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

Objective 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. Methods 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. Results 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. Conclusions These findings confirm the drug's long‐term clinical benefit and safety profile in a routine‐care setting.