Endocrine Abstracts

Introduction: Rare genetic causes of obesity result from disruption of the melanocortin-4 receptor (MC4R) pathway, a regulator of energy balance. Patients with obesity due to variants in multiple genes, including POMC, LEPR, SRC1, and SH2B1, have shown weight and hunger reductions after treatment with setmelanotide, an MC4R agonist. DAYBREAK is a Phase 2 trial of setmelanotide in patients with additional gene variants with suggested relevance to the MC4R pathway (ClinicalTrials.gov identifier: NCT04963231).

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(aged ≥18 years) or BMI ≥97th percentile (aged <18 years) according to age and sex are eligible. Exclusion criteria include recent 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. Setmelanotide will be self-administered subcutaneously. Daily dosage will be age dependent: 2 mg will be administered for 14 days, then 3 mg thereafter in patients ≥12 years old or 1 mg will be administered for 7 days, 2 mg for 7 days, and 3 mg thereafter in patients 6–12 years old. Patients will be eligible to enter Stage 2 (randomized withdrawal period) if they have achieved ≥5% weight loss from baseline (≥18 years old) or ≥0.1-point reduction from baseline in BMI Z score (<18 years old) at the end of Stage 1 (16-week open-label run-in). Eligible patients will be randomized 2:1 to daily setmelanotide or matching placebo for 24 weeks. Primary endpoints include proportion of patients achieving ≥10% weight loss (aged ≥18 years) or ≥0.3-point reduction from baseline in BMI Z score (aged <18 years) 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. Safety will be assessed by severity and frequency of adverse events.

Results: Patient dosing has been initiated as of January 2022.

Conclusions: The Phase 2 DAYBREAK trial will evaluate setmelanotide for weight loss and hunger reduction in individuals with variants associated with the MC4R pathway.