Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials

This work combined two phase 3, open-label, multicentre clinical trials conducted at centers in Europe and North America, evaluating setmelanotide — a selective melanocortin 4 receptor (MC4R) agonist — in patients with severe obesity caused by genetic POMC or LEPR deficiency. Participants received daily subcutaneous injections with dose titration over approximately 1 year of treatment.

Results were significant: 80% of patients with POMC deficiency and 45% of patients with LEPR deficiency achieved at least 10% body weight loss. Beyond weight reduction, there were clinically significant decreases in hunger sensation assessed by standardized scales, a particularly relevant finding in this population suffering from intractable hyperphagia.

• The most common adverse events were skin hyperpigmentation and injection site reactions, both considered tolerable
• No significant cardiovascular adverse effects were reported
• The therapeutic response confirmed that the MC4R pathway can be activated even when upstream genetic defects (POMC/LEPR) are present

These trials represented a milestone by demonstrating that monogenic obesity can be treated pharmacologically in a targeted manner, leading to the FDA approval of setmelanotide (Imcivree) in 2020 as the first specific therapy for obesity due to POMC, PCSK1, or LEPR deficiency.