P256 - ECE_2728 - Impact of setmelanotide on metabolic index scores in Phase 3 trial participants with acquired hypothalamic obesity

Abstract

Acquired hypothalamic obesity (aHO) is a rare complex disease characterized by hyperphagia and reduced energy expenditure, leading to accelerated and sustained weight gain. Commonly associated with pituitary hormone deficiencies, fatigue, or sleep disturbances, aHO puts patients at high risk for metabolic complications like insulin resistance, dyslipidemia, and hepatic steatosis. Non-invasive metabolic markers enable early detection and quantification of cardiometabolic risk, allowing timely, targeted interventions. In the international Phase 3 trial of MC4R agonist setmelanotide (NCT05774756), the primary endpoint of percent change in BMI at Week 52 was met. This posthoc analysis assessed setmelanotide impact on metabolic index scores. Patients with aHO aged ≥4 years in the Phase 3, double-blind TRANSCEND trial were randomized 2:1 to receive setmelanotide (0.5 mg subcutaneously once daily [QD], titrated up to 1.5-3.0 mg QD) or placebo for up to 60 weeks. The modified intent-to-treat (mITT) population was analyzed for changes in lipid accumulation product (LAP), triglyceride-glucose waist circumference index (TYG-WC), visceral adiposity index (VAI), fatty liver index (FLI), and metabolic syndrome z-score (MetS z-score) after 52 weeks of therapeutic dose. Only participants with baseline and week 52 values available were included. Overall, 120 participants were included in the pivotal cohort (81 setmelanotide, 39 placebo), with a mean (SD) age of 19.9 (13.8; range: 4-66) y, a mean BMI in participants ≥18 y of 41.2 (9.7) kg/m2, and a BMI z-score in participants <18 y of 3.61 (1.66). In the mITT population (n = 81), baseline metabolic index scores for each marker were indicative of metabolic dysfunction. The mean (SD) change from baseline to week 52 in the setmelanotide-treated group vs placebo was greater across all indices: for LAP (n = 68 vs n = 36) the change was -36.4 (58.8) vs −2.6 (37.0), P < .0001; TYG-WC (n = 63 vs n = 35) was -138.3 (140.1) vs +21.2 (73.2), P < .0001; VAI (n = 67 vs n = 35) was −1.5 (2.8) vs −0.4 (1.7), P = .0009; FLI (n = 65 vs n = 35) was −24.2 (26.7) vs +4.4 (11.1), P < .0001; and reductions in MetS z-score (n = 53 vs n = 31) were −0.9 (1.0) vs −0.2 (0.4), P < 0.0001, respectively. Setmelanotide treatment in patients with aHO led to significant improvements in multiple metabolic index scores vs placebo. These data suggest reductions in visceral fat burden, hepatic steatosis, and overall cardiometabolic risk. The findings highlight the broad metabolic benefits and strong clinically meaningful efficacy of setmelanotide in this population, supporting its potential as a therapeutic option for patients with aHO.