Novel Monoclonal Antibody Linked to Increased Muscle Development and Reduction in Body Fat

A new study reveals that bimagrumab can have metabolic improvement for those suffering from obesity and type 2 diabetes. 

With obesity being a global health crisis that can lead to serious health complications and the development of chronic irreversible disease states, it is interesting to continue exploring pharmacotherapeutic interventions to reduce harm in this patient population. Previous research has shown that blocking the activin type II receptor (ActRII) leads to increased skeletal muscle growth. Therefore, studies have looked at mechanisms of inactivation of ActRII via the fully human monoclonal antibody bimagrumab, which showed the desired effect of muscle growth and had other positive outcomes, including improvement in insulin resistance and decreases in adipose tissue. 

This was a phase 2 double-masked, placebo-controlled randomized control study over 48 weeks. It was conducted at nine sites from areas in the United States and the United Kingdom. After screening, a total of 72 patients with type 2 diabetes with obesity were randomized in a 1:1 ratio, in either the experimental (n=37) or the control group (n=38). The experimental group received bimagrumab 10mg/kg once monthly, and the control received a placebo. Both groups had participated in diet and exercise modification during the study period. The primary endpoint was the least square mean change from baseline to completion of the follow-up period (48 weeks) in body fat mass. This was assessed by using dual-energy x-ray absorptiometry. 

Additionally, the authors looked at secondary endpoints that included, HbA1c level, waist circumference, and total body weight. A longitudinal mixed-effects model was used for both the primary and secondary endpoints. Finally, a sensitivity analysis was performed to assess if the primary endpoint was affected by nonrandom missingness assumptions. 

After the 48 weeks, the group that received bimagrumab had a total body fat mass decreased by 20.5% (−7.49 kg; 80% CI, −8.33 to −6.64 kg), while the placebo group only decreased by 0.5% (−0.18 kg; 80% CI, −0.99 to 0.63 kg). When compared to one another, the total body fat mass difference was 7.31kg (80% CI, −8.48 to −6.14; P < .001). Furthermore, the study broke down the weight loss percentage in each group and compared them in subgroups: those who lose at least 5%, 10%, and then 15% total body mass. For the bimagrumab group at week 48, 96% of patients lost at least 5% (25 out of 26), whereas the placebo group only had 21% (6 out of 29 patients). 92% of the experimental group lost at least 10% total body fat (24 out of 26 patients) vs. 10% in the placebo group (3 out of 29), and finally, when looking at those who lost at least 15% total body fat, 77% of patients who had received treatment with bimagrumab had met this goal (23 out of 26). Still, only 10% of the placebo group did (3 out of 29). All three assessments had a p-value of < 0.001. In addition, after 48 weeks the bimagrumab group gained 3.6% lean mass (1.70 kg; 80% CI, 1.14 to 2.26 kg) versus the placebo group who lost 0.8% muscle mass (−0.8 kg; 80% CI, −1.9 to 0.3 kg) (p-value < 0.001). The treatment group also had a large difference in waist circumference −9.0 cm (80% CI, −10.3 to −7.7 cm) vs 0.5 cm (80% CI, −0.8 to 1.7 cm) (p-value < 0.001), HbA1c −0.76% (80% CI, −1.05% to −0.48%) vs 0.04% (80% CI, −0.23% to 0.31%) (p-value = 0.005), BMI −2.19 (80% CI, −2.60 to −1.78) vs −0.28 (80% CI, −0.67 to 0.11) ( p-value < 0.001), and loss of total body weight (65.4% vs 10.3%) (p-value < 0.001). Lastly, at around the same rate, adverse events were experienced in both the treatment group (83.8%) and the placebo group (81.6%). Most of the adverse events were mild and included diarrhea and muscle spasms.  

Overall, this study supported and expanded the previous evidence that suggested that causing inhibition of ActRII using the monoclonal antibody bimagrumab when combined with lifestyle modifications will lead to loss of total body fat at exponentially higher rates than diet and exercise alone. It also displayed increased muscle mass and a range of metabolic biomarkers. On top of being efficacious, it also proved safe. While this study had strengths, it also had limitations, including small study size and gender imbalance, with more women in the bimagrumab group. In addition, the study was limited only to patients with overweight or obesity and type 2 diabetes. This was a phase 2 study and focused on that population, but should support the need for more extensive phase 3 studies that could increase the sample size and diversify the treatment group. 

Practice Pearls: 

• When combined with improvements in diet and exercise, once monthly bimgrumab improved glycemic control, reduced body fat, and increased muscle mass in obesity and type two diabetes patients. 

• The antibody blockade of activin type II receptor is a novel pathway for pharmacologic interventions in patients with the metabolic imbalance and increased adiposity.  
• Although a future phase 3 randomized control study is needed, the results of this study should serve as a guide to treatment for clinicians when treating high-risk patients in this population.  

Heymsfield, Steven B et al. “Effect of Bimagrumab vs. Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity: A Phase 2 Randomized Clinical Trial.” JAMA network open vol. 4,1 e2033457. 4 Jan. 2021, doi:10.1001/jamanetworkopen.2020.33457 

Alexa Rodriguez, PharmD Candidate 2022, University of South Florida, Taneja College of Pharmacy