Vienna — The investigational monoclonal antibody trevogrumab was associated with lean mass preservation and greater loss of fat mass in people taking semaglutide, an interim trial data showed.

Findings from Regeneron Pharmaceuticals Inc’s ongoing phase 2 COURAGE trial were presented at European Association for the Study of Diabetes (EASD) 2025 Annual Meeting by Ofri Mosenzon, MD, of the company. The trial also included an arm of another antibody, garetosmab, which was associated with significant side effects.

Both trevogrumab and garetosmab are fully human immunoglobulin G4 monoclonal antibodies developed to block key negative regulators of muscle mass, myostatin, and activin A, respectively.

Top-line results from COURAGE were previously announced in June 2025.

Loss of lean mass occurs during weight loss, regardless of the method. In studies, incretin-based treatments, including semaglutide, liraglutide, and tirzepatide have been associated with 15%-45% of total weight loss as lean body mass, with muscle mass being a substantial proportion of that, Mosenzon said.

“Preservation of lean mass is important for strength and physical function, energy expenditure, and glucose homeostasis. Therefore, there is an unmet need for a weight management therapy that preserves lean mass while promoting greater fat loss,” she added.

Indeed, session co-moderator Roman Vangoitsenhoven, MD, PhD, told Medscape Medical News, “There’s a lot of excitement around the efforts to preserve muscle mass. Several approaches sound promising, although there are also side effects like muscle twitching with some of the molecules. We anxiously await further human trials to see what will be the effect size and the tolerability.”

Regarding trevogrumab in particular, Vangoitsenhoven, assistant professor of medicine at KU Leuven and staff endocrinologist at University Hospitals Leuven, both in Leuven, Belgium, commented, “I don’t think we have seen enough data to be able to say this one is far more promising than the others…I think to be able to say what it really means for the clinic, we need the phase 3 trials.”

COURAGE: Trevogrumab Ups Lean and Cuts Fat

In the three-part ongoing COURAGE trial, 605 adults with obesity (BMI ≥ 30) without diabetes were randomized to receive subcutaneous semaglutide titrated up to 2.4 mg weekly alone, or in combination with weekly subcutaneous trevogrumab 200 mg, trevogrumab 400 mg, or a triple combination of semaglutide 2.4 mg, trevogrumab 400 mg, and intravenous garetosmab 10 mg/kg every 4 weeks, with matching placebos.

Participants had a mean age of about 49 years, about two thirds were women, and 20% were Black individuals. At baseline, they had a mean body weight of 102 kg and BMI of 36.7, 44.7 kg of total fat mass and 53.1 kg of total lean mass.

At 26 weeks, DEXA results showed that semaglutide alone was associated with a 6.5% reduction from baseline in lean body mass compared with just 3.3% with semaglutide + trevogrumab 200 mg, 3.8% with semaglutide + trevogrumab 400 mg, and 2.0% for the triple semaglutide + trevogrumab + garetosmab. The differences between semaglutide alone and the other three groups were all significant (P < .0001).

“So we can definitely say here that lean mass was preserved with trevogrumab with or without garetosmab compared to semaglutide therapy alone therapy,” Mosenzon said.

Percent loss from baseline in total fat mass was 27.1% for the triple combination, 19.1% for semaglutide + trevogrumab 400 mg, 17.3% for semaglutide + trevogrumab 200 mg, and 15.7% for semaglutide alone (P = .0001 and P = .0069 for the triple combination and semaglutide + trevogrumab 400 mg, respectively).

The semaglutide alone and semaglutide plus trevogrumab in both doses all lost about 10% of their total body weight, while the triple combination had a 13.4% weight reduction (P = .0003).

The semaglutide group lost 6.7 kg of fat mass and 3.3 kg of lean mass. By contrast, the dual combination with trevogrumab 200 mg lost 7.6 kg and 1.5 kg, respectively, and the dual trevogrumab 400 mg combination lost 8.5 kg and 1.9 kg, respectively. The triple combination produced losses of 11.8 kg fat mass and 0.9 kg lean mass.

“That means a difference of 2.7 kg in body mass loss on top of their better composition,” Mosenzon said.

Numerical improvements were also seen with trevogrumab in metabolic parameters including waist circumference, high sensitivity C-reactive protein, and lipid parameters including low-density lipoprotein cholesterol, in all treatment groups.

More Adverse Effects Seen With Addition of Garetosmab

Adverse event rates for the dual combinations were similar to those seen with semaglutide alone. However, serious adverse events were higher with the triple combination, 14 vs one each for semaglutide alone and combined with trevogrumab 200 mg, and two with semaglutide and the higher dose of trevogrumab. There were two deaths in the triple combination group.

Adverse events leading to treatment discontinuation occurred in 4.6% with semaglutide alone, 4.7% for semaglutide + trevogrumab 200 mg, and 10.6% for semaglutide + trevogrumab 400 mg compared with 30.9% with the triple combination. The most common adverse event occurring in 10% or more of study participants was muscle spasm, occurring in 4.6%, 6.1%, and 9.3%, respectively, compared with 40.9%.

The COURAGE trial is expected to complete in late 2026.

Multiple Efforts Aimed at Muscle Preservation With GLP-1 Therapy

Regeneron is just one of several manufacturers developing drugs to combat muscle loss associated with GLP-1-induced weight loss. On September 25, 2025, Eli Lilly announced that it was halting a phase 2b trial of its candidate agent, bimagrumab, in combination with tirzepatide in people with obesity and type 2 diabetes for “strategic business reasons,” but it is continuing another phase 2 trial of the agent in people with overweight or obesity who do not have diabetes.

On September 23, 2025, Veru announced a successful meeting with the FDA “providing regulatory clarity” for its selective androgen receptor modulator enobosarm, currently in phase 2 trials for muscle preservation in combination with GLP-1s.

ScholarRock reported positive phase 2 results for its myostatin inhibitor apitegromab in June 2025, but the drug hit a snag in September, when the FDA declined to approve it for the treatment of spinal muscular atrophy.

Vangoitsenhoven told Medscape Medical News that several issues are yet to be worked out with all of these as they move forward, including when they should be used and in whom. “Might these be something that we give during the intensive weight loss phase but not necessarily as maintenance therapy? This is an open question.”

He also noted, “increasingly people are in favor of looking more into muscle function than muscle mass. And there, we know as clinicians that if people are able to lose, say, 15 kg, they might be able to go to the gym [to build muscle]…My gut feeling is that would be a good approach.”

And he pointed out that the loss of muscle mass may be of greater concern for some individuals than others. “A 40-year-old woman with a BMI of 45 going on a GLP-1 and losing a bit of muscle mass is not as bad as, let’s say, a 75 year-old with a BMI of 33. There is a huge heterogeneity in the people starting on GLP-1s.”

This trial was funded by Regeneron Pharmaceuticals. Mosenzon reported being an employee of Regeneron Pharmaceuticals. Vangoitsenhoven reported being a clinical investigator for Amgen, Bayer, Eli Lilly, Boehringer-Ingelheim, Novo Nordisk, Roche; he reported serving or has served on speaker’s bureau or advisory board for Bayer, Boehringer Ingelheim, Eli Lilly, Goodlife Pharma, Novo Nordisk, Prowell, Sanofi; Any financial compensation for these activities has been received by the institution (UZ/KU Leuven).

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X @MiriamETucker and BlueSky @miriametucker.bsky.social.