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

Abstract

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.

Keywords: antiobesity drug; appetite control; clinical trial; phase III study; randomized trial.

Figure 1

Change in coprimary endpoints and scatterplot of change in weight and HQ-CT total score. Least squares mean change (SE) in HQ-CT total score (A) or least squares mean percent change in body weight (B) from baseline to Week 26 for the intent-to-treat population. Estimated treatment differences are from a mixed model repeated measures model with no imputation for missing data. *p<0.05, **p<0.01, ***p<0.001 for change from baseline for beloranib vs placebo. (C) Percent change in weight and absolute change in HQ-CT total score from baseline to Week 26 for each participant in the intent-to-treat population with missing data imputed using last-observation-carried-forward.

Figure 2

Change in HQ-CT individual item scores, participants with ≥5% weight loss, and change in body mass. (A) Least squares mean change (SE) in individual question scores for the HQ-CT at Week 26. Each item had five possible responses with a score ranging from 0 to 4 (Appendix Figure 2). (B) Percentage of participants categorized as body weight responders, i.e. with at least 5% weight loss. (C) Least squares mean change (SE) in body mass from baseline to Week 26 as measured by dual-energy absorptiometry. Data are for the intent-to-treat population. *p<0.05, **p<0.01, ***p<0.001 for beloranib vs placebo.