Background: Enobosarm, a novel oral selective androgen receptor modulator, combined with a GLP-1 receptor agonist (RA) may prevent muscle loss, while preferentially reducing fat resulting in a higher quality weight loss. A meta-analysis was conducted of three randomized clinical studies of enobosarm involving older men, postmenopausal women, and older patients who have muscle loss due to advanced cancer. Loss of appetite occurs with advanced cancer inducing a starvation state similar to GLP-1 RA therapy. Methods: Meta-analysis was conducted of 3 randomized clinical trials evaluating enobosarm 3mg q day versus placebo and who had a Day 84 DXA scan to assess body composition: Phase 2 study in older males (>60 yo) and postmenopausal women (n=48), Phase 2 study in patients with muscle wasting because of advanced cancer (n=61), and Phase 3 study in patients with advanced lung cancer (n=258). Results: At Day 84, DXA scan showed an absolute increase in lean mass of 1.5 kg in enobosarm treated vs placebo (p=0.00004) and % change in lean mass of a 4.04 % in enobosarm vs placebo (p=0.00007). Absolute decrease in fat mass was 0.758 kg in enobosarm treated vs placebo (p=0.015) and % change in fat mass was a loss -4.04 % in enobosarm vs placebo (p=0.006). Enobosarm was generally well tolerated with no increase in gastrointestinal side effects. Conclusion: In meta-analysis of 367 older men, postmenopausal women, and older patients with muscle loss from advanced cancer, enobosarm therapy resulted in reductions in fat mass while preserving lean mass. Meta-analysis supports the potential for enobosarm when combined with a GLP-1 RA may preserve muscle, while preferentially reducing fat resulting in a higher quality weight loss in overweight and obese patients. A Phase 2b randomized controlled trial is currently underway to evaluate enobosarm in older patients receiving a GLP-1 RA for weight loss. Disclosure J. Crawford: Advisory Panel; Pfizer Inc. Research Support; Pfizer Inc., AstraZeneca, helsinn. Advisory Panel; BioAtla. Consultant; Actimed. Advisory Panel; G1 Therapeutics, Enzychem. Consultant; Faraday. Advisory Panel; Jazz. A.S. Dobs: Speaker's Bureau; Halozyme. W.J. Evans: None. C. Prado: Speaker's Bureau; Abbott Nutrition, Nestlé Health Science, Nutricia, Amra medical. Advisory Panel; Pfizer Inc. D. Rodriguez: Employee; Veru. I. Shalev: Employee; Veru. K. Barnette: None. M. Steiner: Stock/Shareholder; Veru, Inc.

Enobosarm is a novel oral selective androgen receptor modulator that has been shown to increase lean mass and decrease fat mass. There is a need for a therapy that can prevent the loss muscle mass and further increase fat loss in patients taking GLP-1 RA for weight loss, especially sarcopenic obese patients who are at-risk for developing muscle atrophy and muscle weakness leading to frailty.

Abstract Background: Targeting the androgen receptor (AR) with an oral selective AR agonist, enobosarm, is a novel approach to overcome ER and CDK4/6 inhibitor resistance to suppress AR+ER+HER2- metastatic breast cancer (mBC). Preclinical studies in CDK4/6 inhibitor and estrogen blocking agent resistant PDX mBC models demonstrated that enobosarm alone suppressed tumor growth. In a small subgroup analysis of patients with ER+HER2- mBC who progressed on estrogen blocking agent and a CDK 4/6 inhibitor from the Phase 2 802 study, enobosarm treatment resulted in a best overall response rate of 30% (2 CRs and 1 PR) and a 6-month clinical benefit rate (CBR) of 50%. Methods: The clinical activity of enobosarm 9mg alone was evaluated compared to standard of care (SOC) in the Phase 3 ARTEST, open-label, randomized, multicenter study in AR+ER+HER2-mBC who have progressed on 2 or greater lines of prior therapies, including estrogen blocking agents and CDK4/6 inhibitors. The study was discontinued for administrative reasons not related to efficacy or safety. Results: At the time study was discontinued, 34 