Effects of MetAP2 inhibition on hyperphagia and body weight in Prader–Willi syndrome: A randomized, double-blind, placebo-controlled trial

Aims: There are no treatments for the extreme hyperphagia and obesity in Prader–Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. Materials and Methods: Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151. Results: One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference −6.3, 95% CI −9.6 to −3.0; P =.0003) and 2.4 mg beloranib groups (−7.0, 95% CI −10.5 to −3.6; P =.0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference − 8.2%, 95% CI −10.8 to −5.6; P <.0001) and 2.4 mg beloranib (−9.5%, 95% CI −12.1 to −6.8; P <.0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo. Conclusions: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.