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

Abstract

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 ≥30kg/m2) and type 2 diabetes (HbA1c 53-97mmol/mol [7-11%] and fasting glucose <15.6mmol/l). Participants were randomised (via a centralised interactive web response system) to placebo, 1.2 or 1.8mg beloranib s.c. twice weekly for 26weeks. 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. In total, 153 participants were randomised, 51 to placebo, 52 to 1.2mg beloranib and 50 to 1.8mg beloranib. In participants who completed week 26, the least squares mean ± SE weight change (baseline 111kg) was -3.1 ± 1.2% with placebo (n = 22) vs -13.5 ± 1.1% and -12.7 ± 1.3% with 1.2 and 1.8mg beloranib, respectively (n = 25; n = 19; p < 0.0001). The change in HbA1c (baseline 67mmol/mol [8.3%]) was -6.6 ± 2.2mmol/mol (-0.6 ± 0.2%) with placebo vs -21.9 ± 2.2mmol/mol (-2.0 ± 0.2%) or -21.9 ± 3.3mmol/mol (-2.0 ± 0.3%) with 1.2 or 1.8mg beloranib (p < 0.0001), respectively. The most common beloranib adverse events were sleep related. One beloranib-treated participant experienced a non-fatal pulmonary embolism. MetAP2 inhibitors represent a novel mechanism for producing meaningful weight loss and improvement in HbA1c. ClinicalTrials.gov NCT02324491 FUNDING: The study was funded by Zafgen, Inc.