Setmelanotide in Bardet‐Biedl Syndrome: A 52‐Week Comparison of Phase 3 Trial Participants With a Matched Registry Cohort

Objective This analysis aimed to assess the efficacy of setmelanotide over 52 weeks in patients with Bardet‐Biedl syndrome (BBS) compared with an external natural history cohort from the international Clinical Registry Investigating BBS (CRIBBS). Methods Patients with BBS ≥ 6 years of age ( n = 29) treated with setmelanotide for 52 weeks in a phase 3 trial (NCT03746522) and a propensity‐score matched external control cohort ( n = 58) from CRIBBS were included. Responder rate at week 52 was defined as ≥ 0.3‐point decrease in BMI z ‐score (patients ≤ 18 years) or ≥ 10% body weight reduction (adults). Secondary outcomes included changes in BMI, BMI z ‐score, and body weight. Results A significantly greater proportion of patients treated with setmelanotide met the primary endpoint compared with control patients (58.6% vs. 6.9%; p < 0.001). In pediatric patients, 71.4% achieved the primary endpoint vs. 10.7% of controls ( p < 0.001); in adults, corresponding numbers were 46.7% vs. 3.3% ( p = 0.001). Secondary outcomes demonstrated consistent benefits of setmelanotide treatment. Sensitivity analysis using inverse probability of treatment weighting confirmed these findings. Conclusions This indirect comparison provides additional strong evidence that setmelanotide significantly improves weight outcomes in patients with BBS. These findings further support its clinical benefit over 52 weeks in managing obesity associated with BBS. Trial Registration: ClinicalTrials.gov identifier: NCT03746522