Introduction
The escalating prevalence of obesity has triggered a surge in associated health complications, including diabetes, cardiovascular issues, liver and kidney diseases. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a significant therapeutic avenue, primarily curbing caloric intake through appetite suppression. However, the marked weight loss observed with GLP-1 RA treatment, along with other appetite-suppressing interventions like bariatric surgery, raises concerns about the composition of the weight being lost.
Notably, GLP-1 RA-induced weight loss can comprise up to 40% lean mass. Furthermore, treatment adherence beyond a year is observed in fewer than 30% of patients, with treatment discontinuation often leading to rapid weight regain, primarily in the form of fat mass. This cycle of muscle loss followed by fat regain can result in unfavorable body composition changes in individuals with obesity, potentially exacerbating metabolic and health concerns. Therefore, combining lean mass-preserving strategies with appetite-suppressing weight-loss therapies could yield substantial benefits.
The Science Behind Muscle Loss and Potential Solutions
Muscle loss during caloric restriction is thought to stem from evolutionary mechanisms designed to conserve energy during periods of food scarcity, as muscle is a significant energy consumer. Research has elucidated mechanisms governing muscle size in adults, with the activation of type II activin receptors (ActRIIA/B) in muscle being a key target. Blocking these receptors has demonstrated significant muscle growth in both animals and humans. However, given that ActRIIA/B receptors mediate various biological processes by responding to numerous ligands, chronic, long-term blockade of these receptors raises potential safety concerns.
Growth differentiation factor-8 (GDF8, also known as myostatin) and activin A (ActA) have been identified as the major ligands mediating the muscle-minimization actions of ActRIIA/B receptors. Regeneron has developed fully human antibodies to specifically block GDF8 (trevogrumab) and ActA (garetosmab). Studies have indicated that combining these blocking antibodies results in greater muscle growth than either antibody alone, matching the muscle growth induced by broader ActRIIA/B pathway blockade. Dual blockade of GDF8 and ActA, therefore, presents a more targeted approach to counteract the ActRIIA/B muscle minimization pathway.
Preclinical Evidence: Preserving Lean Mass with GDF8 and ActA Blockade
Preclinical studies have explored whether GDF8 and ActA blockade could mitigate lean mass loss associated with GLP-1 RA treatment. Results from studies in obese mice and non-human primates (NHPs) suggest that dual blockade with fully human GDF8 and ActA blocking antibodies during GLP-1 RA treatment preserves lean mass, enhances fat loss, and improves metabolic measures. These findings suggest that GDF8 and ActA are crucial regulators of muscle loss during caloric restriction and that blocking these negative regulators during obesity treatment with GLP-1 RAs could offer significant benefits.
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Studies in Obese Mice
To assess whether dual blockade of GDF8 and ActA could attenuate lean mass loss during GLP-1 RA-induced weight loss, researchers tested a combination of antibodies in diet-induced obese (DIO) mice during treatment with semaglutide, a GLP-1 RA approved for obesity and diabetes treatment. The fully human antibodies used are fully active against the highly conserved mouse orthologs of both GDF8 and ActA, and semaglutide also retains full activity in mice.
Obese mice were generated by placing 6-7 week old mice on a 60% high-fat diet for 27 weeks. After 27 weeks, baseline body composition was measured by quantitative NMR (qNMR), and mice were sorted into four groups based on total body fat. The mice were then subjected to 4 weeks of (1) control treatment, (vehicle); (2) semaglutide treatment, (Sema); (3) GDF8 and ActA blocking antibodies on their own (α-MSTN/α-ActA); and (4) a combination of Sema with blocking antibodies to GDF8 and ActA (Sema + α-MSTN/α-ActA); body weights and body composition were assessed throughout the study.
The semaglutide (Sema) and the Sema + α-MSTN/α-ActA groups both exhibited significant and similar reductions in body weight compared to the control group over the 28-day treatment period. The α-MSTN/α-ActA group showed only a modest numerical and non-significant body weight decrease from the control group. Despite the similar decreases in body weight, the Sema group showed significant lean mass loss compared to the control group during the 4-week treatment period, while the Sema + α-MSTN/α-ActA group was not only protected against this lean mass loss but also had a significant increase in lean mass. The α-MSTN/α-ActA group also had significant increases in lean mass.
Importantly, the Sema + α-MSTN/α-ActA group - which had similar body weight reduction but increased lean mass compared to Sema alone - also had markedly greater losses in fat mass, almost twice that seen with Sema alone. These data indicate that semaglutide alone results in weight reduction involving both fat and lean mass loss, while adding α-MSTN/α-ActA to semaglutide results in similar weight reduction but with profoundly beneficial effects on body composition - not only by preserving/increasing lean mass but also by markedly increasing fat loss. Despite having minimal effects on body weight, treatment with α-MSTN/α-ActA alone also showed beneficial shifts in the lean/fat body composition in obese mice.
Obesity in mice is associated with detrimental effects in the liver, including increases in liver fat and triglycerides. While all three treated groups had benefits as assessed by looking at liver fat area and triglycerides, the Sema + α-MSTN/α-ActA combination (which had the largest decreases in overall body fat composition) also had the largest benefits in terms of these liver measures.
