P255 - ECE_1844 - Efficacy and safety of setmelanotide in acquired hypothalamic obesity: Results from a double-blind, multicentre, placebo-controlled, randomised phase 3 trial

Abstract

Hypothalamic melanocortin-4 receptor (MC4R) signalling is crucial for regulating hunger, satiety, and energy expenditure. Tumour/treatment-induced or traumatic brain injury to the hypothalamus can lead to hyperphagia and acquired hypothalamic obesity (aHO), for which no approved treatments exist. We present results of an international Phase 3 trial of the MC4R agonist setmelanotide in aHO (NCT05774756). Patients aged ≥4 years with BMI ≥95th percentile (<18 years) or ≥30 kg/m2 (≥18 years) and aHO were included. Patients were randomized 2:1 to setmelanotide (0.5 mg subcutaneously once daily [QD], titrated to 1.5-3.0 mg QD) or placebo for up to 60 weeks. The primary endpoint was a modified intent-to-treat analysis of the percentage change in BMI at 52 weeks. Secondary endpoints included the proportion of patients with ≥5% BMI reduction and the change in maximal daily hunger score (scored 0-10 in patients ≥12 years). Safety was also assessed. Of 120 patients included, 81 and 39 received setmelanotide or placebo, respectively (female, 60.0%; mean [SD] age, 19.9 [13.8] years; BMI z-score in patients <18 years, 3.61 [1.66]; BMI in patients ≥18 years, 41.2 [9.7] kg/m2). Fourteen patients discontinued treatment before end of trial. The primary endpoint, mean (SE) change in BMI at 52 weeks, was −16.5% (1.4%) for setmelanotide vs +3.3% (2.0%) for placebo, with a significant placebo-adjusted difference of −19.8% (95% CI: −24.6%, −15.1%; P < .0001). A significantly greater proportion of patients who received setmelanotide vs placebo achieved a BMI reduction of ≥5% (79.5% vs 10.4%, P < .0001). The mean (SE) change in the weekly average of the maximal daily hunger score was −2.73 (0.28) for setmelanotide vs −1.45 (0.40) for placebo (P = .0086). Overall, 81 (100%) vs 35 (89.7%) patients receiving setmelanotide vs placebo experienced AEs, the most common of which were skin hyperpigmentation (55.6% vs 7.7%), nausea (50.6% vs 30.8%), vomiting (39.5% vs 17.9%), and headache (38.3% vs 30.8%). In the setmelanotide arm, one death due to seizures (treatment-unrelated) was reported and one serious treatment-related AE of hypernatremia due to vomiting and inability to tolerate desmopressin; after 2 days setmelanotide was reinitiated upon hospital discharge. In the largest randomised, placebo-controlled trial in aHO to date, setmelanotide demonstrated significant effects over placebo in the primary and key secondary efficacy endpoints at 52 weeks, with no new safety signals. Setmelanotide may represent an important treatment option for patients with aHO aged ≥4 years, for which currently no approved treatments exist.