Phase 2b QUALITY Trial: Enobosarm Significantly Reduces Lean Mass Loss in Patients on Semaglutide

Enobosarm demonstrated a statistically significant benefit in preserving lean mass in patients with overweight or obesity undergoing treatment with semaglutide.

Topline results from the Phase 2b QUALITY trial indicate that enobosarm, a novel oral selective androgen receptor modulator (SARM), led to a statistically significant reduction in lean mass loss in patients receiving semaglutide (WEGOVY), a GLP-1 receptor agonist, for weight reduction.

Announced by Veru Pharmaceuticals on January 27, 2025, the trial evaluated enobosarm 3 mg and 6 mg versus placebo in adults aged ≥60 years. The study met its primary endpoint, with additional positive effects on key secondary endpoints, including changes in total fat mass, body composition, and physical function.

Phase 2b QUALITY clinical trial design

The Phase 2b QUALITY clinical study was a multicenter, double-blind, placebo-controlled, randomized, dose-finding study to evaluate the safety and efficacy of enobosarm 3mg, and enobosarm 6mg, compared to placebo in 168 older patients, greater than 60 years of age, who are overweight or have obesity and who are receiving WEGOVY (semaglutide), a GLP-1 receptor agonist (RA), for weight reduction. The primary endpoint was the change in total lean body mass from baseline to 16 weeks, and key secondary endpoints were the change from baseline to 16 weeks in total fat mass, total body weight, and physical function as measured by a stair climb test.

Topline results for the Phase 2b QUALITY clinical study:

*Standard Deviation, **ANCOVA model, least square means analysis using gender and BMI at baseline as covariates, ‡ Fisher’s exact test

• The Phase 2b QUALITY study is the first human study to report the effects of a muscle preservation agent on body composition in older patients who have obesity or are overweight and receiving a GLP-1 receptor agonist.

• In the topline efficacy analysis, the Phase 2b QUALITY clinical study met its primary endpoint with a statistically significant benefit in preservation of total lean body mass in all patients receiving enobosarm + semaglutide versus placebo + semaglutide at 16 weeks.

• Secondary endpoints showed:

⋅ Enobosarm + semaglutide treatment resulted in a greater reduction in total fat mass compared to placebo + semaglutide at 16 weeks.

⋅ There appears to be minor differences in total body weight changes between the enobosarm + semaglutide group and placebo + semaglutide group at 16 weeks. Therefore, enobosarm + semaglutide improved changes in body composition and resulted in more selective and greater loss of fat mass than in subjects receiving placebo + semaglutide.

⋅ The proportion of subjects that lost ≥10% stair climb power was statistically significant and clinically meaningfully reduced in the enobosarm + semaglutide groups compared to placebo + semaglutide group. Therefore, enobosarm reduced the proportion of patients that lost clinically significant physical function versus subjects receiving semaglutide alone.

The Company plans to present the full clinical efficacy and safety data set for the Phase 2b QUALITY clinical study in future scientific conferences and publications after the Phase 2b extension portion of study is completed and unblinded.

Dr. Louis Aronne, an obesity expert, past president of the Obesity Society and a scientific advisor and consultant to Veru, who was not directly involved in the QUALITY study stated: “These topline clinical results are very exciting. 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. This is the first clinical study to demonstrate prevention of both lean mass loss and decline in muscle function associated with weight loss in older individuals treated with a GLP-1 RA. This combined treatment approach could benefit patients with obesity and low amounts of muscle due to age-related muscle loss.”

“Given the promising topline results from the Phase 2b QUALITY clinical trial where enobosarm treatment preserved lean mass, increased fat loss, improved body composition changes, and prevented decline in stair climb physical function in patients receiving WEGOVY (semaglutide), we plan to meet with FDA to discuss the design of the Phase 3 clinical program,” said Mitchell Steiner, M.D., Chairman, President, and Chief Executive Officer of Veru. “The Phase 2b QUALITY study is the first human study to demonstrate that older patients who are overweight or have obesity and receiving only a WEGOVY (semaglutide) GLP-1 RA are at higher risk for accelerated frailty and functional decline. Lean mass loss in the semaglutide group that did not receive enobosarm was significant as 32% of the total weight loss at 16 weeks was made up of lean mass. Loss of lean mass also matters as 42.6% of patients on placebo + semaglutide had at least a 10% decline in stair climb power. The potential for further reduction in physical function because of ongoing loss of lean mass with chronic GLP-1 RA therapy is worrisome and must be evaluated. The expectation is that all GLP-1 RA containing drugs could cause significant loss of lean mass in older patients raising concerns for potential declines in physical function, mobility disability, functional limitations, and loss of balance with a higher risk for falls and fractures.”

