Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alström syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period.

BACKGROUND

Impaired cilial signalling in the melanocortin-4 receptor (MC4R) pathway might contribute to obesity in patients with Bardet-Biedl syndrome and Alström syndrome, rare genetic diseases associated with hyperphagia and early-onset severe obesity. We aimed to evaluate the effect of setmelanotide on bodyweight in these patients.

METHODS

This multicentre, randomised, 14-week double-blind, placebo-controlled, phase 3 trial followed by a 52-week open-label period, was performed at 12 sites (hospitals, clinics, and universities) in the USA, Canada, the UK, France, and Spain. Patients aged 6 years or older were included if they had a clinical diagnosis of Bardet-Biedl syndrome or Alström syndrome and obesity (defined as BMI >97th percentile for age and sex for those aged 6-15 years and ≥30 kg/m

FINDINGS

Between Dec 10, 2018, and Nov 25, 2019, 38 patients were enrolled and randomly assigned to receive setmelanotide (n=19) or placebo (n=19; 16 with Bardet-Biedl syndrome and three with Alström syndrome in each group). In terms of the primary endpoint, 32·3% (95% CI 16·7 to 51·4; p=0·0006) of patients aged 12 years or older with Bardet-Biedl syndrome reached at least a 10% reduction in bodyweight after 52 weeks of setmelanotide. The most commonly reported treatment-emergent adverse events were skin hyperpigmentation (23 [61%] of 38) and injection site erythema (18 [48%]). Two patients had four serious adverse events (blindness, anaphylactic reaction, and suicidal ideation); none were considered related to setmelanotide treatment.

INTERPRETATION

Setmelanotide resulted in significant bodyweight reductions in patients with Bardet-Biedl syndrome; however, these results were inconclusive in patients with Alström syndrome. These results support the use of setmelanotide and provided the necessary evidence for approval of this drug as the first treatment for obesity in patients with Bardet-Biedl syndrome.

FUNDING

Rhythm Pharmaceuticals.

Informations de copyright

Copyright © 2022 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests RMH received study medication, grant support for clinical trials of setmelanotide, payments for lectures and expert testimony, and support for attending meetings from Rhythm Pharmaceuticals; consulting fees from Rhythm Pharmaceuticals and Axovia Therapeutics; participated in the data safety monitoring board for Rhythm Pharmaceuticals; and is a stockholder in Rhythm Pharmaceuticals. AMH received grants from the Weston Family Microbiome Initiative and Canadian Institutes of Health Research, payment as a speaker for Pfizer Canada, is a member of the Bardet-Biedl syndrome advisory board for Rhythm Pharmaceuticals and the 2021 Somatrogon advisory board for Pfizer, and head of the scientific advisory board for the Prader-Willi Syndrome Association USA. WKC received study funding, consulting fees, and payment for speaker bureaus from Rhythm Pharmaceuticals. HD received consulting fees and participated in the Bardet-Biedl syndrome advisory board for Rhythm Pharmaceuticals. GÁM-M received payment for lectures and participated in the Bardet-Biedl syndrome advisory board for Rhythm Pharmaceuticals. CP received support for attending meetings and grant funding for clinical trials of setmelanotide from Rhythm Pharmaceuticals; clinical trials of Prader-Willi syndrome from Millendo; and clinical trials of obesity from Novo Nordisk. JAY received grant support for clinical trials of setmelanotide from Rhythm Pharmaceuticals, grant support for clinical trials of diazoxide choline-controlled release in Prader-Willi syndrome from Soleno Therapeutics, and study medication for clinical trials from Hikma Pharmaceuticals and Versanis Bio. RSM and GY are employees and stockholders of Rhythm Pharmaceuticals. EF received consulting fees and participated in the Bardet-Biedl syndrome advisory board for Rhythm Pharmaceuticals and is a clinical investigator for clinical trials of setmelanotide in Bardet-Biedl syndrome for Rhythm Pharmaceuticals. KC received grant funding from Ysopia, Integrative Phenomics, and Confo Therapeutics; and is a clinical investigator for clinical trials of setmelanotide in Bardet-Biedl syndrome for Rhythm Pharmaceuticals. JA received payment for lectures and participated in the Bardet-Biedl syndrome advisory board for Rhythm Pharmaceuticals.