Cardiometabolic Obesity Drug Program

According to the Centers for Disease Control and Prevention, 41.5% of older adults have obesity and could benefit from weight reduction medication. Up to 34.4% of people over the age of 60 with obesity in the United States have sarcopenic obesity which means they have both obesity and low muscle mass at the same time and are potentially at the greatest risk for developing critically low muscle mass when taking a currently approved GLP-1 RA.

The Company believes there is an urgent unmet need for a drug that can ameliorate the muscle wasting effects of currently approved GLP-1 RA therapies and also allow for preferential loss of fat mass during weight reduction especially in at-risk elderly patients with obesity.

Enobosarm, an oral, novel selective androgen receptor modulator, has demonstrated tissue-selective improvement in body composition with increases in lean mass and decreases in fat mass, improvement in muscle strength and physical function, has no masculinizing effects in women and has neutral prostate effects in men in previous clinical trials.

These clinical trials include two Phase 2 clinical trials in healthy older or sarcopenic subjects (168 subjects) and one Phase 2b clinical trial and two Phase 3 clinical trials in subjects with muscle wasting because of cancer (800 subjects), generating lean mass and safety data from a total of 968 patients. Based on a large safety database which includes 1,581 men and women with treatment duration for up to 3 years, enobosarm has been generally well tolerated in these clinical trials.

The Company submitted an Investigational New Drug Application in January 2024 and in February 2024, the Company received FDA safe to proceed clearance to initiate the Phase 2b, multicenter, double-blind, placebo-controlled, randomized, dose-finding QUALITY and extension maintenance clinical trial to evaluate the safety and efficacy of enobosarm 3mg, enobosarm 6mg, or placebo as a treatment to augment fat loss and to prevent muscle loss in older (≥60 years of age) patients with obesity receiving semaglutide (Wegovy®). The primary endpoint was change from baseline in total lean body mass, and the key secondary endpoints are percent change from baseline in total body fat mass, total body weight, and physical function as measured by stair climb test at 16 weeks. In August 2024, the Company completed enrollment of 168 subjects in 14 clinical sites in the U.S. The purpose of the Phase 2b QUALITY clinical trial is to select the optimal dose of enobosarm in combination with semaglutide (Wegovy®) that best preserves muscle and reduces fat after 16 weeks of treatment. In January 2025, the Company announced positive efficacy results for its Phase 2b QUALITY clinical study, in May 2025, the Company announced positive safety results, and in June 2025, the Company announced positive results for the maintenance extension portion of the QUALITY clinical study.

In September 2025, the Company announced a successful meeting with FDA providing regulatory clarity for the enobosarm program in obesity. The FDA now guides that incremental weight loss with enobosarm added to GLP-1 RA treatment over the GLP-1 RA treatment alone is an acceptable primary endpoint to support approval. The FDA confirmed that enobosarm 3mg is an acceptable dosage for future clinical development. Further, FDA has encouraged Veru to expand the enobosarm development program to include a younger population with obesity as younger patients could also benefit from a muscle preservation drug like enobosarm.

Based on the September 2025 FDA meeting, the Company is planning a Phase 2b PLATEAU clinical study to evaluate the effect of enobosarm 3mg versus placebo on total body weight, physical function, and safety in approximately 200 patients who have obesity and are initiating tirzepatide treatment for weight reduction. The primary efficacy endpoint of the study is the percent change from baseline in total body weight at 72 weeks. An interim analysis will be conducted at 36 weeks to assess the percent change from baseline in lean body mass and fat mass, as measured by DEXA. The key secondary endpoints are total fat mass, total lean mass, physical function (stair climb test), bone mineral density, and patient reported outcome questionnaires for physical function (SF-36 PF-10, and IWQOL-lite CT physical function).

The Phase 2b PLATEAU clinical study is designed to assess the ability of enobosarm treatment to break through the weight loss plateau observed in patients with obesity receiving tirzepatide treatment to achieve clinically meaningful incremental weight reduction and preserve muscle mass and physical function by 72 weeks. The Company expects the clinical study to begin in the first calendar quarter of 2026.

The fully enrolled Phase 2b, a multicenter, double-blind, placebo-controlled, randomized, dose-finding clinical trial designed to evaluate the safety and efficacy of enobosarm 3mg, enobosarm 6mg, or placebo as a treatment to augment fat loss and to prevent muscle loss in older patients (≥60 years of age) receiving semaglutide (Wegovy®) for chronic weight management. 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, participants continued into a Phase 2b extension study where all patients discontinued semaglutide treatment, but continued receiving placebo, enobosarm 3mg, or enobosarm 6mg as monotherapy in a blinded fashion for 12 weeks.