“Older patients who have obesity or who are overweight and are receiving a GLP-1 RA are an ideal target population that have demonstrated in the Phase 2b QUALITY clinical study clinical benefit with enobosarm treatment to provide a greater quality weight loss as lean mass and physical function may be preserved with greater and selective loss of adiposity, that is, better body composition weight reduction may be possible. Further, the expectation is that when patients are treated longer with enobosarm, which results in greater loss of adiposity, there would also be a profoundly greater weight reduction than with semaglutide alone,” said Gary Barnette Ph.D., Chief Scientific Officer, Veru Inc.

Safety

Safety data remains blinded in the ongoing clinical study and the unblinded safety set will be available when the Phase 2b extension study is done in April 2025. However, the aggregate, blinded data, have not shown significant differences compared to different previous studies of enobosarm. The Independent Data Monitoring Committee also met in October 2024 and evaluated the unblinded safety data with a recommendation to continue the study as planned. As a reminder, enobosarm has a large safety database, which includes 27 clinical trials involving 1581 mostly older men and women, some of which included patients dosed for up to 3 years. In this large safety database, enobosarm was generally well tolerated with no increases in gastrointestinal side effects. This is important as there are already significant and frequent gastrointestinal side effects with a GLP-1 RA treatment alone.

Next regulatory steps

As a reminder, the Phase 2b extension clinical trial where all patients will stop receiving a GLP-1 RA, but will continue taking placebo, enobosarm 3mg, or enobosarm 6mg for an additional 12 weeks is ongoing. The blinded Phase 2b extension clinical trial is asking a different question than the Phase 2b QUALITY clinical study which evaluated the ability of enobosarm to improve body composition changes associated with GLP-1 RA weight loss induction. The Phase 2b extension study will evaluate maintenance of weight loss, meaning whether enobosarm can maintain muscle and prevent the fat and weight gain that occurs after discontinuing a GLP-1 RA. If successful, this would provide another important obesity related indication for which enobosarm could be considered. The topline results for the separate blinded Phase 2b extension clinical study are expected in April of 2025.

As the Phase 2b QUALITY study has positive topline clinical results, we are planning to move forward to request an end of Phase 2 meeting with FDA. In the new weight reduction FDA guidance, FDA makes a regulatory path distinction between weight reduction drugs and drugs for body composition changes. FDA states that: “Sponsors seeking an efficacy claim related to changes in body composition would need to consult with FDA early in development to align on the clinical condition being treated. Trial design, including appropriate choice of population and selection of endpoints that measure how a patient feels, functions, or survives, to potentially support such a claim is beyond the scope of this weight reduction guidance.” Based on this updated FDA guidance, enobosarm is being developed as a body composition drug to selectively preserve lean body mass and physical function, and augment loss of fat in older patients who are overweight or have obesity receiving GLP-1 RA containing drug for chronic weight management. We have previously met with FDA to discuss our regulatory path forward as an improvement in body composition drug, and FDA has provided general advice on Phase 3 design.

Anticipated Phase 3 Trial Design

Based on the Phase 2b QUALITY clinical trial, the proposed Phase 3 clinical trial design is currently expected to be a double-blind, placebo-controlled study in older (> 60 years of age), patients who have obesity or who are overweight and who are eligible for treatment with GLP-1 RA. The GLP-1 RA may be either WEGOVY (semaglutide) and/or Zepbound® (tirzepatide). Patients will be randomized to oral daily enobosarm or matching placebo. All subjects will start and receive GLP-1 RA during the study.

The proposed primary objective will be the effect of enobosarm on stair climb power, as measured by the proportion of subjects that lose ≥10% stair climb power from baseline. Proposed key secondary objectives will be to assess the effect of enobosarm on total lean mass, total body weight, total fat mass, bone mineral density, HOMA-IR, and hemoglobin A1c.

