Once-monthly monoclonal antibody reduces body fat, increases muscle in obesity, diabetes

Adults with type 2 diabetes and overweight or obesity assigned a once-monthly monoclonal antibody infusion experienced a marked decrease in fat mass and gains in muscle vs. those assigned placebo, according to findings from a phase 2 study.

“What it suggests is that there may be a completely new mechanism at play here," because patients receiving bimagrumab weren't eating less but were losing the same amount of weight as reported for weight-loss drugs that work by decreasing appetite, says Lee. M. Kaplan, MD, Ph.D., noting that the 6.5% weight loss in the bimagrumab group was similar to that seen with antiobesity medications that suppress appetite. 

The efficacy and safety 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," Steven B. Heymsfield, MD, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge

Bimagrumab, a human monoclonal antibody that blocks activin type II receptors and stimulates muscle growth, was not initially investigated as an obesity treatment, Steven B. Heymsfield, MD, FTOS, a professor in the department of metabolism and body composition at Pennington Biomedical Research Center, Louisiana State University, told Healio. The drug was initially heralded as a potential breakthrough therapy for people with sporadic inclusion body myositis, a rare muscle-wasting disease. However, the drug did not meet its primary endpoint in a phase 2b/3 trial, Novartis announced in a press release in 2016.

“When researchers did the preclinical work, there was absolutely no signal on adipose tissue; it was all muscle growth,” Heymsfield said in an interview. “They had no reason to suspect it, because [activin type II receptors] are mainly muscle. When they did first-in-man studies, they did see some adipose tissue signal and conducted a proof-of-concept study to see if adipose tissue effects were significant. That is what prompted the current investigation — a phase 2 trial with body fat as the primary endpoint. As of today, there is not a clear mechanism.”

Study design

Heymsfield and colleagues analyzed data from 75 adults with type 2 diabetes with overweight or obesity, defined as a BMI between 28 kg/m² and 40 kg/m² (mean age, 60 years; mean BMI 32.9 kg/m²; mean body weight, 93.6 kg; mean fat mass, 35.4 kg; mean HbA1c, 7.8%). The trial was conducted from February 2017 to May 2019. Researchers randomly assigned participants an IV infusion of bimagrumab (10 mg/kg up to 1,200 mg in 5% dextrose solution; n = 37; 62.2% women) or placebo (5% dextrose solution; n = 38; 77.3% women) every 4 weeks for 48 weeks. Both groups received diet and exercise counseling. The primary endpoint was least square mean change from baseline to week 48 in total body fat mass as measured by DXA; secondary and exploratory endpoints were lean mass, waist circumference, HbA1c and body weight changes from baseline to week 48.

Fat mass vs. body weight

At week 48, participants in the bimagrumab groups experienced a mean –20.5% loss in fat mass (mean, –7.5 kg; 80% CI, –8.3 to –6.6) vs. a mean –0.5% reduction for those in the placebo group (–0.18 kg; 80% CI, –0.99 to –0.63).

Participants assigned bimagrumab also experienced a mean gain of 3.6% in lean mass (mean, 1.7 kg; 80% CI, 1.1-2.3) compared with a mean –0.8% reduction in lean mass for the placebo group (mean, –0.4 kg; 80% CI, –1 to 0.1).

Waist circumference decreased by a mean of 9 cm in the bimagrumab group vs. a 0.5 cm gain in the placebo group (P < .001), and HbA1c fell by 0.76 percentage points in the bimagrumab group vs. 0.04 percentage points in the placebo group (P = .005). Weight loss was also greater in the bimagrumab group vs. placebo (mean, –5.9 kg vs. –0.8 kg; P < .001).

Bimagrumab’s safety and tolerability profile was consistent with prior studies. Mild diarrhea and muscle spasms were the most commonly reported adverse events in the bimagrumab group; one patient in the bimagrumab group developed pancreatitis.

“What surprised me the most was the magnitude of the effects on body fat,” Heymsfield said. “The effect is real; this is not a one-off. People lost 7.5 kg of fat, or almost 16 to 20 pounds of fat. That is significant fat loss, particularly for people with diabetes, who tend not to respond very well to anti-obesity treatment.”

There is excitement about bimagrumab and the possible mechanism behind the new findings; however, next steps in the drug’s pipeline are unclear, Heymsfield said. Novartis opted to license the drug and has not disclosed who the licensee is, he added.

“It’s not dead,” Heymsfield said of the therapy. “To be candid, the diabetes space is pretty crowded. You can take metformin for a penny a day. Monoclonal antibodies are also expensive.”

Researchers also noted a signal for elevated pancreatic enzymes, the origin or significance of which is unclear, he said.

“The real future of this drug involves figuring out the mechanism, working through that and finding targets that are druggable,” Heymsfield said. “This study demonstrates the beguiling nature of weight changes. These people lost more fat than body weight. You cannot always rely on weight as an index of efficacy.”