Endocrine Abstracts

Background: Hypothalamic obesity (HO) is an acquired form of severe obesity that can occur following surgical resection of or radiotherapy for brain tumors and is often unresponsive to lifestyle modifications or traditional obesity pharmacotherapies. Here, we report weight- and body composition–related findings from a Phase 2 trial of setmelanotide, a melanocortin-4 receptor agonist, in patients with HO.

Methods: A Phase 2, open-label, 16-week trial of setmelanotide in patients aged ≥6 to ≤ 40 years with HO caused by hypothalamic damage secondary to brain tumor, surgical resection, and/or chemotherapy was performed. Setmelanotide was initiated at 1 or 2mg and increased to 3mg once daily over 2-4 weeks. The primary endpoint was the proportion of patients reaching ≥5% body mass index (BMI) reduction from baseline at Week 16. Secondary and exploratory endpoints included changes from baseline in BMI Z score (patients aged ≥6 to 18 years), body weight, and waist circumference. Change in body composition, measured by dual-energy x-ray absorptiometry was also assessed.

Results: Eighteen (13 pediatric, 5 adult) patients were included. Tumor types leading to HO included craniopharyngioma, astrocytoma, and hamartoma. All patients adhering to treatment (n=17) experienced weight loss, including 2 patients who discontinued because of an adverse event (AE). At Week 16, most (16/18) patients met the primary endpoint (88.9%[90% confidence interval(CI), 69.0%-98.0%]; P<0.0001), with mean (standard deviation[SD]) percent changes in body weight of −12.6%(9.1%) and BMI of −14.5% (9.5%); mean(SD) BMI percent change for patients adhering to treatment (n=17) was −15.4%. Of 18 patients, 14 achieved ≥10% BMI reduction. The mean(SD) BMI Z score change in pediatric patients was −1.3(1.0), and 12 of 13 pediatric patients (92.3% [90% CI, 68.4%-99.6%]; P<0.0001) reached ≥0.2-point reduction. Across all patients, weight loss was primarily due to reduction in fat mass (mean [SD] change from baseline at Week 16, −7.7 [5.3]kg; −16.4%) rather than lean mass (−3.4 [5.5] kg; −6.5%). The mean(SD) waist circumference change from baseline was −12.0 (5.8)cm (mean[SD] percent change, −10.4%[5.2%]). Treatment-related AEs occurred in 15 patients (83.3%); nausea (n=11; 61.1%), skin hyperpigmentation (n=6; 33.3%), vomiting (n=5; 27.8%), and diarrhea (n=4; 22.2%) were the most frequently reported.

Conclusions: Setmelanotide improved BMI, weight, and waist circumference in a heterogeneous population with HO secondary to treatment of 3 different tumor types. Body composition also improved, with relatively larger reductions in fat vs lean mass.