Introduction: Setmelanotide is a melanocortin 4 receptor (MC4R) agonist being investigated for chronic weight management in patients with rare genetic diseases of obesity caused by impairment of the MC4R pathway. The objective of this analysis was to assess the efficacy and safety of setmelanotide in patients with partial insufficiency in the MC4R pathway due to heterozygous mutations in the POMC, PCSK1, or LEPR genes. Methods: This was an open-label, single-arm, Phase 2 study of setmelanotide in rare genetic diseases of obesity, including proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) heterozygous deficiency obesity (NCT03013543). Patients aged ≥6 years with POMC, PCSK1, or LEPR heterozygous deficiency obesity received once-daily setmelanotide, which was titrated for 4 weeks to establish the therapeutic dose of 3 mg daily. Treatment at the therapeutic dose continued for an additional 12 weeks. The primary endpoint was mean percent change from baseline in body weight at Month 3. Hunger scores and adverse events (AEs) were secondary endpoints. A responder was defined as having ≥5% weight loss from baseline at Month 3. Results: A total of 35 patients were included in this analysis, with mean (standard deviation) age of 39.5 (17.6) years and body mass index of 50.3 (9.4) kg/m2. Across all patients, the mean percent change in body weight from baseline to Month 3 was −3.7% (90% confidence interval [CI], −5.3% to −2.1%; n=35). A total of 34.3% of patients (12/35) achieved the responder threshold of ≥5% weight loss from baseline at Month 3. The mean percent change in body weight from baseline to Month 3 was −10.1% (90% CI, −12.4% to −7.9%; n=12) and −0.4% (90% CI, −1.2% to −0.5%; n=23) for responders and nonresponders, respectively. The mean percent change in most hunger score from baseline to Month 3 was −4.4% (90% CI, −5.7% to −3.2%; n=10) and −2.3% (90% CI, −3.2% to −1.5%; n=23) for responders and nonresponders, respectively. Among responders, 4 (33%) had variants that were considered pathogenic/likely pathogenic per American College of Medical Genetics criteria. All patients experienced at least 1 AE. Overall, the most common treatment-emergent AEs were skin hyperpigmentation (51.4%), nausea (48.6%), and injection site pruritis (37.8%). One patient had serious AEs of acute myocardial infarction and gastrointestinal hemorrhage that were considered unrelated to setmelanotide. No AEs led to death. Conclusions: Setmelanotide was associated with reduced body weight and hunger scores in patients with POMC, PCSK1, or LEPR heterozygous deficiency obesity. While the overall mean percent decrease in body weight may have been less than that previously reported in patients with homozygous or compound heterozygous variants, setmelanotide may be a viable treatment option for some patients with POMC, PCSK1, or LEPR heterozygous deficiency obesity.
