ABSTRACT
Background: Hypothalamic injury and impaired melanocortin-4 receptor (MC4R) pathway signaling, often a result of surgery or radiation for a benign tumor, may lead to hypothalamic obesity (HO). After injury, sudden weight gain and appetite changes unresponsive to existing therapies develop. Setmelanotide, an MC4R agonist, is approved for chronic weight management in patients with certain MC4R pathway-associated diseases. We report interim results of a Phase 2 study of setmelanotide in HO (NCT04725240). Methods: Patients aged 6-40 years with body mass index (BMI) >95th percentile (children 6 to <18 years) or >35 kg/m2 (adults >18 years) and HO caused by structural hypothalamic damage secondary to craniopharyngioma or other benign brain tumor, surgical resection, and/or chemotherapy were enrolled. The setmelanotide dose was initiated by age, with 2-4 weeks of titration to 3.0 mg once daily, followed by 12-14 weeks at the target dose. The primary endpoint was the proportion of patients achieving >5% BMI reduction at Week 16. A key secondary endpoint was the composite proportion of children with >0.2-point reduction in BMI Z score and adults with >5% weight loss. Hunger was assessed daily using a numerical rating scale, where 0 = not hungry at all and 10 = hungriest possible. Results: Eleven patients were included (baseline mean [SD;range] age, 14.6 [4.8;6-23] years and mean [SD] BMI, 38.7 [5.7] kg/m2). All patients (90% CI, 76.2%-100%) had >5% reduction in BMI (p<0.0001);81.8% (90% CI, 53.0%-96.7%) had >10% reduction (p<0.0001). Mean (range) change in BMI was -17.2% (-37.2%, -6.7%). Mean (SD) change in hunger score was -2.7 (2.6). Frequent adverse events included nausea (63.6%), vomiting (45.5%), diarrhea (36.4%), and COVID-19 (36.4%). Two patients discontinued because of adverse events. Conclusions: These early results warrant continued evaluation of setmelanotide in this population with a high unmet medical need and no approved therapies.