Regeneron's trevogrumab preserves muscle during semaglutide weight loss

Regeneron Pharmaceuticals has disclosed full Phase 2 results from its COURAGE trial, showing that trevogrumab, an anti-myostatin antibody that blocks the GDF8 signalling pathway, substantially preserved lean mass and muscle volume in people with obesity treated with semaglutide 2.4 mg. The data were presented at the European Association for the Study of Diabetes annual meeting and are in press with The Lancet.

The trial evaluated trevogrumab across two dose cohorts over 52 weeks in adults with a BMI of 30 kg/m² or above. In the lower-dose portion, the 75 mg dose preserved 50.7% of lean mass relative to the semaglutide-plus-placebo arm at 26 weeks and 42.5% at 52 weeks, as measured by dual-energy X-ray absorptiometry. The 25 mg dose showed more modest but still statistically meaningful preservation. Safety data were broadly reassuring: 77% of participants on trevogrumab experienced at least one adverse event, compared with 82% in the placebo group, with nausea, constipation, diarrhoea and vomiting the most commonly reported events.

MRI substudy and sarcopenia subgroup

A predefined MRI substudy provided the most striking headline figure: lower-dose trevogrumab preserved approximately 70% of thigh fat-free muscle volume that would otherwise have been lost with semaglutide monotherapy. At 52 weeks, the 25 mg arm showed 71.8% muscle preservation relative to placebo, while the 75 mg arm showed 68.9%, suggesting a ceiling effect at these doses rather than a clear dose-response in the MRI measure.

A pre-specified subgroup analysis of participants with low lean mass at baseline, defined using the Foundation for the National Institutes of Health sarcopenia imaging criteria, found that this group suffered disproportionately greater lean mass loss on semaglutide alone. Trevogrumab numerically attenuated that loss to a greater degree than in participants without baseline sarcopenia, a finding with direct clinical relevance given that frailty and sarcopenia are among the most serious risks associated with rapid weight loss in older adults.

Julio Rosenstock, lead principal investigator and clinical professor of medicine at the University of Texas Southwestern Medical Center, said the one-year results, "validated by MRI measurements of muscle volume," support "continued clinical development of trevogrumab and future research into muscle preservation as part of obesity care."

Market context and competitive landscape

The question of muscle loss during GLP-1 receptor agonist therapy has moved rapidly from a theoretical concern to a commercial and regulatory priority. Estimates from published observational data suggest that roughly a quarter to a third of total weight loss on GLP-1 agents such as semaglutide or tirzepatide is lean mass rather than fat, a ratio that has prompted clinicians, payers and regulators to begin asking what the long-term functional consequences may be.

Regeneron is not alone in pursuing this angle. A number of companies are exploring anti-myostatin and activin pathway inhibitors as lean mass preservers, and the field has drawn renewed interest since published data on GLP-1-associated muscle loss began appearing in major journals. Bimagrumab, developed by Novartis and subsequently licensed, produced encouraging body composition data in earlier trials, and Eli Lilly has disclosed interest in combination approaches using its own GLP-1 portfolio. The competitive dynamic means Regeneron will need to move efficiently: the company has said it intends to initiate a further Phase 2 study of trevogrumab in older adults with obesity and reduced muscle mass or strength, a population that would likely attract regulatory attention given the functional and falls-related implications of sarcopenia.

Separately, Regeneron noted that partner Hansoh presented Phase 3 data on olatorepatide, a GLP-1/GIP receptor agonist licenced from Hansoh for territories outside mainland China. That programme adds a second obesity asset to Regeneron's pipeline, though neither trevogrumab nor olatorepatide has yet been reviewed by any regulatory authority.