ESPE Abstracts

Background: Variants in SH2B1 or a 220–kilobase pair distal deletion of chromosome 16p11.2, including SH2B1, are associated with severe, early-onset obesity and hyperphagia. The melanocortin-4 receptor (MC4R) agonist setmelanotide is being investigated in individuals with rare variants in genes in the MC4R pathway.

Methods: This ongoing, Phase 2 study (NCT03013543) enrolled individuals aged ≥6 years with obesity due to SH2B1 variants or distal deletion of chromosome 16p11.2. Obesity was defined as body mass index (BMI) ≥30 kg/m² in those aged ≥16 years or BMI ≥95^th percentile in those aged 6–15 years. Following dose titration of setmelanotide, patients received open-label treatment for 3 months. The proportion of patients who were responders (defined as ≥5% weight loss in those ≥18 years old or ≥0.15 reduction in BMI Z score in those <18 years old), mean percent changes in body weight and changes in BMI Z score by age, and adverse events (AEs) were assessed at month 3.

Results: Thirty-five patients, 22 with SH2B1 variants and 13 with 16p11.2 deletion, were enrolled. At baseline, for the 22 patients ≥18 years old, mean (standard deviation [SD]) body weight was 139.7 (35.4) kg, and for the 13 patients <18 years old, mean (SD) BMI Z score was 3.6 (0.6). Fifteen patients (42.9%) experienced ≥5% weight loss (≥18 years old; n = 8) or ≥0.15 reduction in BMI Z score (<18 years old; n = 7) at month 3. For patients ≥18 years old, mean (SD) percent weight change from baseline was −7.2% (2.1%; n = 8 [SH2B1 variants, n = 5; 16p11.2 deletion, n = 3]) for responders, −0.8% (2.3%; n = 14) for nonresponders, and −3.1% (3.9%) overall. For patients <18 years old, mean (SD) change in BMI Z score was −0.25 (0.06; n = 7 [SH2B1 variants, n = 5; 16p11.2 deletion, n = 2]) for responders, −0.03 (0.06; n = 6) for nonresponders, and −0.15 (0.13) overall. One serious AE of melanocytic nevus occurred in an adult patient, for which melanoma was excluded, which was considered not treatment related. Common AEs included skin hyperpigmentation (71.4%), nausea (48.6%), and headache (37.1%). AEs led 9 patients (25.7%) to discontinue the study.

Conclusions: Patients with SH2B1 variants or 16p11.2 deletion syndrome had early-onset severe obesity. In 3 months, 43% achieved ≥5% weight loss or ≥0.15 reduction in BMI Z score, with similar response rates in those with SH2B1 variants (46%) and 16p11.2 deletion (38%). A 3-month trial may be useful to identify those with setmelanotide-responsive variants involving SH2B1 affecting the MC4R pathway.