patients with confirmed AR positivity were randomized to either enobosarm (n=16) or SOC control (n=18). SOC control treatment group received an average of 2.6 (range 1-5) and enobosarm 9mg monotherapy an average of 2.9 (range 1-5) prior lines of treatment. On average, enobosarm or the SOC control was given in the 4th line treatment for AR+ER+HER2- metastatic breast cancer. In the evaluable population, two partial responses were observed in the enobosarm treatment arm versus no responses in the SOC control arm. In patients with ≤3 lines of prior endocrine therapy, the best objective response rate (ORR) was 18.8% for enobosarm and 0% for control. In patients with ≤3 lines of prior endocrine therapy with ≤1 prior treatment with CDK 4/6 inhibitor, best ORR was 33% in the enobosarm group versus no responses in the SOC control (Table 1). CBR on day 180 was 33.3% (4/12) in the enobosarm group vs 0% (0/11) in the control group. Enobosarm treatment was well tolerated without masculinizing adverse events and no increases in hematocrit changes. Conclusions: Activity of enobosarm in this heavily pretreated patient population is encouraging and supports further clinical investigation. The Phase 3 ENABLAR-2 study is underway to further evaluate enobosarm alone or in combination with abemaciclib for the second-line treatment of AR+ER+HER2- metastatic breast cancer in patients who have received a prior estrogen blocking agent and a CDK 4/6 inhibitor. Clinical trial information: NCT04869943. Research Sponsor: Veru Inc. Table 1. Responses in patients with enobosarm versus SOC treatment. Citation Format: Kristine Rinn, Elisa Krill Jackson, Gary Barnette, Domingo Rodriguez, Itay Shalev, Mitchell Steiner, Joyce O'Shaughnessy, Hope Rugo, Adam Brufsky. Clinical Results of Subjects Remaining in the Phase 3 ARTEST Study Enobosarm Therapy in AR+ER+HER2- Metastatic Breast Cancer with 3 or Greater Prior Lines of Therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-27-03.

Background: Enobosarm is a novel oral selective androgen receptor modulator shown to increase lean mass and decrease fat mass. Enobosarm may benefit patients on GLP-1 RA for weight loss by preserving muscle while augmenting fat loss. A pooled analysis was conducted from 4 randomized clinical trials (RCT) to evaluate the safety profile of enobosarm. Methods: The pooled safety analysis of enobosarm (3mg) included: Ph2 study in older males (>60 yo) and postmenopausal women (n=48), two Ph3 studies in patients with advanced lung cancer (n=651), and a Ph2 stress urinary incontinence study (n=328). Results: TEAEs observed with enobosarm were comparable to the placebo group. Most common AEs for enobosarm were nausea (26.6% vs 26.0% in placebo), anemia (25.6% vs 23.9% in placebo), and vomiting (14.8% vs 14.6% in placebo), which were similar to the placebo groups. Notably, there was no increase in gastrointestinal AEs and no evidence of drug induced liver injury with enobosarm compared to placebo treatment. The incidence of deep vein thrombosis was higher (3.3%) in placebo compared to the enobosarm group (1%). Conclusion: In pooled analysis of 1027 older men, postmenopausal women, and older patients with muscle loss from advanced cancer, enobosarm was well tolerated with an AE profile comparable to the control patients. A Ph2b randomized trial is underway to evaluate enobosarm in older patients on a GLP-1 RA for weight loss. Disclosure J. Crawford: Advisory Panel; Pfizer Inc. Research Support; Pfizer Inc., AstraZeneca, helsinn. Advisory Panel; BioAtla. Consultant; Actimed. Advisory Panel; G1 Therapeutics, Enzychem. Consultant; Faraday. Advisory Panel; Jazz. A.S. Dobs: Speaker's Bureau; Halozyme. W.J. Evans: None. C. Prado: Speaker's Bureau; Abbott Nutrition, Nestlé Health Science, Nutricia, Amra medical. Advisory Panel; Pfizer Inc. D. Rodriguez: Employee; Veru. I. Shalev: Employee; Veru. K. Barnette: None. M. Steiner: Stock/Shareholder; Veru, Inc.

