On February 4, 2025 RedHill Biopharma Ltd. (Nasdaq: RDHL) ("RedHill" or the "Company"), a specialty biopharmaceutical company, reported the initiation of a Phase 2 clinical study to evaluate the efficacy of opaganib[3] in combination with darolutamide[4] in men with metastatic castrate-resistant prostate cancer (mCRPC) (Press release, RedHill Biopharma, FEB 4, 2025, View Source [SID1234650037]). Financially supported by Bayer (ETR: BAYN) and the Ramsay Hospital Research Foundation, the 80-patient placebo-controlled randomized study is designed to test the potentially enhancing effect of opaganib in overcoming resistance to standard of care androgen receptor pathway inhibition (ARPI) treatment.
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The study, designed and led by world-renowned prostate cancer researcher Professor Lisa Horvath, from Sydney’s Chris O’Brien Lifehouse, and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group Ltd. (ANZUP), will utilize a companion lipid biomarker test (PCPro) to select mCRPC patients who have a poor prognosis due to standard of care treatment and who may benefit from an opaganib + darolutamide combination treatment approach. The study’s primary endpoint will be improved 12-month radiographic progression-free survival (rPFS). Several secondary and exploratory endpoints will also be evaluated.
"The approach of developing therapeutic combinations and the companion lipid biomarker, PCPro, in parallel is unique in metabolic targeting in metastatic prostate cancer, and this exciting study will test the ability of sphingosine kinase-2 (SPHK2) inhibitors, such as opaganib, to overcome resistance to ARPI treatment," said Professor Lisa Horvath, Chief Clinical Officer and Director of Research at Chris O’Brien Lifehouse. "Cancer cells may block apoptosis (programmed cell death), an important cell-level process designed to help the body get rid of unneeded or abnormal/unhealthy cells – critical in fighting the spread of cancer. We know from our prior research that opaganib enhances androgen receptor signaling inhibitor efficacy in vitro[5], through simultaneous inhibition of three sphingolipid-metabolizing enzymes in human cells (SPHK2, DES1 and GCS), and may potentially provide the key to overcoming darolutamide resistance in men with mCRPC."
"Prostate cancer is the second most diagnosed cancer in the world with around 1.5 million new cases per year, causing the death of almost 400,000 men every year[6], while millions more men are living with prostate cancer resulting in a significant burden of disease," said Dr Mark Levitt, RedHill’s Chief Scientific Officer. "Men with mCRPC have few treatment options available to them, and those positive for the PCPro marker of ARPI-resistance seem to have a particularly poor prognosis. Darolutamide is establishing itself as a key therapy in the treatment of prostate cancer, a market worth approximately $12 billion in 2023, and, if the addition of opaganib can reduce the resistance to darolutamide therapy, this could represent a significant breakthrough in improving the ability to manage advanced treatment-resistant mCRPC for improved outcomes."
The major oncogenic driver for prostate cancer is androgen receptor (AR) signaling. As such, chemical castration or androgen deprivation therapy (ADT), using AR signaling inhibitors has become standard of care therapy. However, despite any initial responses to androgen blockade, all metastatic patients will eventually progress to castration resistance[7]. Studies have shown that elevated circulating levels of ceramide, resulting in elevated levels of sphingosine-1-phosphate (S1P, which promotes cancer growth, metastasis and drug resistance through regulation of cell proliferation, survival and immune processes), may contribute to earlier ADT failure, shorter progression-free survival (PFS) and shorter overall survival[8],[9],[10],[11].
