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/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.Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-018-4677-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

A MetAP2 inhibitor blocks adipogenesis, yet improves glucose uptake in cells

“…These findings suggest a possible therapeutic intervention of obesity and obesity-associated disorders by targeting the vascular compartment. However, a long-term phase 2 clinical trial with beloranib, a MetAP2 inhibitor was associated with venous thrombotic adverse events likely resulting from drug effects on vascular endothelial cells (ECs) [21]. Promising findings observed with various studies support further investigation of other MetAP2 inhibitors that might alleviate some of these risks and adverse effects previously observed.…”

“…In clinical studies of obesity, beloranib, a MetAP2 inhibitor substantially increased weight loss along with improved glycemic control [17][18][19][20]. However, in spite of these promising findings, a phase 2 clinical trial testing the long-term effects of beloranib had to be stopped early because of an imbalance of venous thromboembolism along with other adverse effects in beloranib treated individuals [21].…”

Targeting methionine aminopeptidase 2 in cancer, obesity, and autoimmunity

“…Effects of 13 on adipose tissue and food intake occurred at lower doses than required for antitumour action, and, according to the authors, vascularization was unaffected [48,50,51]. Confident of the safety profile at these lower doses with adverse events of only mild nausea and dizziness [48], Beloranib was taken to Phase II [52]. While impact on bodyweight loss and appetite reduction were promising and most common adverse effects were mild and sleep-related, three cases of venous thromboembolism caused the trial to be terminated early [52].…”

“…Confident of the safety profile at these lower doses with adverse events of only mild nausea and dizziness [48], Beloranib was taken to Phase II [52]. While impact on bodyweight loss and appetite reduction were promising and most common adverse effects were mild and sleep-related, three cases of venous thromboembolism caused the trial to be terminated early [52]. Despite these safety warnings, Zafgen pushed forward into Phase III clinical trials for the treatment of Prader-Willi Syndrome, a rare genetic disorder leading to obsessive food intake and morbidity [53].…”

“…For Beloranib, reduction of adipose tissue and food intake were reported to require lower doses than vasculature effects [48,50], suggesting differential systemic effects might depend on differential tissue distribution. Vasculature-related adverse events halted the development of Beloranib first and then ZFN-1061, the two lead candidates of Zafgen [52,53]. While weight loss activity of MetAP2i was initially thought to be related to angiogenesis inhibition on adipose tissue [56,68], later evidence suggests otherwise, with A-357300, Beloranib, and 17 shown to directly impact the metabolic signature of human primary adipocytes from obese individuals as well as brown adipocytes [17,55].…”