There is a need for a drug when combined with a GLP-1 receptor agonist (RA) can prevent muscle loss, while preferentially reducing fat resulting in high quality weight loss. Older sarcopenic obese patients receiving a GLP-1 RA are at the highest risk for muscle atrophy and muscle weakness leading to frailty. Enobosarm, a novel oral selective androgen receptor modulator, has been studied in 5 clinical muscle studies involving 968 older men, postmenopausal women, and older patients who have muscle loss due to advanced cancer. The totality of the clinical data demonstrates that enobosarm therapy results in dose-dependent reductions in fat mass and increases in muscle mass with improvement in physical function. A placebo controlled Phase 3 clinical trial was conducted evaluating 3mg enobosarm for the treatment of muscle wasting in advanced lung cancer patients undergoing chemotherapy. A post-hoc analysis was performed to assess body composition by DXA scan in a subset of older (≥60 years) patients with obesity (BMI ≥ 30kg/m2) at 12 and 21 weeks. Loss of appetite occurs with advanced cancer inducing a starvation state similar to GLP-1 RA therapy. At 12 weeks, enobosarm 3mg treated subjects had 4.96% increase in total lean mass compared to placebo and a 5.77% reduction in fat mass compared to placebo (n=29). By 21 weeks, enobosarm 3mg treatment resulted in a 14.4% total fat mass loss, and a 4.5% loss of DXA body weight compared to placebo while maintaining lean mass (Figure 1). Enobosarm was generally well tolerated with no increase in gastrointestinal side effects. In a subset analysis of older obese patients, enobosarm therapy resulted in reductions in fat mass while preserving lean body mass (muscle) leading to greater high quality weight loss. A Phase 2b randomized controlled trial is currently underway to evaluate the safety and efficacy of enobosarm in preserving muscle mass and augmenting fat loss in at risk sarcopenic obese or overweight older patients receiving a GLP-1 RA for weight loss.

Abstract Background: Targeting the androgen receptor (AR) with an oral selective agonist, enobosarm, is a novel approach to overcome ER and CDK4/6 resistance to suppress metastatic breast cancer (mBC). Preclinical studies in CDK4/6 inhibitor and estrogen blocking agent resistant PDX mBC models demonstrated that enobosarm alone or in combination with another CDK 4/6 inhibitor suppressed PDX mBC growth. In a subgroup analysis from a Phase 2 study, enobosarm demonstrated efficacy in the treatment of AR+ ER+ HER2- metastatic breast cancer in patients who had tumor progression on estrogen blocking agent and a CDK 4/6 inhibitor with a best overall response rate of 30% (2CRs and 1 PR). A Phase 3 ENABLAR-2 multi-center, open label, study evaluating enobosarm +/- abemaciclib is open and active for the treatment of HR+HER2- mBC. Methods: The two-staged Phase 3 ENABLAR-2, open-label, randomized, multicenter study is being conducted in AR+ER+ HER2- 2nd-line mBC who have progressed on estrogen blocking agent plus palbociclib or ribociclib. In the Stage 1 of the study (160 patients), five treatment arms will be assessed with the primary efficacy endpoint of ORR: enobosarm 9 mg QD, enobosarm 1 mg QD + abemaciclib, enobosarm 3 mg QD + abemaciclib, enobosarm 9 mg QD + abemaciclib, and an estrogen blocking agent, active control (a nonsteroidal AI, exemestane +/- everolimus, or SERD). Secondary efficacy endpoints include progression-free survival (PFS). In Stage 2 of the study, patients will be randomized to receive enobosarm +/- abemaciclib (based on outcome of ORR in Stage 1) or estrogen blocking agent, active control, with the primary endpoint of PFS and secondary efficacy endpoints including, ORR, CBR, OS, as well as changes in quality-of-life measurements (SPPB, EORTC-QLQ, body composition measured by DEXA). Randomization will be stratified by AR% nuclei staining and by line of treatment for metastatic disease. Subjects will receive study drug until disease progression is observed. Preliminary Results: To date, 3 patients have been treated with enobosarm 9 mg in combination with abemaciclib. The combination therapy was well tolerated with no new safety findings. There were no drug-drug interactions between enobosarm and abemaciclib. Two patients have achieved BOR of a partial response with up to 79% and 56% reduction in their target lesion recorded by local reads on day 224 post-treatment initiation (PTI). The third patient has achieved a stable disease and continues to receive treatment (on study 10+ months). Conclusions: Preliminary data of efficacy and safety of enobosarm in combination with abemaciclib are encouraging. The Phase 3 ENABLAR-2 study is underway to further evaluate enobosarm monotherapy or in abemaciclib combination therapy in 2nd-line metastatic breast cancer population. Clinical trial information: NCT05065411. Research Sponsor: Veru Inc Citation Format: Kristine Rinn, Hannah Linden, Lee Schwartzberg, Gary Barnette, Domingo Rodriguez, Itay Shalev, Mitchell Steiner, Adam Brufsky, Joyce O'Shaughnessy. Design of Active Phase 3 ENABLAR-2 Study Evaluating Enobosarm +/- Abemaciclib in Patients with AR+ER+HER2- 2nd-Line Metastatic Breast Cancer Following Tumor Progression on an Estrogen Blocking Agent Plus Palbociclib or Ribociclib [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-27-06.

