While the broad benefits of weight loss, even with modest reductions, have long been appreciated in obesity medicine, concomitant sarcopenia—loss of muscle mass—is often a collateral effect.

The phase 2 BELIEVE trial showed that the addition of bimagrumab, an activin type II receptor-targeted antibody that promotes muscle hypertrophy, could preserve the weight reduction seen with the glucagon-like peptide-1 receptor agonist (GLP-1 RA), semaglutide, while also improving body composition, preserving lean muscle mass, and boosting physical function in adults living with obesity without concomitant diabetes.

Steven B. Heymsfield, MD, Professor of Medicine at the Pennington Biomedical Research Center, summarized the key efficacy data from BELIEVE on Monday, June 23, at the 85^th Scientific Sessions symposium, Can We Improve the Quality of Weight Loss by Augmenting Fat Mass Loss while Preserving Lean Mass? The BELIEVE Study of Bimagrumab + Semaglutide.

“We all know that obesity is a disease of excess adiposity, and the optimal treatment would be to promote mainly fat loss,” Dr. Heymsfield said. However, with caloric restriction, and with other weight loss approaches, there is a risk of some degree of obligatory loss of lean muscle. “The goal of treatment, therefore, would be to optimize the quality of weight loss, maximize fat loss, and minimize lean muscle loss.”

Ronenn Roubenoff, MD, MHS, Roubenoff Consulting, LLC, explained why bimagrumab, which blocks the activin/myostatin signaling in muscle and adipose tissues, was the rational choice of partner for the incretin semaglutide in the BELIEVE study.

“The mechanisms of action of the incretins and the activin pathway drugs are quite distinct,” Dr. Roubenoff said, highlighting previous clinical data showing fat loss, especially visceral and hepatic fat, and muscle gain during weight loss in people treated with bimagrumab.

Bimagrumab does not induce appetite suppression or hypermetabolism. Incretins, on the other hand, reduce appetite, resulting in reduced food intake, thereby promoting weight loss, which is attributed to both fat and lean muscle loss.

In BELIEVE, adults living with obesity, with a body mass index (BMI) of ≥30 kg/m² or BMI ≥27 kg/m² along with ≥1 obesity-associated comorbidity, were randomized to one of nine arms over 48 weeks: placebo, bimagrumab alone (10 or 30 mg/kg), semaglutide alone (1 or 2.4 mg), and combination therapy arms with low-low, low-high, high-low, and high-high dose combinations of the two agents.

After 48 weeks of primary treatment, participants in the placebo and 10 mg/kg bimagrumab arms were switched to higher dose bimagrumab therapy for an additional 24-week extension period, explained Penelope Montgomery, MD, Medical Director, Optimal Clinical Trials, New Zealand, who reviewed key aspects of the BELIEVE study design. Treatments for the other groups remained constant throughout the primary and extension periods.

Dr. Heymsfield reviewed safety and efficacy, with a focus on weight reduction, the primary outcome, and body composition, a key secondary outcome.

Body weight reduction was greater with the high-dose combination versus semaglutide. The mean weight reduction was 24.2 kg with the high-dose combination, compared to 16.5 kg with semaglutide (2.4 mg), translating to a mean change of 20.2%, compared to 14.8%, from baseline to Week 48.

Importantly, this weight reduction was accompanied by a nearly additive effect on fat mass with the high-dose combination, compared to semaglutide or bimagrumab alone. Also, the loss of fat mass with the high-dose combination occurred without a concurrent change in caloric intake.

Lean mass was largely preserved in participants who received the high-dose combination therapy. In DXA scans, lean mass decreased by 2.6% from baseline with the high-dose combination, compared to 7.9% with high-dose semaglutide alone and 0.5% with placebo. As expected, lean mass increased slightly (by 2.3%) in the high-dose bimagrumab arm.

Louis J. Aronne, MD, DABOM, the Sanford I. Weill Professor of Metabolic Research at Weill Cornell Medicine and Director of the Comprehensive Weight Control Center, who shared the results of key secondary outcomes, including changes in visceral fat, inflammation markers, and metabolic parameters, spoke about the health implications of visceral adipose tissue (VAT).

“We want people to lose abdominal visceral fat and subcutaneous abdominal fat, which contributes to the metabolic problems associated with obesity,” Dr. Arrone said. VAT-mediated effects include hepatic/skeletal muscle insulin resistance, reflected in A1C levels, increase in systemic inflammation, dyslipidemia, and altered levels of adipokines.

Dr. Arrone noted that in BELIEVE, waist circumference, a surrogate marker that may encapsulate the effects of VAT, was reduced by a mean of about 22 cm in people treated with the high-dose combination.

“To my knowledge, this is the best result that we have seen,” he said. “To put it in perspective, this reduction would be 8.5 holes on a belt. This is a dramatic reduction.”

The changes in waist circumference paralleled changes in estimated VAT, assessed using DXA scans.

Dr. Arrone highlighted the mean VAT change from baseline, which amounted to a 1.5 kg reduction in the high-dose combination arm. Although modest, he said that this VAT seems to be the culprit “that causes all the metabolic mayhem in obesity.”

Levels of a key biomarker of systemic inflammation, high-sensitivity C-reactive protein, decreased by 83% in the high-dose combination group by Week 48.

A1C levels showed an overall trend toward improvement with high-dose combination therapy, with reductions comparable to or greater than those with semaglutide alone. A1C levels also improved in the subset of participants with prediabetes. Indeed, most (90.9%) or all (100%) patients in the bimagrumab-semaglutide combination arms achieved normoglycemia by week 48.

A “remarkable finding,” according to Dr. Arrone, was the increase in adiponectin levels with the combination therapy. While leptin levels decreased across all treatment arms, adiponectin levels “more than doubled in the high-dose combination arm,” compared to semaglutide.

Adverse events associated with bimagrumab included muscle spasms, diarrhea, and acne, and the overall safety profile of the combination therapy was consistent with known adverse events of the individual drugs.

Some of the unanswered questions that warrant further investigation include the effect of the combination treatment on adiponectin levels, changes in liver enzymes, and increase in cholesterol.

BELIEVE, a proof-of-concept phase 2 study, has provided a completely new perspective on combination approaches in the treatment of individuals living with obesity, according to Dr. Roubenoff.

BELIEVE has paved the way for “combining activin pathway inhibitors with incretins to optimize the degree and quality of weight reduction for people living with obesity,” Dr. Arrone concluded.

On-demand access to recorded presentations from this session will be available to registered participants of the 85^th Scientific Sessions through August 25.