ESPE Abstracts

Background: Patients with rare monogenic obesity caused by biallelic variants of genes such as proopiomelanocortin (POMC; including variants in PCSK1) or leptin receptor (LEPR) deficiency, experience hyperphagia (a pathologic, insatiable hunger) and early-onset, severe obesity. This suggests potential increased risk over time of obesity-related comorbidities, including metabolic syndrome, a cluster of conditions associated with increased risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). In Phase 3 trials, treatment with the melanocortin-4 receptor agonist setmelanotide resulted in significant weight and hunger reductions in patients with POMC or LEPR deficiency; treatment also demonstrated an effect on several parameters of metabolic syndrome. To quantify the effect of setmelanotide on metabolic syndrome risk, we evaluated the effect of 1 year of setmelanotide in pediatric patients on metabolic syndrome severity score based on body mass index (MetS-Z-BMI score), a practical measurement that positively correlates with long-term risk of T2DM and CVD. Each MetS-Z-BMI score 1.0-point increase in childhood increases the odds of future CVD and T2DM by 9.8 and 2.7, respectively.

Methods: Metabolic parameters from Phase 3 trials of patients with POMC (NCT02896192) or LEPR (NCT03287960) deficiency were used to calculate MetS-Z-BMI score change after 1 year of setmelanotide treatment. MetS-Z-BMI score change was evaluated in the <18-year-old (pediatric) and overall age groups. Pediatric patients were classified based on weight outcomes, and clinical responders to setmelanotide were defined as having ≥0.3-point BMI Z score reduction after 52 weeks.

Results: Nine pediatric patients were evaluated (56% female, 11-17 years old). Pediatric patients with POMC or LEPR deficiency who were responders (n=8) achieved a highly relevant reduction in mean (SD) MetS-Z-BMI score after 52 weeks of treatment (−1.18 [0.72]); 1 pediatric patient with LEPR deficiency who did not achieve the clinical response threshold after 52 weeks of treatment demonstrated a BMI Z score reduction of −0.1 and MetS-Z-BMI reduction of −0.34.

Conclusion: One year of setmelanotide treatment is associated with reductions in MetS-Z-BMI score in pediatric patients with POMC or LEPR deficiency that have been associated with reduced risk of developing metabolic syndrome, CVD, and T2DM. These data support the broad benefits of setmelanotide beyond weight loss alone and suggest early initiation of treatment may lead to reduction in future risk of T2DM and CVD.