The Phase 2b QUALITY study is the first human study to report the effects of a muscle preservation drug candidate 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 trial met its prespecified primary endpoint with a statistically significant and a clinically meaningful benefit in all patients receiving enobosarm + semaglutide versus placebo + semaglutide at 16 weeks in total lean mass (71% relative reduction in lean mass loss, p=0.002). Notably, the enobosarm 3mg + semaglutide was the best dose with a 99.1% mean relative reduction in loss of lean mass (p <0.001). The enobosarm 6mg + semaglutide dose did not provide any additional benefit over the 3mg dose in preserving lean mass.

Enobosarm + semaglutide treatment resulted in dose dependent greater loss of fat mass compared to placebo + semaglutide with the enobosarm 6mg dose having a 46% greater relative loss of fat mass compared to placebo + semaglutide group at 16 weeks (p=0.017).

Although mean weight loss by DXA was similar in the enobosarm + semaglutide groups compared to semaglutide alone at 16 weeks, the composition of total weight loss shifted toward greater and more selective fat loss with enobosarm treatment:

• In the placebo + semaglutide group, the median percentage of total body weight loss due to lean mass was 34%, and estimated fat loss was 66%.
• In the enobosarm 3mg + semaglutide group, the median percentage of total body weight loss due to lean mass was 0%, and estimated fat loss was 100%.

The Stair Climb Test is used to measure physical function and is an activity of daily living that measures functional muscle strength, balance and agility. Decline in Stair Climb Test performance in older adults is predictive of increased risk for mobility disabilities, gait difficulties, falls, bone fractures, hospitalizations, and mortality. As a reference point, stair climb power declines by -1.38% per year with aging according to Van Roie E, et al. PLOS ONE.14:e0210653, 2019.

A responder analysis was conducted using a greater than 10% decline in stair climb power at 16 weeks as the cutoff, which corresponds to approximately 7.5 years’ worth of stair climb power loss due to natural aging.

In the placebo + semaglutide group, 43.8% of patients experienced at least a 10% decline in stair climb power at 16 weeks.
In the enobosarm 3mg + semaglutide group, only 17.6% of patients had at least a 10% decline in stair climb power at 16 weeks, representing a 59.8% relative reduction of patients with a ≥10% decline in power compared to the placebo + semaglutide group (p=0.006).
In the enobosarm 6mg + semaglutide group, only 24.5% of patients had at least a 10% decline in stair climb power at 16 weeks, representing a 44.1% relative reduction of patients with a ≥10% decline on power compared to the placebo + semaglutide group (p=0.051).

After completing the efficacy dose-finding portion of the Phase 2b QUALITY clinical trial, 148 participants continued to the Phase 2b Maintenance Extension study, a double-blind study, where all patients discontinued semaglutide treatment, but continued receiving placebo, enobosarm 3mg, or enobosarm 6mg as monotherapy for 12 weeks.

Enobosarm reduced the weight regained after discontinuation of semaglutide (Table 1)

At the end of the Phase 2b QUALITY study active weight loss period of 16 weeks, body weight loss was similar across treatment groups with the semaglutide + placebo group losing an average of 11.88 lbs. After the 12-week Maintenance and Extension study period (Day 112 to Day 196) where all treatment groups discontinued semaglutide, the placebo monotherapy group regained 43% of body weight that was previously lost during Phase 2b QUALITY for a mean percent change of 2.57% (5.06 lbs) in body weight, compared to 1.41% (2.73 lbs) for the 3mg enobosarm group (p=0.038) and 2.87% (5.29lbs) for the 6mg enobosarm group. The 3mg enobosarm monotherapy significantly reduced the body weight regained by 46%. On average, the placebo monotherapy group gained 2.27% in fat mass, while the enobosarm monotherapy cohorts had a loss of fat mass of -0.27% for the 3mg and -0.50% for the 6mg doses. The mean tissue composition of body weight regained was 28% fat and 72% lean mass in the placebo group, versus 0% fat and 100% lean mass in both the 3mg and the 6mg enobosarm groups.

The enobosarm plus semaglutide followed by enobosarm monotherapy regimen was more effective in preserving lean mass and causing and maintaining greater loss of fat by the end of the study (Table 2)

By the end of the study at 30 weeks (Day 1 to Day 196), the placebo plus semaglutide followed by placebo monotherapy group experienced a loss of lean mass, while both enobosarm plus semaglutide followed by enobosarm monotherapy groups (3 mg and 6 mg doses) significantly preserved more than 100% of lean mass (enobosarm 3mg p<0.001 and enobosarm 6mg p=0.004). The enobosarm plus semaglutide followed by enobosarm monotherapy patients had a 58% greater loss of fat with enobosarm 3mg (p=0.085) and a 93% greater loss of fat with enobosarm 6mg (p=0.008) compared to placebo plus semaglutide followed by placebo monotherapy.

