Real-World Efficacy and Safety of Setmelanotide in Adults With Monogenic or Syndromic Obesity: A Prospective Cohort Study.

Abstract

The melanocortin-4 receptor agonist setmelanotide has demonstrated effectiveness in phase 3 clinical trials for patients with monogenic obesity caused by biallelic variants in the leptin receptor (LEPR) and pro-opiomelanocortin (POMC), as well as for individuals with Bardet-Biedl syndrome (BBS). However, real-world evidence remains limited. This study evaluates the long-term effectiveness and safety of setmelanotide in patients who received treatment under a pre-marketing early-access authorization. This ongoing prospective monocentric cohort includes 17 patients with obesity due to BBS (n = 11) or biallelic variants in LEPR (n = 4) or POMC (n = 2) who either started setmelanotide in routine care between 2022 and 2024 or continued therapy after participating in the RM-493-022 clinical trial. The average follow-up time was 14.4 months. Patients experienced a clinically significant weight reduction of 20% from their highest pre-treatment weight within the first year. Those previously treated in a clinical trial maintained their weight loss over time. Additionally, eating behavior improved, with significant reductions in hunger (-62%), food craving (-41%), and external eating evaluated by DEBQ. The overall safety profile was consistent with phase 3 trials data, without any new safety signals. These findings confirm the drug's long-term clinical benefit and safety profile in a routine-care setting.