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 trial assessed the efficacy, safety, and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. Materials and Methods Participants with PWS (12–65 years) 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. Coprimary 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 107 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=0.0003) and 2.4 mg beloranib groups (−7.0, 95% CI −10.5 to −3.6; p=0.0001) vs placebo. Compared to placebo, weight change was greater with 1.8 mg (mean difference −8.2%, 95% CI −10.8 to −5.6; p<0.0001) and 2.4 mg beloranib (−9.5%, 95% CI −12.1 to −6.8; p<0.0001). 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 (two fatal events of pulmonary embolism and two events of deep vein thrombosis) compared to placebo. Conclusions MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviors 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.

Efficacy and safety of methionine aminopeptidase 2 inhibition in type 2 diabetes: a randomised, placebo-controlled clinical trial

“…Importantly, other MetAP2 inhibitors were recently shown to have similar beneficial effects on body weight and glycaemic control, but with a substantially improved safety profile compared with beloranib [7]. Injection-site erythema 1 (2) 2 (4) In addition to reductions in body weight and HbA 1c , improvements in waist and hip circumference, fat mass, lipids, hsCRP, leptin and adiponectin (ESM Table 2) are consistent with previous observations of beloranib [3][4][5][6] and likely result from rapid weight loss as well as other weight-independent effects of MetAP2 inhibition. MetAP2 inhibitors are hypothesised to reduce body weight by increasing fat mobilisation and oxidation [2] and reducing food intake-beloranib produces a marked but transient reduction in food intake in preclinical studies [2] and improves measures of hunger and prospective food intake in obese individuals [3][4][5] and hyperphagia in PWS [6].…”

“…In preclinical models of obesity and diabetes, MetAP2 inhibitors produce weight loss characterised by markedly reduced adiposity and increased glycaemic control, as well as transiently reduced food intake [1,2]. The MetAP2 inhibitor beloranib has demonstrated consistent and substantial weight loss and glucose-lowering effects in clinical studies of general obesity, hypothalamicinjury-associated obesity and Prader-Willi syndrome (PWS) [3][4][5][6]. This phase 2 clinical trial is the first to study the effects of MetAP2 inhibition with beloranib compared with placebo on glycaemic control and body weight in individuals with type 2 diabetes and obesity.…”

A multidisciplinary approach to the clinical management of Prader–Willi syndrome

“…In a phase 3, randomized, placebo‐controlled clinical trials, patients with PWS had a −9.45% placebo‐adjusted change in body weight. In addition, there was a clinically significant decrease in hyperphagia (McCandless et al, ). Unfortunately, two patients with PWS enrolled in the treatment group experienced fatal pulmonary emboli.…”

Single and multiple dose evaluation of a novel MetAP2 inhibitor: Results of a randomized, double‐blind, placebo‐controlled clinical trial

“…In a Phase 2 clinical trial involving patients with obesity and type 2 diabetes, beloranib resulted in a 10% weight loss and a 1.4% reduction in HbA1c (placebo‐corrected) following 26 weeks of treatment . However, beloranib development was discontinued because of an imbalance of venous thromboembolism (VTE) events in the beloranib‐treated groups compared to placebo in beloranib clinical trials . Subsequent pre‐clinical evaluation indicates that the prothrombotic effect of beloranib appears to be explained, at least in part, by extended endothelial cell (EC) exposure that initiates an intracellular procoagulant signaling cascade …”