ESPE Abstracts

Background: Children with metabolic syndrome carry an increased risk for development of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) in adulthood. Patients with rare syndromic obesity, such as Bardet-Biedl syndrome (BBS), experience early-onset, severe obesity, which may convey an increased risk for developing obesity-related comorbidities and metabolic syndrome later in life. In clinical trials, treatment with the melanocortin-4 receptor agonist setmelanotide led to significant weight and hunger reductions in patients with BBS, along with improvements in metabolic parameters. To better understand the effect of setmelanotide on future risk of metabolic syndrome development, we evaluated the effect of 1 year of setmelanotide treatment in pediatric patients with BBS using a metabolic syndrome score (MetS-Z-BMI), a measure where high scores indicate increased long-term risk of metabolic syndrome comorbidities. A 1.0-point increase in MetS-Z-BMI score in childhood increases the odds of future CVD and T2DM by 9.8 and 2.7, respectively.

Methods: Metabolic parameters from a Phase 3 trial of patients with BBS (NCT03746522) were evaluated. MetS-Z-BMI score changes after 1 year of setmelanotide were assessed. MetS-Z-BMI outcomes were analyzed in the overall and <18-year (pediatric) age groups. Patients were classified based on weight outcomes as being clinical responders to setmelanotide (ie, patients ≥18 years old achieving ≥10% weight loss or patients <18 years old achieving ≥0.3-point BMI Z score reduction) or nonresponders at Week 52.

Results: Twenty-two patients were evaluated (59% female, 10-44 years old). Pediatric patients with BBS achieving a clinically meaningful reduction in weight with setmelanotide (n=9) demonstrated a reduction in mean (SD) MetS-Z-BMI score after 52 weeks of treatment (−0.38 [0.53]). By contrast, pediatric patients without weight response to setmelanotide showed an increase in mean (SD) MetS-Z-BMI score after 52 weeks (n=4; +0.42 [0.38]). Clinical response to setmelanotide in the overall population (n=16) was also associated with a reduced mean (SD) MetS-Z-BMI score after 52 weeks (−0.54 [0.56]). This change in score compares favorably to an increased score in patients who were nonresponders after 52 weeks of treatment (n=6; +0.17 [0.50]), a between-group difference of −0.71 (P=0.0129).

Conclusion: Setmelanotide treatment response is associated with reductions in metabolic syndrome severity score in pediatric patients with BBS, which are associated with reduced risk of metabolic syndrome, CVD, and T2DM. These data support the broad benefits of setmelanotide beyond weight loss and hunger reduction, thus supporting early initiation of treatment for potentially reducing future risk of CVD and T2DM.