FRI065 Trial Design Of A Double-blind, Randomized, Placebo-controlled, Phase 3 Study Of Setmelanotide In Patients With Hypothalamic Obesity

Disclosure: C.L. Roth: Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. A.H. Shoemaker: Advisory Board Member; Self; Rhythm Pharmaceuticals, Inc., Saniona. Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. M. Gottschalk: Advisory Board Member; Self; Rhythm Pharmaceuticals, Inc. Consulting Fee; Self; Rhythm Pharmaceuticals, Inc. Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. J.L. Miller: Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. G. Yuan: Employee; Self; Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. S. Malhotra: Employee; Self; Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. C. Scimia: Employee; Self; Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. S. McCormack: None. M.J. Abuzzahab: Consulting Fee; Self; Pfizer, Inc., Rhythm Pharmaceuticals, Inc., Consynance. Other; Self; Study funding from Rhythm Pharmaceuticals, Inc., Ascendis, NovoNordisk, Levo Pharmaceuticals, Lumos, Saniona, and Soleno. Background: Damage to the hypothalamus via physical trauma, tumors, surgical resection, and/or radiotherapy can impair the melanocortin signaling pathway and reduce energy expenditure, potentially leading to hypothalamic obesity, a severe form of obesity with no current specific therapeutic option. Recently, the selective melanocortin-4 receptor agonist setmelanotide demonstrated reduction in weight and hunger for patients with hypothalamic obesity who were treated in a Phase 2 trial. We describe the study design of a planned double-blind, randomized, placebo-controlled, Phase 3 trial of setmelanotide in patients with hypothalamic obesity. Methods: Approximately 120 patients will be enrolled across ≤35 sites globally. Eligibility criteria include age ≥4 years with documented evidence of acquired hypothalamic obesity with associated weight gain before and/or with tumor treatment and body mass index (BMI) ≥30 kg/m(2) (≥18 years) or BMI ≥95th percentile (≥4 to <18 years). Key exclusion criteria include diagnosis of syndromic obesity, weight or BMI loss >2% based on age in the prior 3 months, bariatric surgery within the past 2 years, glycated hemoglobin >11.0%, and glomerular filtration rate <30 mL/min/1.73 m(2). Patients will be randomized 2:1 and stratified by age to receive setmelanotide or placebo. Setmelanotide will be titrated over 2-8 weeks to a maximum daily subcutaneous dose of 1.5-3.0 mg based on age and weight. Double-blind treatment will continue for up to 60 weeks, with visits (in-clinic, at-home, or telehealth) at Weeks 20, 28, 36, 44, and 52 and at an end-of-treatment clinic visit at Week 60. The primary endpoint is the mean percent change in BMI after 52 weeks of treatment for setmelanotide versus placebo. Key secondary endpoints after 52 weeks are the proportion of patients aged ≥18 years with ≥5% reduction in BMI, proportion of patients aged <18 years with ≥0.2-point reduction in BMI Z score, and mean change in weekly average of the daily “most hunger” score in patients aged ≥12 years. Additional secondary endpoints include proportion of patients achieving ≥2-point reduction in weekly average of the daily maximal hunger score, Symptoms of Hyperphagia total score, additional weight-related parameters, and quality of life outcomes. Exploratory endpoints include change after 52 weeks in physical activity (measured by acDetigraphy), fatigue (via Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue(©)/Peds FACIT-F(©) scale), Impacts of Hyperphagia score, caregiver health status (via EuroQol-5-Dimension scale), cardiometabolic parameters, and waist circumference. Safety will be assessed by the frequency and severity of adverse events. Conclusions: This Phase 3 trial designed to assess the efficacy and safety of setmelanotide for weight loss and hunger reduction in patients ≥4 years of age with acquired hypothalamic obesity is planned to initiate in early 2023. Presentation: Friday, June 16, 2023