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

Abstract：

AIMS/HYPOTHESIS:This multicentre randomised double-blind placebo-controlled clinical trial assessed the efficacy and safety of a methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib, in individuals with obesity (BMI ≥30 kg/m2) and type 2 diabetes (HbA1c 53-97 mmol/mol [7-11%] and fasting glucose <15.6 mmol/l). METHODS:Participants were randomised (via a centralised interactive web response system) to placebo, 1.2 or 1.8 mg beloranib s.c. twice weekly for 26 weeks. Participants, investigators and the sponsor were blinded to group assignment. The primary endpoint was the change in weight from baseline to week 26. The trial was terminated early when beloranib development was stopped because of an imbalance of venous thromboembolism events in beloranib-treated individuals vs placebo that became evident during late-stage development of the drug. RESULTS:In total, 153 participants were randomised, 51 to placebo, 52 to 1.2 mg beloranib and 50 to 1.8 mg beloranib. In participants who completed week 26, the least squares mean ± SE weight change (baseline 111 kg) was -3.1 ± 1.2% with placebo (n = 22) vs -13.5 ± 1.1% and -12.7 ± 1.3% with 1.2 and 1.8 mg beloranib, respectively (n = 25; n = 19; p < 0.0001). The change in HbA1c (baseline 67 mmol/mol [8.3%]) was -6.6 ± 2.2 mmol/mol (-0.6 ± 0.2%) with placebo vs -21.9 ± 2.2 mmol/mol (-2.0 ± 0.2%) or -21.9 ± 3.3 mmol/mol (-2.0 ± 0.3%) with 1.2 or 1.8 mg beloranib (p < 0.0001), respectively. The most common beloranib adverse events were sleep related. One beloranib-treated participant experienced a non-fatal pulmonary embolism. CONCLUSIONS/INTERPRETATION:MetAP2 inhibitors represent a novel mechanism for producing meaningful weight loss and improvement in HbA1c. TRIAL REGISTRATION:ClinicalTrials.gov NCT02324491 FUNDING: The study was funded by Zafgen, Inc.

journal_name

Diabetologia

journal_title

Diabetologia

authors

Proietto J,Malloy J,Zhuang D,Arya M,Cohen ND,de Looze FJ,Gilfillan C,Griffin P,Hall S,Nathow T,Oldfield GS,O'Neal DN,Roberts A,Stuckey BGA,Yue D,Taylor K,Kim D

doi

10.1007/s00125-018-4677-0

subject

Has Abstract

pub_date

2018-09-01 00:00:00

pages

1918-1922

issue

eissn

0012-186X

issn

1432-0428

pii

10.1007/s00125-018-4677-0

journal_volume

pub_type

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