Key Takeaways
- Combination Therapy Preserves Muscle Mass: Regeneron’s semaglutide plus trevogrumab combo significantly preserved lean muscle mass in patients with obesity, improving on the muscle loss typically seen with GLP-1 monotherapy.
- Triplet Therapy Maximizes Fat Loss: Adding garetosmab to the semaglutide-trevogrumab regimen enhanced fat reduction by 27.3% over semaglutide alone, while preserving over 80% of lean body mass.
- Safety Profile Varies by Treatment Intensity: Adverse event rates increased with treatment complexity, with the triplet therapy showing higher discontinuation and severe treatment-emergent adverse event rates, though no direct link to treatment-related deaths was established.
Results from the Phase II COURAGE trial show that Regeneron’s combination of semaglutide plus trevogrumab significantly enhanced fat loss while preserving lean muscle mass in patients with obesity. According to the company, the combination demonstrated an even greater fat mass reduction and more substantial lean mass preservation when used as a triplet with garetosmab.1
Can Combining Semaglutide with Myostatin Inhibitors Improve the Quality of Weight Loss?
“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 George D. Yancopoulos, MD, PhD, board co-chair, president, chief scientific officer, Regeneron, in a press release.
Inside the COURAGE Trial: Design and Methodology
- The randomized, double-blind COURAGE trial evaluated the efficacy and safety of trevogrumab, with or without garetosmab, in combination with semaglutide in 999 patients. The study was divided into three parts, with part A assessing healthy participants and parts B and C focused on patients with obesity.
- For these latter groups, treatment was administered over two 26-week periods—one focused on weight loss and the other on weight maintenance.
- The primary endpoints for parts B and C were the percentage change in body weight and total fat mass from baseline to week 26. A key secondary endpoint was the percentage change in lean muscle mass.1,2
Lean Mass Preservation and Fat Reduction Outcomes
- Results, which included data from approximately 50% of participants after 26 weeks, show that semaglutide alone led to an average weight loss of 23 pounds, with 34.5% of that weight loss attributed to reductions in lean muscle mass.
- When trevogrumab was added to semaglutide, both the lower and higher dose combinations demonstrated significantly improved muscle preservation, with 50.8% and 51.3% of the lost weight, respectively, coming from fat rather than lean mass.
- Fat loss also improved relative to monotherapy, with 17.8% and 15.1% greater reductions observed in the lower- and higher-dose arms, respectively.
- The greatest improvements were seen in the triplet therapy arm, which combined semaglutide, trevogrumab, and garetosmab. This group exhibited the highest lean mass preservation—80.9%—and achieved a 27.3% increase in fat mass reduction compared with semaglutide alone.
Safety Findings and Adverse Events
In terms of safety, treatment-emergent adverse events (TEAEs) were reported in the majority of participants across all groups.
- Incidence ranged from 64.9% in the semaglutide-only arm to 77.2% in the triplet therapy group.
- Although severe TEAEs were infrequent overall, they increased with treatment intensity: 2% in the semaglutide group, 1.4% in the low-dose combination, 3.3% in the high-dose combination, and 10.1% in the triplet therapy arm.
- The rate of treatment discontinuation followed a similar pattern, with the triplet arm showing a notably higher rate of 28.3% compared with 4% to 10% in the other groups.
- Two deaths were reported in the triplet group. One was attributed to an unknown cause in a patient with multiple cardiovascular risk factors; the other was the result of cardiac arrest in a patient with a history of cardiovascular disease.
- Regeneron stated that no causal relationship has been established between the deaths and the investigational treatments.1
Next Steps and Future Implications
“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,” continued Yancopoulos, in the press release. “The full data set will be available later this year and will provide further insights to help optimize the dosing regimens in future trials.”
References
1. Interim Results from Ongoing Phase 2 COURAGE Trial Confirm Potential to Improve the Quality of Semaglutide (GLP-1 receptor agonist)-induced Weight Loss by Preserving Lean Mass. Regeneron. June 2, 2025. Accessed June 3, 2025. https://investor.regeneron.com/news-releases/news-release-details/interim-results-ongoing-phase-2-courage-trial-confirm-potential
2. A Study to Test if Trevogrumab or Trevogrumab With Garetosmab When Taken With Semaglutide is Safe and How Well They Work in Adult Patients With Obesity for Weight Loss and Fat Loss (COURAGE). Clinicaltrials.gov. Accessed June 3, 2025. https://clinicaltrials.gov/study/NCT06299098?term=COURAGE,%20regeneron&rank=1
