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

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/m 2 ) and type 2 diabetes (HbA 1c 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 HbA 1c (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 HbA 1c . Trial registration: ClinicalTrials.gov NCT02324491 Funding: The study was funded by Zafgen, Inc.