MetAP2 Inhibitors Show Promise Despite Unexpected Adverse Events Ending Study in T2D

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Weight loss with beloranib was observed as early as week 4 and progressed through to week 26.
Weight loss with beloranib was observed as early as week 4 and progressed through to week 26.

Methionine aminopeptidase 2 (MetAP2) inhibitor drugs showed promise in treatment of type 2 diabetes, obesity, and metabolic disease but were discontinued when patients experienced unexpected serious venous thromboembolism adverse events (AE), according to a study published in Diabetologia

This study assessed the effects of the MetAP2 inhibitor, beloranib, compared with placebo on glycemic control and body weight in individuals with type 2 diabetes and obesity. Participants were randomly assigned to receive beloranib 1.2 mg (n=52), beloranib 1.8 mg (n=49), or a placebo (n=51) 2 times per week for a 26-week period. The study was discontinued after patients were withdrawn from the study due to AEs at a greater rate among the beloranib group than among the placebo group. The study reported no deaths; instead, AEs included symptoms such as sleep disorders, diarrhea, injection-site bruising or erythema, lower-respiratory tract infection, and cough.

Significant weight change and reduction in glycated hemoglobin (HbA1c) were reported in the participants receiving beloranib who completed the study. The weight change in patients taking placebo (n=22) was −3.1 ± 1.2% compared with −13.5 ± 1.1% and −12.7 ± 1.3% in patients taking 1.2 and 1.8 mg beloranib (n=25), respectively (P <.0001). Change in HbA1c of patients taking placebo was −0.6 ± 0.2% vs −2.0 ± 0.2% in patients taking beloranib 1.2 mg and −2.0 ± 0.3% in patients taking beloranib 1.8 mg (P <.0001).

Although the study was stopped because of the imbalance of venous thromboembolism events among patients given the beloranib therapy, the researchers said the positive outcomes of the treatment warrant more research of MetAP2 therapies.

"Beloranib resulted in a statistically significant clinically meaningful improvement in body weight that was supported by improvements in glycemic measures and cardiometabolic variables," the study researchers conclude. "Although beloranib may create or otherwise exacerbate a hypercoagulable state, the significant efficacy findings support further investigation of other MetAP2 inhibitors designed to mitigate venous thromboembolism risk."

This study was sponsored by Zafgen, Inc. Please refer to reference for a complete list of authors' disclosures.

Reference

Proietto J, Malloy J, Zhuang D, et al. Efficacy and safety of methionine aminopeptidase 2 inhibition in type 2 diabetes: a randomised, placebo-controlled clinical trial [published online July 11, 2018]. Diabetologia. doi: 10.1007/s00125-018-4677-0

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