ESPE Abstracts

Background: Disruption of the melanocortin-4 receptor pathway by genetic variants in POMC/PCSK1 or LEPR can result in hyperphagia and severe early-onset obesity. In the primary analyses of 2 pivotal Phase 3 trials, the melanocortin-4 receptor agonist setmelanotide was associated with significant reductions in body weight and hunger in patients with obesity due to proopiomelanocortin (POMC) or leptin receptor (LEPR) deficiency. These previously presented primary analyses were conducted in pivotal cohorts with 21 total patients; however, additional patients were subsequently enrolled.

Methods: In 2 single-arm, multicenter, Phase 3 trials of setmelanotide in patients with obesity due to POMC (NCT02896192) or LEPR deficiency (NCT03287960), patients aged ≥6 years received setmelanotide for 12 weeks. Those with ≥5 kg weight loss (or ≥5% if weighing <100 kg at baseline) entered an 8-week placebo-controlled withdrawal sequence followed by an additional 32 weeks of open-label setmelanotide treatment. Primary endpoint was the proportion of patients with ≥10% weight loss at ~1 year. Secondary endpoints included mean percent change in “most” hunger score at ~1 year. Adverse events (AEs) were also assessed. This updated analysis includes patients enrolled in both the pivotal and supplemental cohorts.

Results: A total of 15 patients with POMC deficiency (10 pivotal, 5 supplemental) and 15 with LEPR deficiency (11 pivotal, 4 supplemental) were enrolled. In the POMC trial, mean age was 17.2 (range, 7.0–30.0) years, and mean (SD) body weight and BMI were 111.3 (35.8) kg and 39.2 (8.2) kg/m², respectively. In the LEPR trial, mean age was 21.7 (range, 8.0–37.0) years, and mean (SD) body weight and BMI were 132.5 (39.3) kg and 49.2 (13.0) kg/m², respectively. A total of 85.7% of patients (12/14; P < 0.0001) in the POMC trial and 53.3% (8/15; P < 0.0001) in the LEPR trial achieved ≥10% weight loss at 52 weeks. The mean (SD) percent change in body weight from baseline to 52 weeks was −25.8% (9.7%; P < 0.0001) and −12.3% (7.5%; P < 0.0001) in the POMC and LEPR trials, respectively. In patients aged ≥12 years, mean (SD) percent change in most hunger score at 52 weeks was −27.1% (−28.1%) and −42.7% (−27.5%) in the POMC and LEPR trials, respectively. There were no treatment-related serious AEs. The most common AEs were injection site reaction and hyperpigmentation.

Conclusions: In patients with early-onset genetic obesity, this expanded POMC/LEPR data set showed clinically meaningful improvements in weight loss and hunger sustained after 1 year on setmelanotide, consistent with earlier pivotal findings.