Setmelanotide for the Treatment of Acquired Hypothalamic Obesity.
BACKGROUND A phase 2 trial of setmelanotide, a melanocortin-4 receptor agonist, showed substantial weight loss in patients with acquired hypothalamic obesity, but additional data are needed. METHODS We conducted a phase 3 trial in which participants were randomly assigned in a 2:1 ratio to receive setmelanotide (at a dose of 1.5 to 3.0 mg) or placebo administered subcutaneously once daily for 52 weeks after a dose-escalation period. Persons at least 4 years of age were potentially eligible for the trial if they had acquired hypothalamic obesity, which was defined by a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) that was at or above the 95th percentile for age and sex (for participants <18 years of age) or at least 30 (for participants ≥18 years of age) and a history of a hypothalamic tumor, lesion, or injury. The primary end point was the mean percent change in BMI from baseline to 52 weeks after the end of the dose-escalation period. Secondary end points included the mean change in the weekly average of the maximal daily hunger score (range, 0 to 10, with higher scores indicating more severe hunger), assessed in participants at least 12 years of age. RESULTS From April 26, 2023, to March 18, 2025, a total of 120 participants were assigned to receive setmelanotide (81 participants) or placebo (39 participants). The mean (±SD) age was 19.9±13.8 years (range, 4 to 66). Among participants 18 years of age or older, the mean BMI was 41.2±9.7; the mean BMI z score among those younger than 18 years of age was 3.61±1.66. The least-squares mean (LSM) change in BMI at 52 weeks was -16.5% (95% confidence interval [CI], -19.3 to -13.8) with setmelanotide and 3.3% (95% CI, -0.6 to 7.2) with placebo (P<0.001), and the LSM change in the weekly average of maximal daily hunger scores was -2.73 (95% CI, -3.28 to -2.18) in the setmelanotide group and -1.45 (95% CI, -2.23 to -0.67) in the placebo group (P = 0.009). Adverse events were reported in 100% of the participants in the setmelanotide group and in 90% of those in the placebo group, and serious adverse events were reported in 28% and 8%, respectively. The most common adverse events with setmelanotide were skin hyperpigmentation, nausea, vomiting, and headache. CONCLUSIONS Setmelanotide led to significantly greater reductions in BMI and hunger than placebo at 52 weeks among participants 4 to 66 years of age with acquired hypothalamic obesity. (Funded by Rhythm Pharmaceuticals; TRANSCEND ClincialTrials.gov number, NCT05774756.).