In a phase 2 randomized clinical trial of adults with type 2 diabetes and obesity, investigational drug bimagrumab (BYM338, Novartis) — a monoclonal antibody that blocks activin type II receptors and stimulates skeletal muscle growth — led to big reductions in total body fat mass and A1c and significant increases in lean mass compared with placebo.
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, and colleagues report in their study published online January 13 in JAMA Network Open.
Preliminary findings from the study of 75 patients treated for 48 weeks — in which neither group ate less despite intensive nutrition advice — were presented at Obesity Week in 2019.
“What it suggests,” he told Medscape Medical News, “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.
“Is this going to be the kind of complementary drug with a different mechanism that’s going to augment the effects of other drugs?” wondered Kaplan, director of the Obesity, Metabolism & Nutrition Institute at Massachusetts General Hospital in Boston, who has previously served as a scientific consultant to Novartis.
Asked about future plans for bimagrumab, a Novartis spokesperson told Medscape Medical News, “We are currently reviewing the program strategy and considering next steps.”
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Four FDA-Approved Weight-Loss Drugs Now Approved
The US Food and Drug Administration (FDA) approval for lorcaserin (Belviq, Belviq XR, Eisai) for weight loss was rescinded on February 13, 2020, when a post-marketing trial revealed an increased occurrence of cancer, leaving four drugs approved for weight loss in the United States, plus several drugs in development, Heymsfield and colleagues write.
The current phase 2 trial was designed to determine the safety and efficacy of bimagrumab — which had originally been studied to see if it would increase lean muscle mass in people with sarcopenia — on total body fat mass and glycemic control in patients with type 2 diabetes and overweight or obesity.
Researchers enrolled 75 adults at eight sites in the United States and one in Wales, UK in 2017 to 2019.
On average, patients were 60 years old with an A1c of 7.8% and a body mass index (BMI) of 32.9 kg/m2; they weighed 93.6 kg and had a fat mass of 35 kg.
Patients received an intravenous infusion of bimagrumab (10 mg/kg up to 1200 mg in 5% dextrose solution) or placebo (5% dextrose solution) every 4 weeks for 48 weeks. They met with a registered dietician at each monthly study visit and had a virtual check-in between visits.
Participants were advised to follow a diet that would cut 500 calories a day and encouraged to follow the American Diabetes Association walking program.
Body fat mass was measured by dual-energy X-ray absorptiometry (DEXA).
There were more women in the bimagrumab group than in the placebo group (62% vs 32%), but baseline BMI, total body fat mass, and A1c were similar in both groups.
Same Caloric Intake, Less Fat Tissue, More Muscle, Smaller Waist
At 48 weeks in the bimagrumab vs placebo group, there was on average (all P < .001):
A loss of 20.5% vs 0.5% (−7.5 vs −0.2 kg) of total body fat mass.
A loss of 6.5% vs 0.8% (−5.9 vs −0.8 kg) of body weight.
A gain of 3.6% vs a loss of 0.8% (1.7 vs −0.4 kg) of lean mass.
Similarly, the relatively large between-group differences in total body fat mass and body weight at 48 weeks with bimagrumab were accompanied by favorable differences in BMI (−2.19 vs −0.28 kg/m2; P < .001) and waist circumference (−9.0 vs 0.5 cm; P < .001), the investigators point out.
Moreover, the reduction of abdominal visceral adipose tissue and waist circumference with bimagrumab “was nearly twice that observed in a recently published study of patients with type 2 diabetes treated with an intensive lifestyle program and the glucagon-like peptide 1 (GLP-1) agonist liraglutide,” they note.
This highlights “the importance of moving away from body weight as a primary efficacy marker of drugs to more metabolically relevant endpoints.”
Also, A1c decreased by 0.76% in the bimagrumab group and increased by 0.04% in the placebo group (P = .005).
Serious adverse events occurred in three patients (8%) in the bimagrumab group (elevated lipase, epigastric pain, pancreatitis, pneumonia) and three patients (8%) in the placebo group (cellulitis, acute coronary syndrome, acute myocardial infarction, worsening gastroparesis, thermal burn).
Adverse events were reported by of 31 of 37 patients in the bimagrumab group, most often mild diarrhea (41%) and muscle spasms (41%), and 31 of 38 patients in the placebo group, most often headache (13%) and upper respiratory tract infection (13%).
The study was funded by Novartis. Heymsfield has reported receiving personal fees from Tanita and Medifast outside the submitted work. Disclosures for the other authors are listed with the article. Kaplan has reported previously serving as a scientific consultant to Novartis.
JAMA Netw Open. Published online January 13, 2021. Abstract