Effect of Bimagrumab vs Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity

Abstract

IMPORTANCE Antibody blockade of activin type II receptor (ActRII) signaling stimulates skeletal muscle growth. Previous clinical studies suggest that ActRII inhibition with the monoclonal antibody bimagrumab also promotes excess adipose tissue loss and improves insulin resistance.OBJECTIVE To evaluate the efficacy and safety of bimagrumab on body composition and glycemic control in adults with type 2 diabetes and overweight and obesity. DESIGN, SETTING, AND PARTICIPANTSThis double-masked, placebo-controlled, 48-week, phase 2 randomized clinical trial was conducted among adults with type 2 diabetes, body mass index between 28 and 40, and glycated hemoglobin (HbA 1c ) levels between 6.5% and 10.0% at 9 US and UK sites. The trial was conducted from February 2017 to May 2019. Only participants who completed a full treatment regimen were included in analysis. INTERVENTIONSPatients were randomized to intravenous infusion of bimagrumab (10 mg/kg up to 1200 mg in 5% dextrose solution) or placebo (5% dextrose solution) treatment every 4 weeks for 48 weeks; both groups received diet and exercise counseling. MAIN OUTCOMES AND MEASURESThe primary end point was least square mean change from baseline to week 48 in total body fat mass (FM); secondary and exploratory end points were lean mass (LM), waist circumference (WC), HbA 1c level, and body weight (BW) changes from baseline to week 48. RESULTS A total of 75 patients were randomized to bimagrumab (n = 37; 23 [62.2%] women) or placebo (n = 38; 12 [31.6%] women); 58 (77.3%) completed the 48-week study. Patients at baseline had a mean (SD) age of 60.4 (7.7) years; mean (SD) BMI of 32.9 (3.4); mean (SD) BW of 93.6 (14.9) kg; mean (SD) FM of 35.4 (7.5) kg; and mean (SD) HbA 1c level of 7.8% (1.0%). Changes at week 48 for bimagrumab vs placebo were as follows: FM, −20.5% (−7.5 kg [80% CI, −8.3 to −6.6 kg]) vs −0.5% (−0.18 kg [80% CI, −0.99 to 0.63 kg]) (P < .001); LM, 3.6% (1.70 kg [80% CI, 1.1 to 2.3 kg]) vs −0.8% (−0.4 kg [80% CI, −1.0 to 0.1 kg]) (P < .001); WC, −9.0 cm (80% CI, −10.3 to −7.7 cm) vs 0.5 cm (80% CI, −0.8 to 1.7 cm) (P < .001); HbA 1c level, −0.76 percentage points (80% CI, −1.05 to −0.48 percentage points) vs −0.04 percentage points (80% CI, −0.23 to 0.31 percentage points) (P = .005); and BW, −6.5% (−5.9 kg [80% CI, −7.1 to −4.7 kg]) vs −0.8% (−0.8 kg [80% CI, −1.9 to 0.3 kg]) (P < .001). Bimagrumab's safety and tolerability profile was consistent with prior studies. CONCLUSIONS AND RELEVANCEIn this phase 2 randomized clinical trial, ActRII blockade with bimagrumab led to significant loss of FM, gain in LM, and metabolic improvements during 48 weeks (continued) Key Points Question What are the effects of bimagrumab, an antibody that blocks activin type II receptors and stimulates skeletal muscle growth, on total body fat mass and glycemic control in patients with type 2 diabetes and excess adiposity? Findings In this phase 2 randomized clinical trial of 75 patients with type 2 diabetes and body mass index between 28 and 40 who received bimagrumab or placebo du...

Next Generation Antiobesity Medications: Setmelanotide, Semaglutide, Tirzepatide and Bimagrumab: What do They Mean for Clinical Practice?

“…At week 48, the changes for bimagrumab vs placebo were as follows: fat mass, −20.5% (−7.5 kg; 80% CI, −8.3 to −6.6 kg) vs. −0.5% (−0.18 kg; 80% CI, −0.99 to 0.63 kg) (P< 0.001); lean mass, 3.6% (1.70 kg; 80% CI, 1.1 to 2.3 kg) vs. −0.8% (−0.4 kg; 80% CI, −1.0 to 0.1 kg) ( P <0.001). 38 Thus rather loss of both lean and fat with weight loss with the typical ratio of 25:75, 29 bimagrumab was associated with loss of fat mass and gain in lean mass. 38 Safety will need to be evaluated further; there were cases of elevations of pancreas and liver enzymes with bimagrumab compared to placebo in this small study.…”

“…Bimagrumab is a human monoclonal antibody that binds to the activin type II receptor to block natural ligands that negatively regulate skeletal muscle growth. 36 , 37 Bimagrumab was tested in a double-blind, placebo-controlled, 48-week, phase 2 randomized clinical trial 38 in adults with type 2 diabetes and BMI 28–40 kg/m 2 . Bimagrumab was dosed at 10 mg/kg up to 1,200 mg in 5% dextrose solution and compared to placebo every 4 weeks for 48 weeks; both groups received diet and exercise counseling.…”

Obesity in Patients with Type 1 Diabetes: Links, Risks and Management Challenges

“…Some examples are the future combinations of drugs such as GLP1 agonists with GIP, Glucagon, or oxynomodulin (dual agonists or triagonists), the combination of Semaglutide with an amylin analog (Cagrilintide) 179 or the novel Bimagrumab which is a monoclonal antibody that binds to the type II activin receptor that regulates skeletal muscle growth, but also decreases adipose tissue improving insulin resistance. 180 …”

Targeting the Activin Receptor Signaling to Counteract the Multi-Systemic Complications of Cancer and Its Treatments

“…In addition to blocking ACVR2 ligands, bimagrumab (BYM-338), a monoclonal antibody against ACVR2 receptors, was found effective in increasing muscle size and attenuating muscle loss in various animal and human studies [18], including in tumor hosts treated with chemotherapy [11]. More recently, in a phase 2 randomized clinical trial, ACVR2 blockade by bimagrumab led to loss of fat mass, gain in lean mass and metabolic improvements in type 2 diabetic patients who were overweight or obese [170], thereby supporting the use of such approach for the pharmacologic management of excess adiposity and metabolic disturbances. Keeping this in mind, the use of such approach in cancer patients, often characterized by extensive loss of adipose tissue mass, may be detrimental (see Section 3.6.2) [171].…”