About the study
The study is a double-blind, placebo-controlled randomized Phase 2 trial of adding opaganib (a sphingosine kinase 2 inhibitor) to darolutamide in men with mCRPC and poor prognosis (as defined by plasma lipid signature, PCPro). Target population is men with mCRPC who have had no treatment with newer, potent AR signaling inhibitors including darolutamide, enzalutamide, apalutamide, or abiraterone. 200 patients who are identified as potentially eligible will have a 5-ml plasma sample taken for PCPro testing. Those who are PCPro-positive (estimated 40% of patients) and agree to enter the study will be randomized on a 1:1 ratio to either the darolutamide 600mg bid + placebo (n=40) arm or the darolutamide 600 mg bid + opaganib 500 mg bid (n=40) arm. Treatment will commence within 7 days of randomization.
About Prostate Cancer
Prostate cancer is the second most diagnosed cancer in the world with around 1.5 million new cases in 2022 – causing around 400,000 deaths, with millions more people living with prostate cancer, resulting in a significant burden of disease. Globally, the number of cases of prostate cancer increased by almost 120% from 1990 to 2019[12].
When prostate cancer spreads outside of the prostate to other parts of the body (such as the lymph nodes or bones) it is classified as advanced or metastatic prostate cancer[13]. Five-year survival rates for prostate cancer diagnosed at Stage 1 is 100%; this drops to just 28% for men with Stage 4 (advanced) disease[14].
About Opaganib (ABC294640)
Opaganib, a proprietary investigational host-directed and potentially broad-acting drug, is a first-in-class, orally administered sphingosine kinase-2 (SPHK2) selective inhibitor with anticancer, anti-inflammatory and antiviral activity, targeting multiple potential indications, including several cancers, diabetes and obesity-related disorders, gastrointestinal acute radiation syndrome (GI-ARS), chemical exposure indications, COVID-19, Ebola and other viruses as part of pandemic preparedness.
Opaganib’s host-directed action is thought to work through the inhibition of multiple pathways, the induction of autophagy and apoptosis, and disruption of viral replication, through simultaneous inhibition of three sphingolipid-metabolizing enzymes in human cells (SPHK2, DES1 and GCS).
Several U.S. government countermeasures and pandemic preparedness programs have selected opaganib for evaluation for multiple indications, including Acute Radiation Syndrome (ARS), Ebola virus disease and others. Funding bodies include the Radiation and Nuclear Countermeasures Program (RNCP), led by the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. government Department of Health & Human Services’ National Institutes of Health and the Administration for Strategic Preparedness and Response’s (ASPR) Center for Biomedical Advanced Research and Development Authority (BARDA).
Opaganib has demonstrated antiviral activity against SARS-CoV-2, multiple variants, and several other viruses, such as Influenza A and Ebola. Opaganib delivered a statistically significant increase in survival time when given at 150 mg/kg twice a day (BID) in a United States Army Medical Research Institute of Infectious Diseases (USAMRIID) in vivo Ebola virus study, making it the first host-directed molecule to show activity in Ebola virus disease. Opaganib also recently demonstrated a distinct synergistic effect when combined individually with remdesivir (Veklury, Gilead Sciences Inc.), significantly improving potency while maintaining cell viability, in a U.S. Army-funded and conducted in vitro Ebola virus study.
Being host-targeted, and based on data accumulated to date, opaganib is expected to maintain effect against emerging viral variants. In prespecified analyses of Phase 2/3 clinical data in hospitalized patients with moderate to severe COVID-19, oral opaganib demonstrated improved viral RNA clearance, faster time to recovery and significant mortality reduction in key patient subpopulations versus placebo on top of standard of care. Opaganib has demonstrated its safety and tolerability profile in more than 470 people in multiple clinical studies and expanded access use. Data from the opaganib global Phase 2/3 study was published in Microorganisms.
Opaganib has received several orphan-drug designations from the FDA in oncology and other diseases and has undergone studies in advanced cholangiocarcinoma (Phase 2a) and prostate cancer. Opaganib also has a Phase 1 chemoradiotherapy study protocol ready for FDA-IND submission.
Opaganib has also shown positive preclinical results in renal fibrosis, and has the potential to target multiple oncology, radioprotection, viral, inflammatory, and gastrointestinal indications.