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Clinical Trial
. 2026 Mar;34(3):579-587.
doi: 10.1002/oby.70125. Epub 2026 Feb 17.

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

Jesús Argente  1   2   3   4 , Andrea M Haqq  5 , Jan Luca Schorfheide  6 , Nicolas Touchot  7 , Caroline Huber  7 , Urs Wiedemann  6 , Jeremy Pomeroy  8 ; Phase 3 BBS Trial Investigators
Collaborators, Affiliations
Clinical Trial

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

Jesús Argente et al. Obesity (Silver Spring). 2026 Mar.

Abstract

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.

Keywords: Bardet‐Biedl syndrome; indirect treatment comparisons; setmelanotide; weight outcomes.

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Conflict of interest statement

Jesús Argente has received compensation for speaking engagements and institutional study funding from Rhythm Pharmaceuticals, Inc., as a clinical investigator and participated in the BBS advisory board for Rhythm Pharmaceuticals. Andrea M. Haqq is an advisory board member for Novo Nordisk, Rhythm Pharmaceuticals, and The Foundation for Prader‐Willi Research USA; a grant recipient for Weston Family Microbiome Initiative and Canadian Institutes of Health Research; and Primary Investigator on clinical trials with Aardvark Therapeutics, Acadia Pharmaceuticals, Eli Lilly, Novo Nordisk, and Rhythm Pharmaceuticals. Jeremy Pomeroy has received compensation for speaking engagements and institutional study funding from Rhythm Pharmaceuticals as a co‐investigator and participated in an advisory board for Rhythm Pharmaceuticals. Jan Luca Schorfheide and Urs Wiedemann are employees of stradoo GmbH, contracted by Rhythm Pharmaceuticals to perform the analyses. Nicolas Touchot and Caroline Huber are employees at Rhythm Pharmaceuticals and have received salary and stock options for their employment.

Figures

FIGURE 1
FIGURE 1
Propensity matching outcomes in the (A) pediatric and (B) adult populations. Standardized mean differences for each covariate before (unadjusted, open circles) and after (adjusted, filled circles) propensity score matching. A covariate was determined as balanced if the value is < 0.25 [40]. ATB, active treatment baseline.
FIGURE 2
FIGURE 2
Primary endpoint responder rates in the (A) combined adult and pediatric populations, (B) pediatric population, and (C) adult population. The responder rate was defined as: a ≥ 0.3‐point reduction in BMI z‐score in patients < 18 years of age at baseline (pediatric population) or a ≥ 10% reduction from baseline in body weight in patients ≥ 18 years of age at baseline (adult population). BBS, Bardet‐Biedl syndrome; CRIBBS, Clinical Registry Investigating BBS.
See this image and copyright information in PMC

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