Testosterone, many steroidal androgens, and nonsteroidal ligands that bind to androgen receptor and exert tissue-specific transcriptional activity (selective androgen receptor modulators [SARMs]) are being developed as function-promoting therapies to treat functional limitations associated with aging and chronic diseases. This narrative review describes preclinical studies, mechanisms, and randomized trials of testosterone, other androgens, and nonsteroidal SARMs. Sex differences in muscle mass and strength and empiric use of anabolic steroids by athletes to increase muscularity and athletic performance provide supportive evidence of testosterone's anabolic effects. In randomized trials, testosterone treatment increases lean body mass, muscle strength, leg power, aerobic capacity, and self-reported mobility. These anabolic effects have been reported in healthy men, hypogonadal men, older men with mobility limitation and chronic diseases, menopausal women, and HIV-infected women with weight loss. Testosterone has not consistently improved walking speed. Testosterone treatment increases volumetric and areal bone mineral density, and estimated bone strength; improves sexual desire, erectile function, and sexual activity; modestly improves depressive symptoms; and corrects unexplained anemia in older men with low testosterone levels. Prior studies have not been of sufficient size or duration to determine testosterone's cardiovascular and prostate safety. The efficacy of testosterone in reducing physical limitations, fractures, falls, progression to diabetes, and correcting late-onset persistent depressive disorder remains to be established. Strategies to translate androgen-induced muscle mass and strength gains into functional improvements are needed. Future studies should evaluate the efficacy of combined administration of testosterone (or a SARM) plus multidimensional functional exercise to induce neuromuscular adaptations required for meaningful functional improvements.

Supplementary Methods - PDF file 62K, Additional methods to support the manuscript 1. Cloning and protein purification 2. AKR1C3 enzyme activity and thin layer chromatography (TLC)

Supplementary Figures and Tables - PDF file 898K, Supplementary Table ST1: AKR1C3 over-expression in HEK-293 cells reduces IC50 of androgens. Supplementary Table ST2: Finasteride increases the testosterone formation. Supplementary Figure S1: Over-expression of AKR1C3 increases LNCaP xenograft growth in intact mice. Supplementary Figure S2: AR target FKBP51, but not AR, protein expression is increased in LNCaP-AKR1C3 xenograft tumors. Supplementary Figure S3: AKR1C3 translocation to nucleus requires AR. Top panel. NIH3T3-AKR1C3 cells infected with adenovirus LacZ. Bottom panel. NIH3T3-AKR1C3 cells infected with adenovirus AR.Supplementary Figure S4: AKR1C3 migrates with AR. Supplementary Figure S5: Duolink assay demonstrates interaction between AR and AKR1C3 in LNCaP-AKR1C3 cells. Supplementary Figure S6: AKR1C3 synergizes with SRC-2 in AR transactivation assay. Supplementary Figure S7: AKR1C3 dependent- androgen induced- AR transactivation is not cell type dependent. Transient transactivation studies conducted in COS-1 cells Supplementary Figure S8: AKR1C3-dependent increase in transactivation is selective to AR. Supplementary Figure S9: R1881 induced- AKR1C3 dependent- AR transactivation is not observed with other AKR1C. Supplementary Figure-S10: Different domains mediate the enzymatic and activator functions of AKR1C3. Supplementary Figure S11: GTx-560 is specific for AKR1C3. Supplementary Figure S12: HEK-293-AKR1C3 enzyme activity. Supplementary Figure S14: GTx-560 inhibits AKR1C3-dependent Adione-induced AR transactivation at all concentration of AKR1C3. Supplementary Figure S15: Expression of steroidogenic enzymes in VCaP cells

