ESPE Abstracts

Background: Rare genetic diseases of obesity are often driven by gene variants in the melanocortin-4 receptor (MC4R) pathway. The MC4R agonist setmelanotide demonstrated significant reductions in body weight in patients ≥6 years old with various rare genetic diseases of obesity, including proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency and Bardet-Biedl syndrome (BBS). While these conditions are characterized by severe obesity and hyperphagia in the first years of life, few clinical trials have evaluated pharmacotherapies for patients aged <6 years with obesity. In addition, there are few safe and effective therapeutic options available for use in this population. The VENTURE trial will evaluate the safety, tolerability, and efficacy of setmelanotide in patients aged 2 to <6 years with POMC, PCSK1, or LEPR deficiency obesity or BBS (ClinicalTrials.gov identifier: NCT04966741).

Methods: This 1-year, open-label, Phase 3 trial will enroll ~15 pediatric patients (aged 2 to <6 years) with BBS or biallelic variants in POMC, PCSK1, or LEPR confirmed by genetic testing, obesity, and symptoms or behaviors of hyperphagia. Key exclusion criteria are significant hepatic, dermatologic, or metabolic conditions. Caregivers will administer setmelanotide via subcutaneous injection beginning at 0.5 mg daily. Doses will be increased by 0.5 mg every 2 weeks as tolerated, until the maximum target dose (based on weight bands to support similar exposure to adults receiving 2-3 mg) is reached. Patients will attend study visits every 4 weeks after achieving maximum dose level through Week 20 then every 8 weeks through Week 52. The primary endpoint is the proportion of patients demonstrating a >0.2-point decrease from baseline to Week 52 in BMI Z score. Key secondary endpoints are mean change from baseline to Week 52 in BMI Z score, mean change in the percent of the 95th BMI percentile, mean percent change in BMI, and mean change in vital signs, laboratory evaluations, bone age, and Ages & Stages Questionnaires®, Third Edition (ASQ®-3). Incidence and severity of treatment-emergent adverse events will also be reported. Exploratory endpoints include pharmacokinetics and changes in metabolic parameters, waist circumference, hunger, caregiver burden, and quality of life assessed by caregiver-reported outcome instruments. In conclusion, this trial will provide relevant safety and efficacy data for the potential early treatment of patients aged 2 to <6 years with POMC, PCSK1, or LEPR deficiency obesity, or patients with BBS.