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

## TL;DR

Setmelanotide significantly reduces weight in patients with Bardet-Biedl syndrome compared to usual care over a year.

## Contribution

This study provides long-term evidence of setmelanotide's efficacy in managing obesity in Bardet-Biedl syndrome patients.

## Key findings

- 58.6% of setmelanotide-treated patients met the primary weight reduction endpoint compared to 6.9% in controls.
- Pediatric patients showed a 71.4% response rate versus 10.7% in controls.
- Secondary outcomes like BMI and body weight showed consistent improvements with setmelanotide.

## Abstract

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).

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.

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.

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

Bardet‐Biedl syndrome (BBS) is characterized by dysfunction in the hypothalamic melanocortin‐4 receptor (MC4R) pathway, potentially leading to hyperphagia and early‐onset obesity. This substantially impacts quality of life and increases the risk of obesity‐related complications.Setmelanotide, an MC4R agonist that is approved in Europe, Canada, and the United States, has shown its efficacy in hunger and weight reductions in patients with BBS and obesity in a phase 3 clinical trial with a 14‐week double‐blind, placebo‐controlled period followed by a 52‐week open‐label period.

Bardet‐Biedl syndrome (BBS) is characterized by dysfunction in the hypothalamic melanocortin‐4 receptor (MC4R) pathway, potentially leading to hyperphagia and early‐onset obesity. This substantially impacts quality of life and increases the risk of obesity‐related complications.

Setmelanotide, an MC4R agonist that is approved in Europe, Canada, and the United States, has shown its efficacy in hunger and weight reductions in patients with BBS and obesity in a phase 3 clinical trial with a 14‐week double‐blind, placebo‐controlled period followed by a 52‐week open‐label period.

In absence of a placebo‐controlled comparison beyond 14 weeks in the phase 3 clinical trial, an indirect treatment comparison over 52 weeks was performed using matched controls from the international Clinical Registry Investigating BBS (CRIBBS).The indirect treatment comparison confirmed statistically and clinically meaningful reductions in BMI and body weight in pediatric and adult patients with BBS over 52 weeks compared with usual care, with consistent results across sensitivity analyses, reinforcing the robustness of the findings.

In absence of a placebo‐controlled comparison beyond 14 weeks in the phase 3 clinical trial, an indirect treatment comparison over 52 weeks was performed using matched controls from the international Clinical Registry Investigating BBS (CRIBBS).

The indirect treatment comparison confirmed statistically and clinically meaningful reductions in BMI and body weight in pediatric and adult patients with BBS over 52 weeks compared with usual care, with consistent results across sensitivity analyses, reinforcing the robustness of the findings.

These findings support the therapeutic value of setmelanotide and its use in managing obesity associated with BBS, potentially leading to improved quality of life and mitigating long‐term obesity‐related complications.

These findings support the therapeutic value of setmelanotide and its use in managing obesity associated with BBS, potentially leading to improved quality of life and mitigating long‐term obesity‐related complications.