Impact of Setmelanotide on Metabolic Syndrome Risk in Patients With Bardet-Biedl Syndrome.

Abstract

Bardet-Biedl syndrome (BBS) is a rare genetic disease associated with disruptions in melanocortin-4 receptor pathway signaling that can contribute to increased risk for metabolic syndrome and obesity-related comorbidities. Here, MetS-Z-BMI scores, a continuous measure based on body mass index (BMI), were calculated to determine metabolic syndrome severity and response to treatment with the melanocortin-4 receptor agonist setmelanotide in BBS. All patients from a phase 3 study (NCT03746522) of setmelanotide with data required for the calculation of MetS-Z-BMI scores were included. Mean MetS-Z-BMI score was determined at baseline and Week 52; subgroup analyses were conducted by sex, age, genotype, and response to setmelanotide. MetS-Z-BMI scores were evaluable for 22 of 32 patients enrolled. Baseline mean (SD) MetS-Z-BMI score across patients was 1.1 (0.5); baseline mean (SD) odds ratios of future cardiovascular disease or type 2 diabetes were 3.1 (1.5) and 3.7 (1.7), respectively, for adults and 10.2 (4.7) and 2.8 (1.3), respectively, for pediatric patients. Overall, mean (SD) MetS-Z-BMI score at Week 52 was reduced by 0.34 (0.62). Mean (SD) MetS-Z-BMI scores significantly differed depending on achievement of predetermined weight-based thresholds of ≥10% weight loss (patients aged ≥18 years) or ≥0.3-point reduction in BMI Z score (patients aged <18 years) at Week 52 (achievers, -0.64 [0.54]; nonachievers, 0.08 [0.47]; P = .0043). No significant difference was observed with other subgroup comparisons. MetS-Z-BMI score reductions were observed after 52 weeks of treatment, suggesting that setmelanotide may decrease metabolic syndrome severity and risk of future obesity-related comorbidities in those with BBS.