Regeneron Phase 2b Study Shows Antibodies Help Preserve Lean Mass During Weight Loss with Semaglutide
Interim results from COURAGE trial suggest combining semaglutide with muscle-preserving antibodies significantly enhances fat loss while preserving lean mass in obesity treatment.
Interim results from Regeneron's phase 2 COURAGE trial show that adding muscle-preserving antibodies to semaglutide (Wegovy; Novo Nordisk) therapy significantly reduces loss of lean muscle mass while enhancing fat reduction in adults with obesity. The combination of semaglutide with trevogrumab (anti-GDF8/anti-myostatin) preserved 50%-80% of lean mass compared to semaglutide monotherapy, where approximately 35% of weight loss came from muscle tissue rather than fat.
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The study is investigating novel combinations of trevogrumab with or without a second antibody garetosmab (anti-activin A) added to semaglutide, according to a Regeneron statement.
The interim analysis, conducted when 50% of participants reached treatment week 26, showed that participants receiving semaglutide monotherapy lost 7.9 lbs of lean mass (34.5% of total weight loss), while combination therapy groups demonstrated significantly better lean mass preservation. The combination of semaglutide plus lower-dose trevogrumab preserved 50.8% of lean mass compared to monotherapy, the higher-dose combination preserved 51.3%. The “triplet” combination that included garetosmab preserved 80.9% of lean mass that would have been lost with semaglutide alone, Regeneron stated.
After 26 weeks of treatment, COURAGE study participants move into the 26-week weight-maintenance phase for which they will be randomly assigned to receive either monotherapy with higher-dose trevogrumab or placebo, according to the statement.
"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," George D. Yancopoulos, MD, PhD, Regeneron board cochair, president and chief scientific officer, said in the statement. "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."
GLP-1 receptor agonists are highly effective for weight loss and have demonstrated pluripotent effects on cardiometabolic health. It has become clear, however, that substantial muscle loss typically accompanies the reduction in fat mass. Recent research suggests that muscle loss, as indicated by decreases in fat-free mass ranges from 25% to 39% of the total weight lost over 36–72 weeks.2 "This substantial muscle loss can be largely attributed to the magnitude of weight loss, rather than by an independent effect of GLP-1 receptor agonists, although this hypothesis must be tested," according to research published in the Lancet Diabetes & Endocrinology.3
COURAGE
For the COURAGE trial, investigators randomly assigned participants who had obesity (body mass index [BMI] of 30 kg/m² or greater) to receive semaglutide alone or in combination with a low or a high dose of trevogrumab or the high dose trevogrumab plus garetosmab. Researchers measured body composition changes using dual-energy X-ray absorptiometry (DXA) scans and assessed 3 primary efficacy endpoints in this interim analysis when half of the participants had reached week 26: percent change from baseline at week 26 in lean mass, fat mass, and body weight.1
Fat mass reduction and lean mass preservation improved across all combination groups compared to semaglutide monotherapy, according to the statement. While semaglutide alone reduced fat mass by 15.3 lbs (66.3% of total weight loss), the combination therapies achieved greater fat loss: 16.9 lbs with lower-dose combination (78.1% of weight loss), 18.9 lbs with higher-dose combination (76.3% of weight loss), and 25.4 lbs with the triplet combination (84.4% of weight loss). The triplet combination demonstrated a 27.3% increase in fat loss compared to semaglutide monotherapy.1
Total weight loss varied among groups, with semaglutide monotherapy-treated participants losing 23.0 lbs (10.4% body weight reduction), those taking the lower-dose combination losing 21.6 lbs (9.9%), and participants receiving the higher-dose combination losing 24.8 lbs (11.3%). Participants who received semaglutide, trevogrumab at the higher dose plus garetosmab lost approximately 30.0 lbs (13.2%). The triplet combination showed statistically significant improvement in total weight loss (P <.05).
Tolerability was variable, according to the statement, with the combination of semaglutide and trevogrumab showing a level similar to semaglutide monotherapy. The discontinuation rate among participants who received the triplet combination was substantially higher, however. Treatment-emergent adverse events (TEAEs) leading to discontinuation occurred in 4.6% of those receiving semaglutide only, 4.1% of those receiving the lower-dose combination, 10.6% receiving the higher-dose combination, and 28.3% of participants receiving the triplet therapy. Severe TEAEs affected 2.0% of monotherapy patients compared to 10.1% receiving triplet therapy.
Regeneron reported 2 deaths in the triplet group during the 26-week period: one from an undetermined cause in a participant with multiple cardiovascular risk factors and another from cardiac arrest in a person with cardiovascular disease history. Regeneron has not identified a causal association between treatment and these events.
The preservation of lean mass while enhancing fat loss could improve long-term metabolic outcomes and reduce the risk of muscle weakness associated with substantial weight loss. However, the safety profile of combination therapy, particularly with garetosmab, requires careful consideration for clinical application.
