Monoclonal antibody helps preserve muscle mass regardless of protein intake

Treatment with bimagrumab appears to prevent muscle loss resulting from inadequate protein intake and increase muscle mass in the setting of enough protein intake, according to data from phase I and IIa studies.

“Activin signalling pathways inhibit muscle fibre growth in skeletal muscle and increase lipid storage in adipose tissue,” reported lead study investigator Dr Laura Coleman of Versanis Bio, Boston, Massachusetts, US.

Bimagrumab is a monoclonal antibody with a high affinity to activin type II receptors (ActRIIA and ActRIIB), Coleman said. The drug has been shown to help increase muscle mass and decrease fat mass without altering food intake. [JAMA Netw Open  2021;4:e2033457]

Healthy individuals

The phase I study included 63 domiciled healthy volunteers between 50 and 75 years of age. These volunteers were randomly assigned to receive bimagrumab at either 3 mg/kg (n=19, mean age 56.6 years, 63 percent men, mean body mass index [BMI] 25.6 kg/m²) or 10 mg/kg (n=21, mean age 56.3 years, 57 percent men, mean BMI 25.5 kg/m²) or placebo (n=23, mean age 57.4 years, 48 percent men, mean BMI 26.8 kg/m²).

Protein intake was half the recommended dietary allowance (RDA) in 21 volunteers, met the recommended RDA in 21, and exceeded the RDA by 1.5 times in the remaining 21.

In the placebo group, low protein intake led to reduced thigh muscle volume measured by MRI at day 29 after treatment (0.5x RDA: mean change –3.4 percent). This low protein intake-associated muscle loss was mitigated by bimagrumab treatment at both 3- and 10-mg/kg doses (mean changes 0.6 percent and 0.8 percent, respectively). [Coleman L, et al, EASD 2023]

Of note, high dietary protein intake increased the effect of bimagrumab on thigh muscle volume, Coleman pointed out.

Thigh muscle volume increased by 2.5 percent and 3.3 percent with 3- and 10-mg/kg bimagrumab among volunteers with protein intake meeting the RDA, and by 3.9 percent and 5.9 percent, respectively, among those with protein intake 1.5 times the RDA (p<0.01 vs placebo for all comparisons).

“We observed similar data for lean body mass measured by dual energy x-ray absorptiometry (DXA),” Coleman said.

In terms of safety, both doses of bimagrumab were safe and well tolerated. Most adverse events were mild to moderate in intensity, with the most common being acne, muscle twitching/spasm/tightness, and diarrhoea.

There were two serious AEs documented. One was a treatment-related elevation in ALT, and the other was an unrelated endometrial adenocarcinoma. No clinically significant abnormal laboratory values were seen, except for increased ALT and AST in two volunteers.

People with obesity/overweight and T2D

In the 48-week phase IIa study, 75 participants (mean age 60.4 years, 47 percent women) with overweight or obesity (mean BMI 32.9 kg/m²) and T2D were randomly assigned to receive once-monthly intravenous dosing of either bimagrumab 10 mg/kg (n=37) or placebo (n=38). Treatment was given in addition to a lifestyle intervention, which consisted of 500 Kcal per day deficit, protein intake of 1.2 g/kg per day, and the American Diabetes Association walking program. The primary endpoint was total body fat mass measured by DXA.

Bimagrumab-treated participants achieved an approximately 7-percent weight loss, 20-percent fat loss, and 4-percent increase in lean mass.

“These were all in the setting of a stable caloric and protein intake,” noted Coleman.

The present data, she added, were in contrast with those of the semaglutide 20-week appetite study, wherein caloric intake was reduced, consistent with the mechanism of action of the drug. [Diabetes Obes Metab 2021;23:754-762]

“Most weight loss methods that are based on reducing appetite and food intake lead to loss of lean mass of somewhere between 25 percent and 40 percent as a proportion of total weight loss. This could vary with a number of factors, but in general … about a quarter of weight loss is due to lean mass,” according to Coleman.

The effects of bimagrumab seen in the phase IIa study are in line with one of the goals of obesity treatment, which is to maximize fat loss while maintaining lean tissue mass and function, she said.