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The above study was repeated with the same treatments in obese mice to independently confirm and extend these observations. The repeated study (1) confirmed similar effects of the various treatments on body weight, (2) confirmed that the semaglutide treatment groups (with and without concomitant α-MSTN/α-ActA) involved similar decreases in caloric intake, and (3) confirmed the above qNMR assessments of the changes in lean and fat mass.
Studies in Obese Primates
To determine whether the findings in obese mice would translate to obese primates, a 20-week study was conducted in obese cynomolgus monkeys fed a high-fat, high-fructose diet. The primary endpoints for this study were change in body weight and body composition (assessed by dual x-ray absorptiometry [DXA] scanning for total mass, fat mass, and lean mass), and food intake, glycated hemoglobin (HbA1c%), and lipid profiles were also assessed.
Semaglutide was dosed for the full period, while antibody dosing with the α-MSTN and α-ActA antibodies was started in Week 2 as an add-on to semaglutide and dosed through Week 12 (and was presumed to have more durable actions due to the extended half-life of the antibodies). Animals who did not receive semaglutide or antibodies received a corresponding vehicle injection on the same day as the dosed animals throughout the study.
During the run-in period, both arms initially treated with semaglutide only for 2 weeks (Sema; Sema+α-MSTN+α-ActA) showed similar reductions in their body weight, food intake, and total, fat, and lean mass compared to the vehicle-treated arms (Vehicle; Vehicle+α-MSTN+α-ActA). Shortly after adding the antibody treatments at the 2-week timepoint, the two semaglutide arms continued to parallel each other in terms of body weight and total mass but began to diverge in terms of fat and lean mass. The Sema + α-MSTN + α-ActA arm began to show progressively greater fat loss than the Sema arm and progressively greater increases in lean mass. In the absence of Sema, the α-MSTN + α-ActA arm had modest increases in body weight and food intake, accompanied by modest decreases in fat mass and the largest increase in lean mass. Directionally, these findings in obese monkeys reflected the above observations in obese mice.
In terms of metabolic parameters, all the treated arms had beneficial changes in their HbA1c%, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels, with the Sema+α-MSTN+α-ActA arm, which showed the largest combination of fat decrease and lean mass increase, showing the biggest beneficial changes.
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Regeneron's COURAGE Trial: Investigating Semaglutide, Trevogrumab, and Garetosmab Combinations in Humans
Regeneron is actively exploring novel therapeutic approaches for obesity, including unimolecular solutions targeting multiple pathways responsible for weight loss and clinical trials combining GLP-1 therapy with muscle-preserving antibodies.
The Phase 2 COURAGE trial is investigating combinations of semaglutide, trevogrumab (anti-GDF8/anti-myostatin), with or without garetosmab (anti-activin A), for obesity treatment. The 26-week results confirmed that 33% of weight loss induced by semaglutide was due to loss of lean mass and that adding trevogrumab could prevent about half of this lean mass loss.
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.
Key Findings from the COURAGE Trial
Interim results demonstrated that approximately 35% of semaglutide-induced weight loss was due to loss of lean mass. Combining semaglutide with trevogrumab, with or without garetosmab, helped preserve lean mass while increasing loss of fat mass.
Specifically, results from approximately 50% of participants after 26 weeks showed 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 and Tolerability
The combination of semaglutide with trevogrumab was generally well-tolerated. Adverse events that occurred in ≥5% of participants in any treatment group included muscle spasms, nausea, constipation, fatigue, diarrhea, headache, vomiting, gastroesophageal reflux disease, upper respiratory tract infection, nasopharyngitis, UTI, influenza, and COVID-19. However, the triplet combination of semaglutide with both antibodies had a substantially higher rate of discontinuations due to tolerability issues and other adverse events. 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; however, Regeneron has not identified a causal association between treatment and these events.
Implications and Future Directions
The COURAGE trial results suggest a potential advancement in obesity treatment by combining semaglutide with trevogrumab to preserve lean mass and enhance fat loss. The company believes that the combination demonstrated an even greater fat mass reduction and more substantial lean mass preservation when used as a triplet with garetosmab.
Regeneron plans to make the full data set available to provide further insights to help optimize the dosing regimens in future trials.
Discussion
GLP-1 RAs are effective anti-obesity medications (AOMs), but they raise concerns due to the potential loss of lean mass, particularly muscle, and the rapid weight regain as fat after treatment discontinuation. The initial treatment with GLP-1 RAs can result in negative effects on body composition, while treatment interruptions and treatment cycling can further exacerbate this problem. Decreasing muscle in individuals with obesity may have profoundly negative metabolic consequences and exacerbate many obesity-related health conditions. While moderate exercise can lead to healthier weight loss with GLP1-RAs, patient adherence can be challenging. Widespread use of GLP-1 RAs may result in widespread public health concerns, particularly in individuals with obesity and low lean muscle mass (OLLMM) and the elderly.
Regeneron's research and clinical trials aim to address the limitations of GLP-1 RAs by developing therapies that preserve muscle mass during weight loss, increase fat loss, and improve overall metabolic health.