MON-732 - Weight Reduction After 1 Year of Oral Bivamelagon in Acquired Hypothalamic Obesity

Introduction: Hypothalamic melanocortin-4 receptor (MC4R) signaling drives the regulation of hunger, satiety, and weight. Hypothalamic injury may disrupt MC4R signaling, resulting in acquired hypothalamic obesity (aHO) due to severe hunger or hyperphagia, reduced energy expenditure, and accelerated and sustained weight gain. In a Phase 2 double-blind trial with the oral MC4R agonist bivamelagon in aHO, there were dose-related body mass index (BMI) reductions from baseline to Week 14 across the 200-, 400-, and 600-mg doses, compared with BMI increases with placebo. This analysis presents efficacy and safety data following 1 year of study treatment, comprised of the original 14 weeks of double-blind treatment followed by 38 weeks of open-label extension (OLE) bivamelagon.

Methods: Twenty-eight participants aged ≥12 years with BMI ≥95th percentile (aged 12 to < 18 years) or BMI ≥30 kg/m2 (aged ≥18 years) with aHO following hypothalamic tumor, lesion, or injury were randomized 1:1:1:1 to once-daily oral bivamelagon 200, 400, or 600 mg or placebo for 14 weeks (NCT06046443). Participants demonstrating adequate safety/tolerability and who would benefit from initiating or continuing bivamelagon could proceed into the OLE and receive 38 weeks of bivamelagon 600 mg.

Results: Twenty-eight participants were randomized to one of 4 dosing cohorts for 14 weeks. Participants on placebo had a mean change of +2.2%; participants on bivamelagon had dose-dependent mean changes of −2.7% to −9.3% (last observation carried forward). Twenty-six participants entered the OLE and had Week 52 data for analysis. The mean change in BMI from baseline to Week 52 was −8.7% (placebo/600 mg bivamelagon, n=7), −6.7% (200/600 mg bivamelagon, n=6), −10.8% (400/600 mg bivamelagon, n=6), and −16.6% (600/600 mg bivamelagon, n=7). In 13 pediatric participants, the mean BMI z-score change from baseline was −0.51 (placebo/600 mg bivamelagon; n=3), −0.22 (200/600 mg bivamelagon; n=3), −0.69 (400/600 mg bivamelagon; n=3), and −0.62 (600/600 mg bivamelagon; n=4). Overall, the mean change in the weekly average of the maximal daily hunger score ranged from −1.94 to −4.84 across cohorts. Common adverse events (AEs; ≥25%) during 38 weeks of OLE bivamelagon, across all participants, were vomiting (53.8%), nausea (46.2%), and diarrhea (34.6%); of participants with those AEs, >80% were Grade 1 AEs.

Conclusion: Open-label treatment with bivamelagon 600 mg out to 1 year resulted in deepening reductions in weight-related and hunger measures across the original bivamelagon cohorts. While most participants in the original placebo cohort gained weight during the first 14 weeks, weight reduction was observed during the subsequent 38 weeks while receiving bivamelagon 600 mg. These sustained weight and hunger reductions support the forthcoming double-blind, placebo-controlled Phase 3 trial.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*