Abstract Purpose: Sabizabulin, an oral cytoskeleton disruptor, was tested in a phase Ib/II clinical study in men with metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods: The phase Ib portion utilized a 3+3 design with escalating daily oral doses of 4.5–81 mg and increasing schedule in 39 patients with mCRPC treated with one or more androgen receptor–targeting agents. Prior taxane chemotherapy was allowed. The phase II portion tested a daily dose of 63 mg in 41 patients with no prior chemotherapy. Efficacy was assessed using PCWG3 and RECIST 1.1 criteria. Results: The MTD was not defined in the phase Ib and the recommended phase II dose was set at 63 mg/day. The most common adverse events (>10% frequency) at the 63 mg oral daily dosing (combined phase Ib/II data) were predominantly grade 1–2 events. Grade ≥3 events included diarrhea (7.4%), fatigue (5.6%), and alanine aminotransferase/aspartate aminotransferase elevations (5.6% and 3.7%, respectively). Neurotoxicity and neutropenia were not observed. Preliminary efficacy data in patients treated with ≥1 continuous cycle of 63 mg or higher included objective response rate in 6 of 29 (20.7%) patients with measurable disease (1 complete, 5 partial) and 14 of 48 (29.2%) patients had PSA declines. The Kaplan–Meier median radiographic progression-free survival was estimated to be 11.4 months (n = 55). Durable responses lasting >2.75 years were observed. Conclusions: This clinical trial demonstrated that chronic oral daily dosing of sabizabulin has a favorable safety profile with preliminary antitumor activity. These data support the ongoing phase III VERACITY trial of sabizabulin in men with mCRPC.

You have accessJournal of UrologyCME1 May 2022MP27-15 SABIZABULIN HAS BOTH CYTOTOXIC AND CYTOSTATIC ACTIVITY IN PHASE 1B/2 CLINICAL OF MEN WITH METASTATIC CASTRATION RESISTANT PROSTATE CANCER WHO PROGRESSED ON ANDROGEN RECEPTOR TARGETING AGENTS Mark Markowski, Mario Eisenberger, Christopher Pieczonka, Robert Getzenberg, Domingo Rodriguez, K. Gary Barnette, MItchell Steiner, Daniel Saltzstein, Emmanuel Antonarakis, and Ronald Tutrone Mark MarkowskiMark Markowski More articles by this author , Mario EisenbergerMario Eisenberger More articles by this author , Christopher PieczonkaChristopher Pieczonka More articles by this author , Robert GetzenbergRobert Getzenberg More articles by this author , Domingo RodriguezDomingo Rodriguez More articles by this author , K. Gary BarnetteK. Gary Barnette More articles by this author , MItchell SteinerMItchell Steiner More articles by this author , Daniel SaltzsteinDaniel Saltzstein More articles by this author , Emmanuel AntonarakisEmmanuel Antonarakis More articles by this author , and Ronald TutroneRonald Tutrone More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002570.15AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Sabizabulin is a novel oral cytoskeleton disruptor being developed for use in metastatic castration resistant prostate cancer (mCRPC). A Phase 1b/2 clinical study was conducted to establish the maximum tolerated dose (MTD) and evaluate the preliminary efficacy in men with mCRPC resistant to androgen receptor targeting agents (ARTAs). METHODS: The Phase 1b portion of the study in 39 men utilized escalating and expanding dose and duration. The Phase 2 portion studied 41 men with mCRPC at the recommended Phase 2 dose (RP2D) of 63 mg daily. Based upon the Phase 1b/2 data, sabizabulin appears to have both cytotoxic and cytostatic activity. A analysis was conducted evaluating the best clinical response (BCR) defined as either an objective response assessed by PCWG3 criteria and/or stable disease defined as > 5 cycles ( > 15 weeks) of continuous treatment. RESULTS: Of the combined 80 patients in the Phase 1b/2 portions of the study, the BCR was 37.5% (30/80) and 5 of the responders remain on study with the longest being treated for more than 30 months. Of the patients with measurable disease at study entry, the BCR was 59% (17/29). Prior to study entry, 11/30 (37%) of those with a BCR had previously been treated with and subsequently progressed on a minimum of 2 ARTAs. The remaining 19/30 (63%) had progressed on a single ARTA agent. 