The Phase 2b QUALITY and Maintenance Extension clinical trial confirms that preserving lean mass with enobosarm plus semaglutide led to greater fat loss during the active weight loss period, and after semaglutide was discontinued, enobosarm monotherapy significantly prevented the regain of both weight and fat mass during the maintenance period such that by end of study there was greater loss of fat mass while preserving lean mass for a higher quality weight reduction compared to the placebo group.

Detail of these topline efficacy results are provided in Table 1 and Table 2 below:

*Analysis of Covariance (ANCOVA)
**Mixed Model for Repeated Measures (MMRM)
***Total weight (mass) regain that is due to lean mass (change in kg) or fat mass (change in kg)

**Mixed Model for Repeated Measures (MMRM)

Adverse events (AEs) and adverse events of special Interest (Table 3 below)

In the double-blind Phase 2b QUALITY Maintenance Extension clinical trial (Day 112-196), enobosarm monotherapy had a positive safety profile. After discontinuation of semaglutide, there were essentially no gastrointestinal side effects, no evidence of drug induced liver injury (by Hy’s law), and no increases in obstructive sleep apnea observed at any dose of enobosarm compared to placebo monotherapy. There were no AEs of increases in prostate specific antigen in men. There were no AEs related to masculinization in women. There were no reports of suicidal ideation observed (Columbia-Suicide Severity Rating Scale). The enobosarm 3mg dose continued to have a positive safety profile in the Phase 2b maintenance extension clinical trial.

¹Adverse events (at least 4 subjects in any dose group) and adverse events of special interest from Day 112 to Day 196.
²All graded as mild in severity, all returned to or toward baseline/upper limit of normal, no associated increases in alkaline phosphatase or total bilirubin.
³Glomerular filtration rate is an estimated value using the CKD-EPI creatinine 2021 calculation that inputs serum creatinine level. Note that serum creatinine levels are known to increase with greater muscle mass.

¹Adverse events (at least 4 subjects in any dose group) from Day 1 to Day 112.
²Graded as mild in severity, levels returned to below baseline while on drug, no associated increase in alkaline phosphatase or total bilirubin.
³All graded as mild in severity, all returned to or toward baseline/upper limit of normal, no associated increases in alkaline phosphatase or total bilirubin.

¹Adverse events (at least 4 subjects in any dose group) and adverse events of special interest from Day 112 to Day 196.
²All graded as mild in severity, all returned to or toward baseline/upper limit of normal, no associated increases in alkaline phosphatase or total bilirubin.
³Glomerular filtration rate is an estimated value using the CKD-EPI creatinine 2021 calculation that inputs serum creatinine level. Note that serum creatinine levels are known to increase with greater muscle mass.

In August 2025, the Company announced selection of a novel modified release oral formulation for enobosarm, a selective androgen receptor modulator, for chronic weight loss management, following confirmation of pharmacokinetic endpoints in a clinical study. The single dose, open label pilot study evaluated the plasma concentration versus time profile of a proprietary, patentable modified release formulation of enobosarm 3mg. The new formulation demonstrated the intended distinct target product release profile, which includes a reduction in maximum plasma concentration (Cmax), a delayed time to maximum plasma concentration (Tmax), a distinct secondary peak plasma concentration, and similar extent of absorption (AUC) compared to historical values for enobosarm immediate release capsules. The novel modified release oral formulation of enobosarm was developed in collaboration with Laxxon Medical using smart delivery systems, including the Company’s proprietary patented SPID®-Technology to create advanced, unique oral delivery release profiles, as well as an innovative additive manufacturing process.

In the US, 42% of older adults (> 60 years of age) have obesity (CDC) and 34% of these patients also have sarcopenia, or low muscle reserve. Accordingly, enobosarm is targeting at risk older patients who have obesity and who may already have low muscle mass, also known as sarcopenic obesity, and the further drop in muscle mass of all-important muscles increases risk of muscle weakness, functional limitations, mobility disability, falls, higher hospitalizations, and greater mortality. It should be emphasized that enobosarm may potentially be combined with any one of the many GLP-1 RA weight loss drugs. The combination of enobosarm with a GLP-1 receptor agonist potentially represents a multi-billion-dollar global opportunity.