COURAGE Trial confirms potential to improve the quality of semaglutide-induced weight loss by preserving lean mass

Interim results from the ongoing Phase 2 COURAGE trial - investigating novel combinations of semaglutide (GLP-1 receptor agonist) and trevogrumab (anti-GDF8/anti-myostatin) with or without garetosmab (anti-activin A) for the treatment of obesity - demonstrated that approximately 35% of semaglutide-induced weight loss was due to loss of lean mass.

The outcomes also demonstrated that combining semaglutide with trevogrumab with or without garetosmab helped preserve lean mass while increasing loss of fat mass. The interim analysis was conducted when 50% of patients reached week 26 in the trial.

The combination of semaglutide with trevogrumab was generally well-tolerated; the triplet combination of semaglutide with both antibodies had a substantially higher rate of discontinuations due to tolerability issues and other adverse events, consistent with the safety profile previously seen with garetosmab alone.

COURAGE was designed to investigate the quality of weight loss in patients with obesity (BMI ≥30 kg/m2). Treatment is divided into two 26-week periods comprised of a weight-loss phase and a weight-maintenance phase. The three primary efficacy endpoints were assessed in this interim analysis when 50% of patients reached week 26 (end of weight-loss phase), and included percent change from baseline at week 26 in lean mass, fat mass and body weight.

During the weight-loss phase, patients were randomized to receive semaglutide alone or in combination with two different doses of trevogrumab (lower- or higher-dose combo), or higher-dose trevogrumab plus garetosmab (triplet). At this interim analysis, 34.5% of semaglutide-induced weight loss was due to lean mass loss, while patients in all combination groups preserved more lean mass with greater fat loss from baseline compared to semaglutide alone. Detailed results at data cutoff of this interim analysis are shown in Table 1:

NOTE: Lean mass and fat mass was calculated using dual-energy X-ray absorptiometry (DXA) scan, while body weight was measured using a scale; as a result, the lean and fat mass numbers may not exactly sum to body weight. Results are based on MMRM analysis using efficacy estimand that excludes data after the treatment discontinuation. ***p<0.001; *p<0.05; p-values are for the primary endpoints of % change from baseline at week 26 in each category, and were not corrected for multiplicity. After 26 weeks, patients enter into the weight-maintenance phase in which they receive either higher-dose trevogrumab monotherapy or placebo through the end of the trial (week 52). Data from this phase are not yet available. SE=Standard Error.

Available safety data at data cutoff across treatment groups at 26-weeks are shown in Table 2:

Table 2 NOTE: Two deaths occurred in the triplet group, one due to an undetermined cause in a patient with multiple cardiovascular risk factors and the second due to a cardiac arrest in a person with a history of cardiovascular disease. Regeneron has not identified a causal association between treatment and these events. TEAE=Treatment emergent adverse events; SAE=Serious adverse events

“Recent advancements have resulted in patients being able to lose significant amounts of body weight. Unfortunately, this weight loss comes at the cost of muscle loss, and we know muscle is important to overall health,” said Dr George D Yancopoulos, Board Co-Chair, President and Chief Scientific Officer at Regeneron. “These early insights from the COURAGE trial are consistent with recently published pre-clinical data in rodents and non-human primates, and clearly establish the principle that blocking GDF8 with or without activin A can preserve muscle and further increase fat loss in patients being treated with GLP-1 therapy, thereby improving the quality of weight loss. The full data set will be available later this year and will provide further insights to help optimize the dosing regimens in future trials.”

The safety and efficacy of trevogrumab and garetosmab have not been evaluated by any regulatory authority.