11 (37%) were previously treated with enzalutamide or apalutamide and 8 (27%) with abiraterone as single agents. 8 (27%) received enzalutamide and abiraterone and 3 (10%) patients received more than two ARTAs. As described previously, the safety profile continues to be favorable with no clinically relevant neutropenia or neurotoxicity and the most commonly observed adverse events being gastrointestinal in nature. CONCLUSIONS: In this analysis, sabizabulin has demonstrated not only cytotoxic, but also significant cytostatic activity with similar responses in men that have progressed on a single or multiple ARTA agents. Sabizabulin is a novel agent with the potential provide men with mCRPC a well-tolerated chronic treatment cytostatic option after progressing on an ARTA and is being tested in the open Phase 3 VERACITY trial. Source of Funding: Veru Inc © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e456 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mark Markowski More articles by this author Mario Eisenberger More articles by this author Christopher Pieczonka More articles by this author Robert Getzenberg More articles by this author Domingo Rodriguez More articles by this author K. Gary Barnette More articles by this author MItchell Steiner More articles by this author Daniel Saltzstein More articles by this author Emmanuel Antonarakis More articles by this author Ronald Tutrone More articles by this author Expand All Advertisement PDF DownloadLoading ...

Sabizabulin is an oral, novel microtubule disruptor with dual antiviral and anti-inflammatory activities. A randomized, multicenter placebo-controlled Phase 3 clinical trial was conducted in hospitalized moderate-severe COVID-19 patients at high-risk for acute respiratory distress syndrome (ARDS) and death. Patients were randomized (2:1) to sabizabulin 9mg or placebo oral daily dose (up to 21 days). In a planned interim analysis, sabizabulin treatment resulted in a 55.2% relative reduction in mortality compared to placebo. The primary endpoint was all-cause mortality up to day 60. Key secondary endpoints were days in intensive care unit (ICU), on mechanical ventilation, and in hospital. Randomization was stratified by oxygen requirement at baseline (WHO 4 = supplemental oxygen, WHO 5 = NIV/forced oxygen, WHO 6 = mechanical ventilation). The WHO 4 patients also were required to have at least one comorbidity (Asthma, Chronic Lung Disease, Diabetes, Hypertension, Severe Obesity (BMI ≥40), ≥65 years of age, in a nursing/long-term care facility, or immunocompromised). A post-hoc analysis of the key efficacy outcomes in WHO 4 at baseline patients with a comorbidity was conducted. A total of 88 patients classified as WHO 4 with a baseline comorbidity underwent randomization (59 sabizabulin/29 placebo). Baseline characteristics were similar. Sabizabulin treatment resulted in a 22.4 absolute percentage point and 81.2% relative reduction in deaths compared to the placebo (odds ratio 6.22, 95% CI [1.58 to 24.48], p=0.0090). Mortality rate was 5.2% (3 of 58) for sabizabulin versus 27.6% (8 of 29) for placebo. Key secondary endpoints: sabizabulin treatment resulted in relative reductions of 74.7% in days in ICU (p=0.0021), 80.7% in days on mechanical ventilation (p=0.0019), and 39.8% in days in hospital (p=0.0191) vs placebo. Statistically and clinically significant reductions in mortality, days in the ICU, on mechanical ventilation, and in the hospital were observed in the sabizabulin treated compared to placebo hospitalized COVID-19 WHO-4 patients with at least one comorbidity suggesting that the antiviral action of sabizabulin contributes early in the prevention of COVID-19 progression to ARDS and death. Tara L. Gonzales, MD, Veru Inc.: Employee