Trial demonstrated that approximately 35% of semaglutide-induced weight loss was due to loss of lean mass
Combining semaglutide with muscle-preserving antibodies protected lean mass – sparing approximately 50%-80% of the lean mass lost with semaglutide alone – while also increasing loss of fat mass
TARRYTOWN, NY, USA I June 02, 2025 I Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced 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. The trial demonstrated that approximately 35% of semaglutide-induced weight loss was due to loss of lean mass, and further 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.
“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, M.D., Ph.D., 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.”
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 include:
| Semaglutide monotherapy (n=151) | Lower-dose combo (n=149) | Higher-dose combo (n=152) | Triplet (n=147) | |
| Lean mass | ||||
| Change in lean mass (SE), in lbs (% of total weight loss) | -7.9 (0.64) lbs (-34.5%) | -3.7 (0.64) lbs*** (-17.0%) | -4.2 (0.66) lbs*** (-16.8%) | -2.0 (0.75) lbs*** (-6.6%) |
| % preservation of lean mass (compared to semaglutide monotherapy) | — | 50.8% | 51.3% | 80.9% |
| Fat mass | ||||
| Change in fat mass (SE), in lbs (% of total weight loss) | -15.3 (0.90) lbs (-66.3%) | -16.9 (0.90) lbs (-78.1%) | -18.9 (0.93) lbs* (-76.3%) | -25.4 (1.06) lbs*** (-84.4%) |
| % increase in fat loss (compared to semaglutide monotherapy) | — | 17.8% | 15.1% | 27.3% |
| Body weight | ||||
| Change in body weight (SE), in lbs (% change in body weight) | -23.0 (1.12) lbs (-10.4%) | -21.6 (1.15) lbs (-9.9%) | -24.8 (1.15) lbs (-11.3%) | -30.0 (1.26) lbs*** (-13.2%) |
SE=Standard Error
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.
Available safety data at data cutoff across treatment groups at 26-weeks were as follows:
| Participants with at least one: | Semaglutide monotherapy (n=151) | Lower-dose combo (n=148) | Higher-dose combo (n=151) | Triplet (n=149) |
| TEAE | 64.9% | 68.2% | 68.2% | 77.2% |
| Severe TEAE | 2.0% | 1.4% | 3.3% | 10.1% |
| TE-SAE | 0.7% | 0.7% | 1.3% | 6.7% |
| TEAE leading to treatment discontinuation | 4.6% | 4.1% | 10.6% | 28.3% |
| Treatment-related TEAE | 47.0% | 48.6% | 56.3% | 63.8% |
NOTE: Two deaths occurred in the triplet group, one due to an undetermined cause in a patient with multiple cardiovascular risk factorsand 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
The safety and efficacy of trevogrumab and garetosmab have not been evaluated by any regulatory authority.
About Regeneron in Obesity
Obesity is a complex, multifaceted disease and a growing public health concern that affects more than a billion people worldwide. Despite the revolutionary impact of GLP-1 receptor agonists (GLP-1RAs) on weight loss, the quality of this weight loss can be negatively impacted because these agents can cause profound muscle loss. Moreover, a high percentage of patients cycle on and off treatment – while off treatment they can regain almost all of the weight lost, but mostly in the form of fat, leaving them with negatively altered body composition.
At Regeneron, we are developing a pipeline focused on the quality of weight reduction. We have several independent approaches focused on promoting and preserving muscle during weight loss, so as to increase the amount of fat loss since adiposity is the principal driver of comorbidities and metabolic diseases associated with obesity. In addition, Regeneron has an extensive pipeline of agents to address some of these co-morbidities and metabolic diseases, which have the potential to be combined with GLP-1RAs. The combination of our science, pipeline, research and clinical innovation uniquely positions us to make a meaningful difference in obesity and obesity-related diseases.
About Regeneron’s VelocImmune® Technology
Regeneron’s VelocImmune technology utilizes a proprietary genetically engineered mouse platform endowed with a genetically humanized immune system to produce optimized fully human antibodies. When Regeneron’s co-Founder, President and Chief Scientific Officer George D. Yancopoulos was a graduate student with his mentor Frederick W. Alt in 1985, they were the first to envision making such a genetically humanized mouse, and Regeneron has spent decades inventing and developing VelocImmune and related VelociSuite® technologies. Dr. Yancopoulos and his team have used VelocImmune technology to create a substantial proportion of all original, FDA-approved fully human monoclonal antibodies. This includes Dupixent® (dupilumab), Libtayo® (cemiplimab-rwlc), Praluent® (alirocumab), Kevzara® (sarilumab), Evkeeza® (evinacumab-dgnb), Inmazeb® (atoltivimab, maftivimab and odesivimab-ebgn) and Veopoz® (pozelimab-bbfg). In addition, REGEN-COV® (casirivimab and imdevimab) had been authorized by the FDA during the COVID-19 pandemic until 2024.
About Regeneron
Regeneron (NASDAQ: REGN) is a leading biotechnology company that invents, develops and commercializes life-transforming medicines for people with serious diseases. Founded and led by physician-scientists, our unique ability to repeatedly and consistently translate science into medicine has led to numerous approved treatments and product candidates in development, most of which were homegrown in our laboratories. Our medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, neurological diseases, hematologic conditions, infectious diseases, and rare diseases.
Regeneron pushes the boundaries of scientific discovery and accelerates drug development using our proprietary technologies, such as VelociSuite®, which produces optimized fully human antibodies and new classes of bispecific antibodies. We are shaping the next frontier of medicine with data-powered insights from the Regeneron Genetics Center® and pioneering genetic medicine platforms, enabling us to identify innovative targets and complementary approaches to potentially treat or cure diseases.
For more information, please visit www.Regeneron.com or follow Regeneron on LinkedIn, Instagram, Facebook or X.
SOURCE: Regeneron Pharmaceuticals
