Bimagrumab, an Activin Type II Receptor Antagonist, for the Treatment of Obesity and Type 2 Diabetes: A Randomized ClinicalTrial

IMPORTANCE Antibody blockade of the activin type II receptor (ActRII) signaling pathway stimulates skeletal muscle growth. Previous clinical studies suggest that ActRII inhibition with the human monoclonal antibody bimagrumab also promotes excess adipose tissue loss and improves insulin resistance. OBJECTIVE This multicenter randomized study determined the efficacy and safety of bimagrumab on body composition and glycemic control in adults with overweight and obesity and who had type 2 diabetes. DESIGN This was a double-blind, placebo-controlled 48-week phase 2 study. SETTING Nine sites in the United States and United Kingdom participated in the study from February 2017 through May 2019. PARTICIPANTS Adults (n=75) with body mass index 28–40 kg/m2 64 who had type 2 diabetes and glycated hemoglobin levels 6.5%–10.0%. INTERVENTION Participants were randomized to intravenous bimagrumab or placebo every 4 weeks for 48 weeks. All patients received diet and exercise counseling. MAIN OUTCOME MEASURES The primary endpoint was least squares mean change from baseline (80% CI) to Week 48 in total body fat mass. Key secondary and exploratory endpoints included changes in lean mass, waist circumference, glycated hemoglobin, and body weight from baseline to Week 48. RESULTS At Week 48, 77.3% of patients completed the study. Total body fat mass decreased by 21% in bimagrumab-treated patients vs 0.5% in those treated with placebo (P<0.001). Secondary endpoints for bimagrumab vs placebo included a lean mass increase of 3.6% vs a decrease of 0.8% (P<0.001); waist circumference decrease of 9.00 cm vs increase of 0.45 cm (P<0.001); glycated hemoglobin reduction of 0.76 percentage points vs 0.04 percentage points (P=0.005); and weight reduction of 6.5% vs 0.8% (P<0.001). Bimagrumab was safe and well-tolerated. CONCLUSIONS AND RELEVANCE ActRII blockade with bimagrumab led to marked loss of total body fat, gain in lean mass, and metabolic improvements over 48 weeks in patients with overweight and obesity who had type 2 diabetes. ActRII pathway inhibition provides a novel approach for the pharmacologic management of excess adiposity and accompanying metabolic disturbances. TRIAL REGISTRATION Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT03005288.