Monoclonal Antibody Induces Weight Loss in Type 2 Diabetes

A human monoclonal antibody that failed in treating muscle-wasting disease may find new life as an anti-obesity and anti-diabetes drug, according to results of a phase II clinical trial.

In 75 overweight or obese patients with type 2 diabetes, those who received monthly injections of bimagrumab lost 20.5% of their total body fat mass over 48 weeks of treatment, said Steven Heymsfield, MD, of Pennington Biomedical Research Center in Baton Rouge, Louisiana, and colleagues. Lean mass increased by 3.6% and glycated hemoglobin (HbA1c) levels dropped by 0.76%.

As shown in the study online in JAMA Network Open, total fat mass increased by 0.5% in patients who received placebo injections. In addition, lean mass decreased by 0.8% and HbA1c dropped by 0.04% in the placebo group (P=0.005 for HbA1c; P<0.001 for other comparisons).

The loss in fat mass and gain in lean mass led to a net 6.5% reduction in body weight in patients who received bimagrumab compared with a 0.8% weight gain in those who received placebo (P<0.001), the study found.

“The current study confirms and extends earlier reports showing that antibody blockade of ActRII [activin type II receptor] with bimagrumab in human participants leads to a marked loss in fat mass, an increase in lean mass, and improvement in a range of metabolic biomarkers,” the team wrote. “These findings suggest that blockade of the activin receptor with bimagrumab could provide a novel pharmacologic approach for managing patients with type 2 diabetes with excess adiposity.”

At baseline, study participants had a mean body-mass index of 32.9, mean HbA1c of 7.8%, and mean age of 60. Approximately half were women. All were randomized 1:1 to intravenous infusion of bimagrumab (10 mg/kg up to 1,200 mg in 5% dextrose solution) or placebo (5% dextrose solution). Double-blind treatment was given every 4 weeks for 48 weeks, and both groups received diet and exercise counseling.

The study’s primary endpoint was mean change from baseline to week 48 in total body fat mass. Secondary endpoints included lean mass, waist circumference, HbA1c level, and body weight changes from baseline. Patients on antidiabetic therapy were excluded from the study, except for those receiving metformin or dipeptidyl peptidase4 inhibitors, as these were considered weight neutral.

Adverse events were reported by more than 80% of both the treatment and the placebo groups. The most common adverse events with bimagrumab were mild diarrhea and muscle spasms. Overall, eight adverse events leading to study discontinuation occurred in five patients in the bimagrumab group and none in the placebo group. These events were: pancreatitis (one patient), Helicobacter pylori infection (one patient), muscle spasms (two patients), and an increase in serum lipase (reported twice in one patient) along with upper abdominal pain and cholelithiasis, the researchers reported.

They explained that bimagrumab is a fully human monoclonal antibody, which by binding to the activin type II receptor, prevents the actions of ligands that negatively regulate skeletal muscle growth. The drug was originally developed to treat sporadic inclusion body myositis, a rare progressive muscle wasting disease. However, bimagrumab failed to meet its primary endpoint in a phase II/III study.

In an email to MedPage Today, Heymsfield elaborated: “The drug was designed to target the activin II receptor on skeletal muscle and through that mechanism stimulate muscle development. An unexpected finding in the first human studies was a very significant effect on adipose tissue and insulin sensitivity, and that led Novartis to commission the current Phase II study in patients with obesity and diabetes.”

A novel feature of bimagrumab is the increase in lean mass/skeletal muscle along with weight loss, he and his co-authors noted in the study. “Decrements in lean mass are typically observed with low calorie dieting, partially offset only when the weight loss program includes a moderate or high intensity exercise prescription. An important goal of obesity treatment is that there should be minimal loss of lean tissues and their associated functions.”

Study limitations, the team said, included the gender imbalance across the investigational groups. There were 23 women randomized to bimagrumab versus just 12 to placebo. As a result, baseline body weight was lower in the bimagrumab group, and this imbalance may also have resulted in an underestimation of the lean mass gain in the treatment group.

“Given the strength of the current study findings, we are certain both industry and non-industry scientists will further explore these effects in humans,” Heymsfield told MedPage Today. “How does the antibody work to stimulate fat loss and improve insulin sensitivity? There are some clues, but this is fertile research ground.”