Background: Rare genetic diseases of obesity can be caused by genetic variants leading to disrupted activity of the melanocortin-4 receptor pathway (MC4R). Setmelanotide, an MC4R agonist, is being investigated in a basket study of populations with rare variants in different genes in the MC4R pathway who have early-onset, severe obesity and hyperphagia.
Methods: This ongoing, Phase 2, open-label study (NCT03013543) enrolled patients aged ≥6 years with obesity due to steroid receptor coactivator 1 (SRC1) insufficiency. Obesity was defined as body mass index (BMI) ≥30 kg/m2 or BMI ≥95th percentile in those aged ≥16 years or 615 years, respectively. Patients received open-label setmelanotide treatment until Month 3, following dose titration. Adverse events (AEs) and mean percent change in body weight (in those ≥18 years old) or mean change in BMI Z score (in those <18 years old) were assessed at Month 3, as was the proportion of responders (defined as ≥5% weight loss in those ≥18 years old or ≥0.15 reduction in BMI Z score in those <18 years old).
Results: A total of 30 patients with SRC1 insufficiency were enrolled in the trial. At baseline, the mean patient age was 30.6 (range, 9.066.0) years, with 20 patients aged ≥18 years; for patients ≥18 years old, mean (standard deviation [SD]) body weight was 139.7 (25.1) kg and for patients <18 years old, BMI Z score was 3.0 (0.6); 24 patients (80.0%) were female and none were cognitively impaired. Nine patients (30.0%) experienced ≥5% weight loss (≥18 years old; n = 6) or ≥0.15 reduction in BMI Z score (<18 years old; n = 3) at Month 3 and were considered responders. For patients ≥18 years old, mean (SD) percent weight change was −7.9% (2.2%; n = 6) for responders, −2.3% (1.9%; n = 14) for nonresponders, and −3.9% (3.3%; n = 20) overall. For patients <18 years old, mean (SD) change in BMI Z score was −0.48 (0.28; n = 3) for responders, −0.09 (0.03; n = 7) for nonresponders, and −0.21 (0.23; n = 10) overall. No serious AEs occurred. Common AEs included skin hyperpigmentation (66.7%), nausea (36.7%), and injection site bruising (30.0%). One patient (3.3%) withdrew from setmelanotide because of an AE.
Conclusions: Patients with SRC1 insufficiency had severe obesity despite a relatively young age; 30% achieved a clinically meaningful response to setmelanotide in 3 months. A 12-week trial may be useful to identify setmelanotide-responsive variants in the MC4R pathway.
22 Sep 2021 - 26 Sep 2021