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

• Published in: Diabetes, obesity & metabolism Vol. 19; no. 12; pp. 1751 - 1761
• Main 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, Taylor, Kristin, Hughes, Thomas E., Kim, Dennis D., Butler, Merlin G.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-12-2017; Wiley Subscription Services, Inc
• Subjects: Adolescent; Adult; Aminopeptidase; Aminopeptidases - antagonists & inhibitors; Aminopeptidases - metabolism; antiobesity drug; appetite control; Appetite Depressants - administration & dosage; Appetite Depressants - adverse effects; Appetite Depressants - therapeutic use; Body Mass Index; Body weight; Body weight loss; Cinnamates - administration & dosage; Cinnamates - adverse effects; Cinnamates - therapeutic use; clinical trial; Clinical trials; Cyclohexanes - administration & dosage; Cyclohexanes - adverse effects; Cyclohexanes - therapeutic use; Dose-Response Relationship, Drug; Double-Blind Method; Double-blind studies; Early Termination of Clinical Trials; Embolism; Epoxy Compounds - administration & dosage; Epoxy Compounds - adverse effects; Epoxy Compounds - therapeutic use; Evidence-based medicine; Female; Glycoproteins - antagonists & inhibitors; Glycoproteins - metabolism; Humans; Hyperphagia; Hyperphagia - etiology; Hyperphagia - physiopathology; Hyperphagia - prevention & control; Injection; Intention to Treat Analysis; Male; Methionine; Methionyl Aminopeptidases; Motivation; Obesity; Obesity - etiology; Obesity - prevention & control; phase III study; Prader-Willi syndrome; Prader-Willi Syndrome - drug therapy; Prader-Willi Syndrome - physiopathology; Protease Inhibitors - administration & dosage; Protease Inhibitors - adverse effects; Protease Inhibitors - therapeutic use; randomized trial; Sesquiterpenes - administration & dosage; Sesquiterpenes - adverse effects; Sesquiterpenes - therapeutic use; Severity of Illness Index; Statistical analysis; Thrombosis; Venous Thrombosis - chemically induced; Venous Thrombosis - physiopathology; Weight control; Weight Loss - drug effects; Young Adult; clinical trial; antiobesity drug; appetite control; randomized trial; phase III study
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/dom.13021

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.