As weight loss drugs boom in popularity, some companies are focusing their sights on therapies for muscle loss prevention, a common side effect of weight loss treatments.
In recent years, blockbuster glucagon-like peptide 1 receptor agonist (GLP-1RA) therapies like Eli Lilly’s Zepbound (tirzepatide) and Novo Nordisk’s Wegovy (semaglutide), which are approved for weight management, have been shown to cause a loss of lean muscle mass in patients. This has raised concerns for some. As per a 2025 systematic review, treatment with GLP-1RAs led to an approximately 25% loss in lean body mass.
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Companies like Eli Lilly, Regeneron Pharmaceuticals, and Scholar Rock are attempting to prevent this muscle loss through the therapeutic inhibition of myostatin using antibodies and other methods.
Myostatin is a part of the TGFβ superfamily of growth factors and is responsible for preventing muscle growth. While myostatin therapies have previously been studied for musculoskeletal disorders like spinal muscular atrophy (SMA), GlobalData reports that there are at least six anti-myostatin therapies in clinical development for weight loss and diabetes-related indications.
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Myostatin inhibition is a very safe mechanism for weight loss and muscle preservation, and patients typically have no adverse effects, says Dr. Martin Brenner, the CEO at iBio. The company did not want to compete with Eli Lilly or Novo Nordisk, so it is developing muscle loss prevention therapies for when patients stop using GLP-1RAs, he adds. The San Diego-based biotech has plans to take its myostatin inhibitor lead candidate, IBIO-600, to a Phase I study in early 2026, adds the CEO.
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By GlobalDataThe development of therapies to prevent muscle loss is “a very controversial point,” says Dr. Morris Birnbaum, the associate director for the University of Pennsylvania’s Institute for Diabetes, Obesity and Metabolism. In GLP-1RA treatment, loss of lean mass is expected alongside fat loss, but most clinicians view this as a symptom of patients’ lesser food intakes rather than a mechanistic side effect of the drugs, says Birnbaum. Thus, it is not known if therapeutic intervention for GLP-1RA-related muscle loss is needed, says Birnbaum.
Preventing muscle loss via myostatin inhibition should help maintain weight loss outcomes and prevent frailty in older patients, says Brenner. However, Birnbaum questions the new wave of therapies for muscle loss, saying, “Is this [GLP-1 related muscle loss] a normal physiological adaptation to weight loss, or is it a treatable pathophysiology that’s going to be out there?”
Muscle loss prevention therapies may be most helpful as adjunct therapies to GLP-1 therapies rather than monotherapies, adds Birnbaum. These therapies may also be beneficial for patients who cycle on and off GLP-1RA regimens to prevent major changes in muscle mass as treatment changes, adds Birnbaum. Regulators and insurers will be most interested in seeing how improvements in lean muscle mass lead to a better quality of life, so an objective assessment of physical function will be needed while studying these therapies, says Dr. Dimitris Papamargaritis, a National Institute for Health and Care Research (NIHR) Clinical Lecturer in Diabetes and Endocrinology.
Muscle loss prevention trials
The US Food and Drug Administration (FDA) has yet to approve any anti-myostatin therapies for any therapy areas. Scholar Rock is approaching a potential approval for its anti-myostatin antibody apitegromab for SMA, with a prescription drug user fee act (PDUFA) date set on 22 September, as per a January press release.
The Cambridge, Massachusetts-based company is also investigating the therapy in the Phase II EMBRAZE study (NCT06445075) for the preservation of lean muscle mass for overweight or obese patients. In this study, patients will receive apitegromab alongside Wegovy or Zepbound. The ongoing trial investigates patients’ percent change in lean body mass as its primary endpoint, but its protocol lacks any quality-of-life (QOL) endpoints, as per the trial’s ClinicalTrials.gov entry. Whether changes in lean body mass translate to improvements in physical function and QOL is something that requires further investigation, says Papamargaritis.
Regeneron is researching its myostatin inhibitor trevogrumab as a combination therapy with Wegovy to improve the quality of weight loss for adults with obesity in the Phase II COURAGE trial (NCT06299098). The Phase II trial is assessing improvements in patients’ functionality via endpoints such as the change in physical functioning domain score of SF-36, and changes in the weight on the Quality of Life-Lite for Clinical Trials (IWQOL-Lite-CT) test, which are both based on FDA-validated clinical outcomes. This trial uses functional outcomes, so biotechs investigating muscle loss prevention therapies will likely learn a lot from the study’s design, says Brenner.
Typical quality of life (QoL)-related tests that could be used to evaluate muscle functionality in these trials include the six-minute walk test and the hand-grip strength, says Papamargaritis. Alongside the these two endpoints, iBio is also considering a stair climb test and gait speed test for its upcoming trial, says Brenner. The company is exploring the use of smartphones to collect data from functional measures, he adds. “I think there is a lot of promise for digital endpoints you can average over time,” adds Birnbaum. These endpoints are just being developed and validated now, he says.
Pfizer is currently developing an anti-myostatin therapy for the muscle-loss-related disease cachexia, releasing positive Phase II data in September 2024. For clinical trials studying drugs to treat muscle-wasting diseases like cachexia, the FDA has prioritized proof of improved muscle function, rather than improved muscle mass, says Birnbaum.
Assessments of overall health will be useful in this space, says Papamargaritis. He lists important questions for these therapies, like, “Does it improve overall health and factors like sleep apnea, metabolic dysfunction-associated steatotic liver disease? Are the therapy’s effects independent of weight loss?”
Future prospects of myostatin inhibitors
Functional clinical endpoints may “massively” affect the uptake of muscle loss prevention therapies, says Birnbaum, stating that if there is a price premium, payers will want to see relevant outcomes.
Moreover, Birnbaum does not see GLP-1-related muscle loss as a disease, saying, “I do not think there is going to be a tremendous market.”
“I am skeptical that any drugs designed to preserve muscle mass during weight loss will produce enough clinical benefit to justify their high cost,” says Dr. Max Petersen, an assistant professor in medicine at the Washington University in St. Louis Division of Endocrinology and Metabolism in Missouri.
While several anti-myostatin therapies are being investigated for their effects on muscle loss, some companies are also exploring these drugs for their weight loss capabilities. “The weight loss we see [with myostatin inhibitors] is not close to what we’ve seen with GLP-1 therapies,” says Papamargaritis. He lists the study of Eli Lilly’s anti-myostatin drug bimagrumab as an example. In a Phase II obesity study, at Week 48, patients who took Eli Lilly’s myostatin inhibitor bimagrumab saw a 6.5% decrease in mean body weight. Comparatively, in the Phase III STEP-1 study (NCT03548935), patients who took Wegovy saw a mean change in body weight of -14.9%. Bimagrumab is a monoclonal antibody therapy in Phase II development for diabetes and weight loss treatment. Lilly is researching the therapy as a monotherapy and as a combination therapy with GLP-1RAs to reduce muscle loss.
Adverse events like muscle cramps have also been an issue with bimagrumab in the past, so this would have to be observed in future studies, adds Birnbaum.
Birnbaum suspects that the market for these therapies may be limited to patients with underlying muscle diseases like sarcopenic obesity. Sarcopenic obesity occurs when patients experience age-related skeletal muscle loss and obesity simultaneously. Improvements in QoL-related endpoints could make such therapies attractive for sarcopenic obesity patients, says Papamargaritis. Obese elderly patients are much more common than they were 20 or 30 years ago, so there is almost certainly a substantial group of elderly people in this patient group, says Birnbaum.
