@article{3230bd94e8f945829e0e1e6123da9040,
title = "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",
author = "McCandless, \{Shawn E.\} and Yanovski, \{Jack A.\} and Jennifer Miller and Cary Fu and Bird, \{Lynne M.\} and Parisa Salehi and Chan, \{Christine L.\} and Diane Stafford and Abuzzahab, \{M. Jennifer\} and David Viskochil and Barlow, \{Sarah E.\} and Moris Angulo and Myers, \{Susan E.\} and Whitman, \{Barbara Y.\} and Dennis Styne and Elizabeth Roof and Dykens, \{Elisabeth M.\} and Scheimann, \{Ann O.\} and Jaret Malloy and Dongliang Zhuang and Kristin Taylor and Hughes, \{Thomas E.\} and Kim, \{Dennis D.\} and Butler, \{Merlin G.\}",
note = "Funding Information: The authors thank study volunteers for their participation, and supporting investigators and key trial staff, including David Arendt, Carrie Bailey, Christine Benoit, Sheila M. Brady, Ananth Chandrasekaran, Ovidiu A. Galescu, Andrea Hale, Hailee Hunt-Hawkins, Susan Kearns, Lalani Khetani, Audrey Lynn, Brittany Machus, Humaira Masoud, M. Richardson, Ira L. Tigner Jr, M. Tran, Kimberly Wallis and R. Winograd. The authors also thank Alice Chen and Joyce M. Simpauco for assistance with clinical operations (funded by Zaf-gen, Inc.), and Sonja K. Billes for writing assistance (funded by Zafgen, Inc.). JAY is a Commissioned Officer in the United States Public Health Service and is supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The opinions and assertions expressed herein are those of the authors, and are not to be construed as reflecting the views of the Public Health Service or the US Department of Health and Human Services. Funding Information: This study was funded by Zafgen, Inc. Funding Information: MJA, MAA, SEB, MGB, CLC, EMD, CF, JMiller, SEMyers, ER, PS, AS, DStafford, DStyne, DV, BYW and JAY have received institutional grant support from Zafgen. LMB has received personal fees, nonfinancial support and institutional support from Zafgen. SEMcCand-less has received institutional grant support and personal consulting fees from Zafgen. JMalloy, DZ, KT and DDK are employees of and hold stock in Zafgen. TEH is an employee of and holds stock in Zaf-gen, and has patents issued to Zafgen. Funding Information: The authors thank study volunteers for their participation, and supporting investigators and key trial staff, including David Arendt, Carrie Bailey, Christine Benoit, Sheila M. Brady, Ananth Chandrasekaran, Ovidiu A. Galescu, Andrea Hale, Hailee Hunt-Hawkins, Susan Kearns, Lalani Khetani, Audrey Lynn, Brittany Machus, Humaira Masoud, M. Richardson, Ira L. Tigner Jr, M. Tran, Kimberly Wallis and R. Winograd. The authors also thank Alice Chen and Joyce M. Simpauco for assistance with clinical operations (funded by Zafgen, Inc.), and Sonja K. Billes for writing assistance (funded by Zafgen, Inc.). JAY is a Commissioned Officer in the United States Public Health Service and is supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The opinions and assertions expressed herein are those of the authors, and are not to be construed as reflecting the views of the Public Health Service or the US Department of Health and Human Services. Data from this study were presented at ENDO 2016, the annual meeting of the Endocrine Society, in Boston, MA, ICO 2016, the XIII International Congress on Obesity, in Vancouver, Canada, and IPWSO, the 9th Congress of the International Prader-Willi syndrome Organization in Toronto, Canada. MJA, MAA, SEB, MGB, CLC, EMD, CF, JMiller, SEMyers, ER, PS, AS, DStafford, DStyne, DV, BYW and JAY have received institutional grant support from Zafgen. LMB has received personal fees, non-financial support and institutional support from Zafgen. SEMcCandless has received institutional grant support and personal consulting fees from Zafgen. JMalloy, DZ, KT and DDK are employees of and hold stock in Zafgen. TEH is an employee of and holds stock in Zafgen, and has patents issued to Zafgen. EMD, ER, JAY, JMiller, KT, TEH and DDK designed the study. MJA, MAA, ER, DStafford, BYW, JMalloy and KT coordinated the study. MJA, MAA, SEB, LMB, MGB, CLC, SEMcCandless, JMiller, SEMyers, ER, PS, AS, DStafford, DStyne, DV, BYW, JAY and KT were responsible for screening and enrollment of participants, and arranged informed consent. MJA, MAA, SEB, LMB, MGB, CLC, CF, SEMcCandless, JMiller, SEMyers, ER, PS, AS, DStafford, DStyne, DV, BYW and JAY provided participant care and/or took samples. EMD and ER contributed to HQ-CT validation and interpretation. DZ had full access to all data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis. DZ and JMalloy contributed to the statistical analysis. MJA, LMB, MGB, EMD, TEH, ER, JAY, DZ, JMalloy, KT and DDK participated in data review and/or interpretation. MGB, SEMcCandless, JAY, JMalloy, DZ and KT contributed to the writing of the report. All authors critically reviewed the report and approved the final version. Publisher Copyright: {\textcopyright} 2017 John Wiley \& Sons Ltd",
year = "2017",
month = dec,
doi = "10.1111/dom.13021",
language = "English (US)",
volume = "19",
pages = "1751--1761",
journal = "Diabetes, Obesity and Metabolism",
issn = "1462-8902",
publisher = "John Wiley and Sons Inc.",
number = "12",
}