Mitchell Steiner, MD, Veru, Inc: Board Member|Veru, Inc: Stocks/Bonds K. Gary Barnette, PhD, Veru Inc.: Employee|Veru Inc.: Ownership Interest Michael S. Gordon, MD, Agenus: Grant/Research Support|Arcus: Grant/Research Support|Astex: Grant/Research Support|ATEA: Grant/Research Support|Beigene: Grant/Research Support|Caremission: Ownership Interest|Celldex: Grant/Research Support|Corcept: Grant/Research Support|Daiichi: Grant/Research Support|Deciphera: Grant/Research Support|Endocyte: Grant/Research Support|Forma: Grant/Research Support|FujiFilm: Grant/Research Support|Genentech/Roche: Grant/Research Support|I-MAB Pharma: Grant/Research Support|Imaginab: Advisor/Consultant|Imaginab: Grant/Research Support|Imaging Endpoints: Advisor/Consultant|Incyte: Grant/Research Support|Kinevant: Grant/Research Support|Medelis: Ownership Interest|Medimmune: Grant/Research Support|Morphic Tx: Advisor/Consultant|Nikang: Grant/Research Support|OncoResponse: Grant/Research Support|OnQuality: Advisor/Consultant|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pionyr: Grant/Research Support|Plexxicon: Grant/Research Support|Qualigen: Advisor/Consultant|RedHill Bio: Grant/Research Support|Revolution Medicine: Grant/Research Support|Riboscience: Grant/Research Support|Seattle Genetics: Grant/Research Support|Serono: Grant/Research Support|SQZ Biotech: Grant/Research Support|Syndax: Grant/Research Support|Theseus: Grant/Research Support|Tolero: Grant/Research Support|Tracon: Grant/Research Support|Vedanta: Grant/Research Support|Veru: Grant/Research Support Eduardo Sprinz, MD; MsC, ScD, Gilead: Advisor/Consultant|Gilead: Board Member|GSK: Advisor/Consultant|GSK: Board Member|GSK: Grant/Research Support|GSK: Honoraria|Janssen: Advisor/Consultant|Janssen: Board Member|Janssen: Honoraria Domingo Rodriguez, n/a, Veru: Stocks/Bonds Domingo Rodriguez, n/a, Veru: Stocks/Bonds.

5049 Background: Sabizabulin is a novel oral cytoskeleton disruptor being developed for use in metastatic castration resistant prostate cancer (mCRPC). A Phase 1b/2 clinical study was conducted to establish the maximum tolerated dose (MTD) and evaluate the preliminary efficacy in men with mCRPC resistant to androgen receptor targeting agents. Methods: The Phase 1b portion of the study in 39 men utilized escalating and expanding dose and duration. The Phase 2 portion studied 41 men with mCRPC at the recommended Phase 2 dose of 63 mg daily. Efficacy was assessed by bone/CT scans. A final analysis of the safety and efficacy data including the primary endpoint, the median progression-free survival was conducted. Results: Although the MTD was not reached in the Phase 1b, the recommended Phase 2 dose was set at 63 mg/day to maximize GI tolerability. The most common adverse events (> 10% frequency) at the 63 mg oral daily dosing (combined Phase 1b/2 data) were predominantly Grade 1-2. Grade ³3 events included diarrhea (7.4%), fatigue (5.6%) and ALT/AST elevations (5.6% and 3.7%, respectively). Neurotoxicity and neutropenia were not observed. Preliminary efficacy data in patients treated with ≥1 continuous cycle (21 days) of 63 mg or higher (n = 55) included an objective response rate of 6/29 (20.7%) in patients with measurable disease (1 complete, 5 partial). 14/48 (29.2%) of the patients had PSA declines. The Kaplan-Meier median radiographic progression-free survival was estimated to be 11.4 months (95% C.I. 29.63-65.79) (n = 55). Durable responses lasting > 2.75 years were observed with 14.5% (8/55) demonstrating a response greater than 12 months. Conclusions: This clinical trial demonstrated that chronic oral daily dosing of sabizabulin has a favorable safety profile with significant preliminary cytotoxic and cytostatic antitumor activity. These data support the ongoing Phase 3 VERACITY trial of sabizabulin in men with mCRPC who have progressed on an androgen receptor targeting agent. Clinical trial information: NCT03752099.