ESPE Abstracts (2021) 94 P2-222

ESPE2021 ePoster Category 2 Fat, metabolism and obesity (59 abstracts)

Design of a Phase 2, Double-Blind, Placebo-Controlled Trial of Setmelanotide in Patients With Genetic Variants in the Melanocortin-4 Receptor Pathway

Sadaf Farooqi 1 , Martin Wabitsch 2 , Wendy Chung 3 , Olga Ohayon 4 , Cecilia Scimia 4 , Guojun Yuan 4 , Bhavik Shah 4 & Murray Stewart 4


1Welcome-MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, United Kingdom; 2Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany; 3Division of Molecular Clinical Genetics, Department of Pediatrics, Columbia University, New York, USA; 4Rhythm Pharmaceuticals, Inc., Boston, USA

Background: Rare genetic causes of obesity include variants in genes within the melanocortin-4 receptor (MC4R) pathway, a principal regulator of energy balance. Weight and hunger reductions following treatment with the MC4R agonist setmelanotide have been demonstrated in patients with obesity due to variants in multiple genes, including POMC, LEPR, SRC1, and SH2B1. We describe a trial design of setmelanotide in patients with additional specific gene variants based on an evidence-based framework that suggested relevance to the MC4R pathway.

Methods: This Phase 2, double-blind, placebo-controlled, 2-stage study will enroll ~500 patients in Stage 1 to achieve ~130 qualified patients in Stage 2. Patients aged 6 to 65 years with pathogenic, likely pathogenic, or uncertain significance genetic variants based on American College of Medical Genetics criteria in a preselected set (n = 31) of MC4R pathway genes, including LEP, SIM1, MRAP2, and KSR2, and body mass index (BMI) ≥40 kg/m2 or BMI ≥97th percentile according to age (for those aged ≥18 or <18 years, respectively) and sex are eligible. Exclusion criteria include recent intensive diet or exercise resulting in >3% weight loss, bariatric surgery within 6 months of enrollment, significant features or diagnosis of syndromic obesity, glycated hemoglobin >10.0%, and glomerular filtration rate <60 mL/min. Patients or caregivers will self-administer subcutaneous setmelanotide. For patients aged ≥12 years, daily dosages will be 2 mg for 14 days, then 3 mg thereafter; for patients aged 6 to <12 years, daily dosages will be 1 mg for 7 days, 2 mg for 7 days, and 3 mg thereafter. Patients achieving ≥5% weight loss from baseline or ≥0.1-point reduction from baseline in BMI Z score (for those aged ≥18 or <18 years, respectively) at the end of Stage 1 (16-week open-label run-in) will be eligible to enter Stage 2 (randomized withdrawal period). Eligible patients will be randomized 2: 1 to continue daily setmelanotide or receive matching placebo for 24 weeks. The primary endpoint is the proportion of patients achieving ≥10% weight loss or ≥0.3-point reduction from baseline in BMI Z score (for those aged ≥18 or <18 years, respectively) from baseline at Week 40. Secondary endpoints are initial response to open-label setmelanotide and changes in body weight, waist circumference, hunger, and quality of life. Exploratory endpoints are change in metabolic parameters and treatment responses stratified by genes. Safety will be assessed by severity and frequency of adverse events. The first patient will be enrolled before the end of 2021.

Volume 94

59th Annual ESPE (ESPE 2021 Online)

22 Sep 2021 - 26 Sep 2021

European Society for Paediatric Endocrinology 

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