The duration of treatment is expected to be 52 weeks which will allow us to also capture the benefits of enobosarm improvements on body composition for greater loss of adiposity and weight reduction. Based on the responder rates of the stair climb power observed in this Phase 2b clinical study, the predicted trial sample size is expected to be approximately 470 total subjects with a 90% power and an alpha of 0.05.

About the Enobosarm Phase 2b QUALITY clinical trial

The fully enrolled Phase 2b, multicenter, double-blind, placebo-controlled, randomized, dose-finding QUALITY clinical trial evaluated the safety and efficacy of enobosarm 3mg, enobosarm 6mg, or placebo as a treatment to preserve muscle and augment fat loss in 168 patients with sarcopenic obesity or overweight elderly (>60 years of age) patients receiving semaglutide (Wegovy®). The primary endpoint was total lean body mass, and the key secondary endpoints were total body fat mass and physical function as measured by stair climb test at 16 weeks. After completing the efficacy dose-finding portion of the Phase 2b QUALITY clinical trial, it is expected that participants will then continue in blinded fashion into a Phase 2b extension clinical trial where all patients will stop receiving a GLP-1 RA, but will continue taking placebo, enobosarm 3mg, or enobosarm 6mg for an additional 12 weeks. The Phase 2b extension clinical trial will evaluate whether enobosarm can maintain muscle and prevent the fat and weight gain that occurs after discontinuing a GLP-1 RA. The top-line results of the separate blinded Phase 2b extension clinical study are expected in the second calendar quarter of 2025.

About Sarcopenic Obesity

The clinical condition to improve body composition by preserving muscle and enhancing the loss of adiposity. We believe the market for this condition is quite large. Based on Medicare statistics, 22% of the US population is over 60 years of age, and according to the CDC, 42% of older adults have obesity in the United States and could benefit from a weight loss medication. Up to 34 % of obese patients over the age of 60 have sarcopenic obesity, sarcopenia being age-related loss of muscle. This large subpopulation of sarcopenic obese patients is especially at risk when taking GLP-1 drugs for weight reduction as they may already have critically low amounts of muscle due to age-related muscle loss. Because of the magnitude and the speed of muscle loss while on GLP-1 RA therapy for weight loss, GLP-1 RA drugs may accelerate the development of frailty and muscle weakness in obese or overweight elderly patients.

Muscle weakness may lead to poor balance, decreased gait speed, mobility disability, functional limitations, loss of independence, and higher risk for falls and fractures. In fact, the safety section of the package insert for Wegovy has been updated based on the recently reported SELECT cardiovascular outcomes clinical trial which now highlights a 400% increase in pelvic and hip fractures that was observed in patients greater than 75 years of age receiving Wegovy compared to placebo (2.4% versus 0.6%). Fractures of the hip and pelvis typically occur because of falls which increase with decreased muscle mass.

About Enobosarm

Enobosarm (aka ostarine, MK-2866, GTx-024, and VERU-024), a novel oral daily selective androgen receptor modulator (SARM), has been previously studied in 5 clinical studies involving 968 older normal men and postmenopausal women as well as older patients who have muscle wasting because of advanced cancer. Advanced cancer causes the loss of appetite where there is significant unintentional loss or wasting of both muscle and fat mass which is similar to what is observed with in patients taking GLP-1 RA drugs. We believe the totality of the clinical data from these previous five clinical trials demonstrates that enobosarm treatment leads to dose-dependent increases in muscle mass with improvements in physical function as well as significant dose-dependent reductions in fat mass. The patient data generated from these five enobosarm clinical trials in both elderly patients and in patients with a cancer induced appetite suppression provide strong clinical rationale for enobosarm. The expectation is that enobosarm in combination with a GLP-1 RA would potentially augment the fat reduction and total weight loss while preserving muscle mass.

Enobosarm has a large safety database, which includes 27 clinical trials involving 1581 men and women, some of which included patients dosed for up to 3 years. In this large safety database, enobosarm was generally well tolerated with no increases in gastrointestinal side effects. This is important as there are already significant and frequent gastrointestinal side effects with a GLP-1 RA treatment alone.