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Cited by 206Genetic and Kidney Cyst DiseasesPharmacology and Obesity TreatmentRegulation of Appetite and Obesity

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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

Open access
Haqq, Andrea M, Chung, Wendy K, Dollfus, Hélène, Haws, Robert M, Martos-Moreno, Gabriel Á, Poitou, Christine, Yanovski, Jack A, Mittleman, Robert S, Yuan, Guojun, Forsythe, Elizabeth, Clément, Karine, Argente, Jesús·2022·The Lancet Diabetes & Endocrinology
DOI 10.1016/s2213-8587(22)00277-7PMC PMC9847480
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Abstract

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 2 for those aged ≥16 years). Patients were randomly assigned (1:1) using a numerical randomisation code to receive up to 3·0 mg of subcutaneous setmelanotide or placebo once per day during the 14-week double-blind period, followed by open-label setmelanotide for 52 weeks. The primary endpoint, measured in the full analysis set, was the proportion of patients aged 12 years or older who reached at least a 10% reduction in bodyweight from baseline after 52 weeks of setmelanotide treatment. This study is registered with ClinicalTrials.gov, NCT03746522.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.

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Authors
Haqq, A. M., Chung, W. K., Dollfus, H., Haws, R. M., Martos-Moreno, G. Á., Poitou, C., Yanovski, J. A., Mittleman, R. S., Yuan, G., Forsythe, E., Clément, K., & Argente, J.
Affiliations
  • University of Alberta (CA)
  • Columbia University (US)
  • Hôpitaux Universitaires de Strasbourg (FR)
  • Marshfield Clinic Research Foundation (US)
  • Inserm (FR)
  • National Institutes of Health (US)
  • Rhythm (United states) (US)
  • University College London (GB)
Corresponding author
Argente, Jesús
ORCID
Venue
The Lancet Diabetes & Endocrinology
Publisher
Elsevier BV
Published
2022-12
Volume
10
Issue
12
Pages
859-868
ISSN
2213-8587 (ISSN-L)
DOI
10.1016/s2213-8587(22)00277-7
PMC
PMC9847480
OpenAlex
W4308426407
Cited by
206
References
26
Citations by year
2026: 55 · 2025: 62 · 2024: 58 · 2023: 29 · 2022: 1
FWCI
22.61
Type
journal article
Language
en
Update notices
erratum (2023-02-01)
Open access
Licence
Locations
  • The Lancet Diabetes & Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion)
Funders
  • National Institutes of Health
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (ZIAHD000641)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
  • Health Sciences › Medicine › Pharmacology (medical) › Pharmacology and Obesity Treatment
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Keywords
setmelanotide, Bardet-Biedl syndrome, Alström syndrome, melanocortin-4 receptor agonist, early-onset obesity, hyperphagia, weight loss, rare genetic disorders, drug safety, adverse events, children and adolescents, adults, open-label extension, treatment discontinuation
MeSH terms
alpha-MSH, Humans, Obesity, Treatment Outcome, Bardet-Biedl Syndrome, Receptor, Melanocortin, Type 4, Alstrom Syndrome

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