Background: Rare genetic variants along the central melanocortin pathway, including variants in LEPR, may result in obesity characterized by early-onset, severe obesity, hyperphagia, and endocrine abnormalities. This Phase 3 trial evaluated efficacy and safety of setmelanotide in individuals with LEPR deficiency obesity.

Methods: This 1-year, open-label, multicenter, phase 3 trial, included a titration period for participants to reach their therapeutic dose. Those who reached a threshold body weight loss in the first open-label phase entered a placebo-withdrawal period followed by a second open-label treatment. Primary endpoint was the proportion of participants who achieved ≥ 10% body weight loss at 1 year.

Results: A total of 11 participants were enrolled and 9 of 11 completed the trial at 1 year. Five out of 11 participants achieved ≥ 10% weight loss at 1 year, mean percent change of body weight and mean percent change of most hunger score from baseline to 1 year were -12.5% and -41.9%, respectively. Of the 11 participants, 8 achieved ≥ 25% reduction in most hunger score at 1 year. Adverse events included injection site reaction, hyperpigmentation of the skin, and nausea. One participant discontinued the study due to hypereosinophilia and one participant died (passenger in a car accident; unrelated to study drug) Three participants experienced at least one serious adverse event, all unrelated to setmelanotide.

Conclusions: Setmelanotide resulted in statistically significant reductions in body weight and hunger scores among participants with LEPR deficiency obesity. Additionally, setmelanotide was generally well tolerated, and adverse events were typically mild. In patients with LEPR deficiency who are resistant to other obesity interventions, setmelanotide is a promising investigational that targets the central melanocortin pathway to potentially reduce hunger and body weight. (ClinicalTrials.gov number NCT03287960).