In 2020, there will be an estimated 191,930 new cases of prostate cancer and about 33,330 men will die from the disease making prostate cancer the second leading cause of cancer deaths according to the American Cancer Society. In the U.S., 5% of men with prostate cancer will have metastatic cancer and up to 30% of men with high-risk, localized prostate cancer will develop metastatic cancer following initial therapy. The median survival of patients with metastatic prostate cancer ranges from 3.2-4.5 years.1,2 For these men with advanced prostate cancer, 1st line therapy is androgen deprivation therapy (ADT), or medical castration. ADT-induced estrogen deficiency side effects can cause men to delay, pause and/or discontinue ADT, increases morbidity and mortality, and can significantly impact quality of life. ADT-induced side effects include hot flashes, bone loss and fractures, fatigue and libido, and adverse lipid and metabolic changes. Although most will initially respond, nearly all these patients will progress to metastatic castration resistant prostate and have a poor prognosis with an average survival of 1.5 years. New 2nd line hormonal agents, like XTANDI® (enzalutamide) and ZYTIGA® (abiraterone/prednisone) have resulted in an additional four to five months of average survival, but again, nearly all men on these agents will become resistant to these agents and develop progressive metastatic prostate cancer.
Drugs that target tubulin have been shown to be the most effective cytotoxic chemotherapy for the treatment of metastatic prostate cancer. Tubulin, a component of microtubules, is required for cancer cell replication and to shuttle the androgen receptor into the nucleus where the receptor stimulates genes for cancer cell proliferation. Docetaxel and cabazitaxel are examples of FDA-approved chemotherapy drugs that are given intravenously (IV) that target tubulin to treat metastatic prostate cancer. Although effective, the challenges for this class of chemotherapy agents, also known as taxanes, include that they must be given IV and that the cancer cells develop resistance to taxanes in a variety of ways: Cancer cells may (i) express multidrug resistance proteins which pump the taxane chemotherapy meant to kill the cancer cells, out of the cancer cells; (ii) develop tubulin mutations so taxanes are no longer able to bind to the mutated tubulin; and/or (iii) overexpress beta-tubulin so that there is plenty of tubulin present for cell replication even if some tubulin is bound by taxanes. There are also serious safety concerns with IV taxanes which include serious hypersensitivity reactions, neutropenia, myelosuppression and neurotoxicity such as peripheral neuropathy and muscle weakness.
VERU-111 is a novel, proprietary, next generation, first-in-class oral selective antitubulin agent that targets and disrupts alpha and beta tubulin subunits of microtubules. In cancer cells, microtubules are critical for transport of growth factor receptors, cellular proliferation, and metastases. In preclinical effectiveness and toxicity studies, orally administered VERU-111 demonstrated significant antitumor activity against castration and novel androgen blocking agent (abiraterone or enzalutamide) resistant human prostate cancer models. Furthermore, VERU-111 had significant antitumor effects against cancers that overexpress multidrug resistant proteins, like P-glycoprotein, a common mechanism by which cancer cells become resistant to cancer drugs. At oral doses that had significant antitumor effects, VERU-111 had a favorable safety profile as it did not cause neutropenia or myelosuppression, common dose limiting side effects of other classes of commercially available antitubulins such as intravenous taxanes or intravenous vinca alkaloids. In addition to prostate cancer, VERU-111 had antitumor effects in other cancer types including preclinical human models for triple negative breast cancer, ovarian cancer and pancreatic cancer that are sensitive and resistant to taxanes. VERU-111 has the potential to be the first FDA approved oral, selective antitubulin agent that targets and disrupts alpha and beta tubulin subunits of microtubules to treat cancer.
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Veru initially plans to develop VERU-111 as a 3rd line therapy after androgen deprivation (1st line) and enzalutamide or abiraterone (2nd line) have failed and before having to be treated with intravenous taxane chemotherapy (Prechemotherapy). Veru is conducting an open label Phase1b/2 clinical trial evaluating the safety and effectiveness of VERU-111 in men who have metastatic castration resistant prostate cancer who have also become resistant to novel androgen blocking agents like abiraterone or enzalutamide. In the recently completed Phase 1b, the dose escalation portion of the study, patients received VERU-111 to determine safety and the optimal dose for testing in Phase 2. The open label, single arm, Phase 2 portion of the clinical trial will evaluate the efficacy and safety of VERU-111 in 39 mCRPC patients who have become resistant to a secondary novel androgen blocking agent (abiraterone or enzalutamide). Enrolled men will receive 63 mg of VERU-111 per day, the dose that was selected based on the Phase 1b portion of the study conducted in 39 men. Dose increases of VERU-111 up to a dose of 72 mg will be allowed in the study. In the Phase 1b study, VERU-111 was well tolerated with no reports of neurotoxicity, hypersensitivity (allergic) reactions and febrile neutropenia which are side effects common to intravenous taxane chemotherapy. The key efficacy endpoints of the Phase 2 study are radiographic imaging of progression-free survival and prostate-specific antigen (PSA) reductions. Patients will continue to receive VERU-111 until radiographic evidence of prostate cancer progression is observed.
In the U.S., there is a $5 billion annual market for 2nd line hormone therapies for prostate cancer and a $4.8 billion annual market for IV-given taxanes and vinca alkaloids (Docetaxel $1 billion and cabazitaxel $500 million in prostate cancer) per Decision Resources Group and Allied Market Research. VERU-111 could also be developed as an oral dosing alternative for the treatment of metastatic prostate, breast, ovarian, and pancreatic cancers that are resistant to taxanes.