Results of a phase 2 trial showed an activin type II receptor (ActRII) blockade, achieved via bimagrumab, led to significant loss of fat mass (FM), gain in lean mass (LM), and metabolic improvements among patients with type 2 diabetes (T2D) and overweight or obesity. Findings were published in JAMA Network Open.
Overweight and obesity are often accompanied by insulin resistance, chronic inflammation, and related comorbid diseases, but the combination of lifestyle management and pharmacotherapy has been increasingly recognized as an effective and safe treatment option for affected patients, researchers explained. Currently, 5 medications are approved for long-term use by the FDA for patients with overweight or obesity.
Bimagrumab, developed by Novartis, is a fully human monoclonal antibody that binds to the ActRII and thus prevents the actions of natural ligands that negatively regulate skeletal muscle growth. However, the underlying mechanisms linking ActRII inhibition with reductions in FM and the mechanisms of improved insulin sensitivity are largely unknown.
Building on clinical findings of a 10-week study that showed “a single intravenous dose of bimagrumab…not only increased lean mass but significantly reduced total body fat mass (FM) and improved insulin sensitivity compared with placebo,” researchers conducted a phase 2 trial to determine the treatment’s efficacy and safety in adult patients with T2D and overweight or obesity. In comparison, the previous study tested bimagrumab in healthy volunteers with insulin resistance who were not dieting.
The randomized clinical trial took place across 9 sites in the United States and United Kingdom between 2017 and 2019. A total of 75 patients aged between 18 and 75 years, with glycated hemoglobin (A1C) between 6.5% and 10%, and with a body mass index (BMI) between 28 and 40 were enrolled in the study; 58 patients completed the trial.
All participants also had a stable body weight between 65 and 140 kg and “were not taking antidiabetic therapy at the time of screening or were receiving stable metformin monotherapy, dipeptidyl peptidase 4 (DPP4) inhibitor monotherapy, or combination therapy of metformin and a DPP4 inhibitor,” as these medications generally have weight-neutral effects.
Patients were randomized 1:1 to receive 10 mg/kg (up to a maximum of 1200 mg in 5% dextrose solution) of bimagrumab (n = 37) or placebo (n = 38) every 4 weeks for 48 weeks, for a total of 12 doses. Doses were administered via a 30-minute intravenous infusion, and the treatment period ended approximately 4 weeks after the last dose administration. All patients had a follow-up period of 8 weeks, met with a registered dietitian at each monthly study visit, and received counseling for physical activity.
The majority of patients randomized to bimagrumab were women (62.2%) compared with 31.6% in the placebo group. At baseline, patients exhibited a “mean (SD) age of 60.4 (7.7) years; mean BMI of 32.9 (3.4); mean body weight (BW) of 93.6 (14.9) kg; mean FM of 35.4 (7.5) kg; and mean A1C level of 7.8% (1.0%).”
Of the 58 participants who completed the trial, researchers found the following changes at week 48 for the bimagrumab arm vs placebo group, respectively:
- 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)
- 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 < .001)
- A1C 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)
- 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)
- 8 adverse events leading to study discontinuation occurred in 5 patients in the bimagrumab group and none in the placebo group.
Six patients reported 9 serious adverse events, including pancreatitis and pneumonia; overall, “adverse events were reported by 31 of 37 patients (83.8%) in the bimagrumab group and 31 of 38 (81.6%) in the placebo group.” Adverse events reported by the treatment group included mild diarrhea and muscle spasms, and 1 patient in the treatment group reported the development of acne, which has been reported in prior studies of bimagrumab.
The relatively small sample size and gender imbalance across groups mark limitations to this study.
However, results confirm “that inhibition of this receptor in human participants leads to not only increases in lean mass but profound decreases in body fat, along with improvements in glycemic control. Inhibition of ActRII may provide a novel pathway for the pharmacologic management of excess adiposity and accompanying metabolic disturbances,” the researchers concluded.
Heymsfield SB, Coleman LA, Miller R, 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 Netw Open. 2021;4(1):e2033457. doi:10.1001/jamanetworkopen.2020.33457