1. Efficacy and safety of methionine aminopeptidase 2 inhibition in type 2 diabetes: a randomised, placebo-controlled clinical trial.
- Author
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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, and Kim D
- Subjects
- Adolescent, Adult, Aged, Aminopeptidases metabolism, Anti-Obesity Agents therapeutic use, Blood Glucose drug effects, Body Weight drug effects, Double-Blind Method, Female, Glucose metabolism, Glycated Hemoglobin metabolism, Glycoproteins, Humans, Hypoglycemic Agents therapeutic use, Male, Metalloendopeptidases metabolism, Methionyl Aminopeptidases, Middle Aged, Obesity drug therapy, Obesity metabolism, Weight Loss drug effects, Young Adult, Aminopeptidases antagonists & inhibitors, Cinnamates therapeutic use, Cyclohexanes therapeutic use, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 metabolism, Epoxy Compounds therapeutic use, Metalloendopeptidases antagonists & inhibitors, Sesquiterpenes therapeutic use
- 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 (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.- Published
- 2018
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