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- Title
Effects of MetAP2 inhibition on hyperphagia and body weight in Prader-Willi syndrome: A randomized, double-blind, placebo-controlled trial.
- Authors
McCandless, Shawn E.; Yanovski, Jack A.; Miller, Jennifer; Fu, Cary; Bird, Lynne M.; Salehi, Parisa; Chan, Christine L.; Stafford, Diane; Abuzzahab, M. Jennifer; Viskochil, David; Barlow, Sarah E.; Angulo, Moris; Myers, Susan E.; Whitman, Barbara Y.; Styne, Dennis; Roof, Elizabeth; Dykens, Elisabeth M.; Scheimann, Ann O.; Malloy, Jaret; Zhuang, Dongliang
- 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. 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.
- Subjects
PRADER-Willi syndrome; OBESITY treatment; HYPERPHAGIA; METHIONINE aminopeptidase; WEIGHT loss; DRUG efficacy; PLACEBOS; THERAPEUTICS
- Publication
Diabetes, Obesity & Metabolism, 2017, Vol 19, Issue 12, p1751
- ISSN
1462-8902
- Publication type
Article
- DOI
10.1111/dom.13021