 participants aged ≥12 years with body mass index (BMI) ≥95th percentile (12 to <18 years) or ≥30 kg/m2 (≥18 years) with aHO following hypothalamic tumor, lesion, or injury were enrolled. Participants were randomized 1:1:1:1 to bivamelagon low (200 mg), middle (400 mg), or high dose (600 mg) or placebo for 14 weeks (all oral and once daily). The primary endpoint was the mean percentage change in BMI at 14 weeks. Secondary endpoints were the mean change in BMI, the percentage of participants with ≥5% reduction in body weight, and mean change in the weekly average of the maximal daily hunger score. Safety was assessed throughout the trial. Eligible participants (who demonstrated adequate safety/tolerability, and, in the opinion of the investigator, would benefit from initiating or continuing treatment with bivamelagon) could proceed into the open-label extension (OLE) phase for up to 38 weeks. All participants continuing into the OLE were retitrated from 200 mg up to a maximum of 600 mg bivamelagon, as tolerability allowed, to preserve double blinding. Results: At the time of submission, 21 of 28 participants completed the 14-week trial (1 discontinuation), 20 of whom continued to receive treatment in the OLE. Overall, 46.4% were female, mean (SD; range) age at baseline was 25.4 (16.8; 12-68) years, mean (SD) BMI was 38.7 (8.4) kg/m2, and mean (SD) BMI-Z (<18 years) was 3.13 (1.21). The most common etiology of aHO was craniopharyngioma (82.1%), and the mean (SD) time from confirmed hypothalamic injury to enrollment was 7.0 (5.0) years. Topline results from the double-blind 14-week stage of the trial will be presented. Presentation: Saturday, July 12, 2025