Bimagrumab Demonstrates Significant Fat Loss, Muscle Gain, and Glycemic Improvement in Phase 2 Trial for Obesity and Type 2 Diabetes

For many patients with obesity, combining lifestyle management with pharmacotherapy is a safe and effective treatment option. However, the current range of available medications is limited, with only four weight-loss drugs approved by the U.S. FDA to date.

Recently, JAMA Network Open, a subsidiary journal of The Journal of the American Medical Association (JAMA), published promising results from a Phase 2 clinical trial of bimagrumab, an investigational innovative drug. Compared with the placebo group, bimagrumab significantly reduced total body fat and increased lean body mass (muscle mass) in patients with type 2 diabetes and obesity, without reducing caloric intake, while also improving blood glucose levels. Moreover, compared with existing weight-loss medications, bimagrumab demonstrated certain advantages in some metrics.

Bimagrumab is an investigational drug developed by Novartis. It is a monoclonal antibody that blocks the type II activin receptor (ActRII) and stimulates skeletal muscle growth. In preclinical studies, ActRII blockade also promoted the differentiation and activity of brown adipose tissue—unlike white adipocytes, which primarily store fat, brown adipocytes mainly burn energy. In early clinical trials, bimagrumab not only increased muscle mass in healthy volunteers but also significantly reduced total body fat and improved insulin resistance, suggesting that bimagrumab may be suitable for treating obesity and related metabolic disorders.

This study was conducted in adults with type 2 diabetes and obesity, aiming to determine the efficacy and safety of bimagrumab on body composition and glycemic control. Considering that some glucose-lowering medications may also have weight-loss effects, patients receiving other glucose-lowering therapies were excluded, except for those treated with metformin or DPP-4 inhibitors (which have a neutral effect on body weight).

A total of 75 patients were randomly assigned to receive intravenous injections of bimagrumab (10 mg/kg, up to a maximum of 1200 mg) or placebo every 4 weeks for 48 weeks. Both groups also received dietary and exercise counseling: participants were advised to reduce their daily caloric intake by 500 kcal and to engage in walking exercises in accordance with American Diabetes Association (ADA) guidelines. During monthly follow-up visits, they met with registered dietitians, with additional online communication provided throughout the study period.

The mean age of these patients was 60 years. At baseline, the mean body mass index (BMI) was 32.9 kg/m², mean body weight was 93.6 kg, mean body fat mass was 35 kg, and mean glycated hemoglobin (HbA1c) level was 7.8%.

After 48 weeks, patients in the bimagrumab group showed significant improvement in multiple indicators compared to those in the placebo group:

Greater reduction in total body fat: -20.5% vs -0.5% (-7.5 kg vs -0.2 kg)

Greater weight reduction: -6.5% vs -0.8% (-5.9 kg vs -0.8 kg).

Lean body mass (muscle) increased by 3.6% (1.7 kg), whereas it decreased by 0.8% (-0.4 kg) in the placebo group.

Greater improvement in BMI: -2.19 kg/m² vs -0.28 kg/m²

Greater reduction in waist circumference: −9.0 cm vs +0.5 cm

HbA1c levels decreased by 0.76%, while HbA1c increased by 0.04% in the placebo group

Notably, in this study, although nutritional advice was provided, the actual food intake of patients in both groups did not decrease; however, the weight loss in the bimagrumab group (6.5%) was comparable to that achieved with appetite-suppressing weight-loss medications.

Dr. Lee M. Kaplan, Director of the Obesity, Metabolism, and Nutrition Institute at Massachusetts General Hospital (MGH), commented, “This suggests that the drug may work through a novel mechanism.”

The research team further highlighted that bimagrumab nearly doubled the reduction in waist circumference compared to the effects of GLP-1 agonists combined with intensive lifestyle management in patients with type 2 diabetes, as reported in another recent study. This underscores that “the primary efficacy of a drug should be evaluated not only by body weight but also by other metabolism-related indicators.”

The drug demonstrated a favorable safety and tolerability profile in the study. Among the 37 patients in the bimagrumab group, 31 reported adverse events, most commonly mild diarrhea (41%) and muscle spasms (41%). In the placebo group, 31 of the 38 patients reported adverse events, most commonly headache (13%) and upper respiratory tract infection (13%). Serious adverse events occurred in 3 patients (8%) in the bimagrumab group (elevated lipase, upper abdominal pain, pancreatitis, pneumonia) and in 3 patients (8%) in the placebo group (cellulitis, acute coronary syndrome, acute myocardial infarction, exacerbated gastroparesis, thermal burn).

Steven B. Heymsfield, PhD, corresponding author of the paper and a researcher at Louisiana State University, stated, “These exciting results suggest the potential for a novel drug mechanism that can achieve weight loss, reduction in body fat, increase in lean mass, and other metabolic health benefits.” Currently, the research team is evaluating subsequent development plans for this drug, with the expectation that it will yield more positive outcomes in clinical studies, thereby providing patients with new therapeutic options.

References

[1] Heymsfield SB, Coleman LA, Miller R, et al., (2021). Effect of Bimagrumab vs Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity: A Phase 2 Randomized Clinical Trial. JAMA Netw Open, DOI: 10.1001/jamanetworkopen.2020.33457

[2] Monoclonal Antibody Drops Fat, Ups Muscle in Obesity, Diabetes. Retrieved February 2, 2021, from https://www.medscape.com/viewarticle/944602

[3] Bimagrumab Benefits Patients With Obesity, Type 2 Diabetes. Retrieved February 2, 2021, from https://www.medpagetoday.org/endocrinology/diabetes/90916