Enobosarm Preserves Lean Body Mass in Older Adults Treated with Semaglutide for Weight Reduction: Topline Phase 2b Data

Topline results from the Phase 2b QUALITY clinical trial suggest that enobosarm, a selective androgen receptor modulator (SARM), may significantly reduce loss of lean body mass in adults aged 60 years and older with overweight or obesity who are receiving semaglutide (Wegovy; Novo Nordisk) for weight reduction.

The study demonstrated that participants in the semaglutide plus enobosarm-treated group lost 71% less lean mass, and 27% more fat mass compared to those on semaglutide plus placebo, satisfying the key primary endpoint (P =.002), according to a news release from enobosarm developer Veru.1 In addition, 32% of total weight loss in the placebo group was attributed to lean mass reduction, compared to only 9.4% in the enobosarm group.

QUALITY is the first human study to report the effects of a muscle preservation agent on body composition in older adults being treated with a glucagon-like peptide-1 receptor agonist (G:P-1 RA) for obesity, Veru indicated.

The problem, which has been shown to be an effect associated with the GLP-1 RA class, is not insignificant with studies suggesting that muscle loss can range from 25% to 39% of the total weight lost over 36–72 weeks.2 It is thought that the effect is related and proportional to the amount of weight loss and not to an action of the drugs, but is is concerning. In context, on an annual basis, the decline in muscle mass with GLP-1 RAs is several times greater than what would be expected from age-related muscle loss, according to data published in Lancet Diabetes and Endocrinology.2

“Weight loss through any modality produces a loss of both lean and fat mass. The greater magnitude of weight loss seen with bariatric surgery and GLP-1 RA based drugs has produced an unmet medical need to preserve muscle and physical function in older patients receiving these treatments,” Louis Aronne, MD, Sanford I. Weill Professor of Metabolic Research, Medicine , Weill Cornell Medical College, in New York, said in the news release.1 The need for muscle preservation is even more important with age, Aronne added, noting that the “combined treatment approach could benefit patients with obesity and low amounts of muscle due to age-related muscle loss.” Aronne, a scientific advisor to Veru, was not involved in the current study.1

The randomized, double-blind, placebo-controlled dose-finding trial enrolled 168 participants to evaluate the efficacy and safety of 2 doses of enobosarm (3 mg and 6 mg) versus placebo. Over 16 weeks, changes in body composition were assessed, including lean body mass (key primary endpoint), total fat mass, total body weight, and physical function via stair-climb tests (key secondary endpoints).1

Key Findings

• Lean mass preservation: Participants on enobosarm plus semaglutide experienced a mean lean mass reduction of -1.2% (±5.15%), compared to -4.1% (±4.80%) in the semaglutide plus placebo group.
• Fat loss: The enobosarm group achieved greater fat mass loss (-10.9% ± 8.07%) than the placebo group (-8.6% ± 6.26%), though this secondary endpoint did not reach statistical significance (P =.096).
• Physical function: The proportion of participants with a 10% or greater decline in stair-climb power was significantly lower in the enobosarm group (19.4%) compared to the placebo group (42.6%; P =.005).
• Total weight loss: Total body weight changes were comparable between groups, with patients on enobosarm losing a mean of -4.4 kg, slightly less than the -4.7 kg seen in the placebo group.

The findings, Veru suggested, highlight the potential for enobosarm to improve overall body composition by selectively preserving muscle while enhancing fat loss, addressing a critical unmet need in older patients undergoing weight reduction therapy with GLP-1 receptor agonists.1

While the safety data will remain blinded until the April 2025 conclusion of the phase 2b study, the aggregate blinded data have shown no differences in safety compared with previous studies of enobosarm. The SARM has been studied in trials with more than 1500 older individuals with favorable overall tolerability and no increases in gastrointestinal side effects.

“The QUALITY study results are a significant step forward in demonstrating enobosarm’s ability to preserve muscle and physical function in older patients. These findings could lead to improved outcomes for a population vulnerable to accelerated frailty during weight loss therapy,” Mitchell Steiner, MD, chair, president, and CEO of Veru, commented.1

Veru plans to meet with the FDA to discuss phase 3 trial design, focusing on the ability of enobosarm to preserve lean mass and physical function. The proposed trial will enroll older patients with obesity or overweight who are eligible for GLP-1 receptor agonist therapy, such as semaglutide or tirzepatide.1

Veru announces positive topline data from phase 2b QUALITY clinical study: enobosarm preserved lean mass in patients receiving Wegovy (semaglutide) for weight reduction. News release. Veru. January 27, 2025. Accessed January 27, 2025. https://ir.verupharma.com/news-events/press-releases/detail/225/veru-announces-positive-topline-data-from-phase-2b-quality

Pradoa CM, Phillips SM, Gonzales MC, Heymsfield SB. Muscle matters: the effects of medically induced weight loss on skeletal muscle. Lancet Diabetes Endocrinol. 2024;12(11):785-787. https://www.thelancet.com/journals/landia/article/PIIS2213-8587(24)00272-9/abstract#