On December 15, 2025 RedHill Biopharma Ltd. (Nasdaq: RDHL) ("RedHill" or the "Company"), a specialty biopharmaceutical company, reported positive in vivo results, indicating that opaganib combined with venetoclax reduces Chronic Lymphocytic Leukemia (CLL) cells by half compared to controls, and further demonstrates opaganib’s potential as an add-on therapy to venetoclax in venetoclax-resistant CLL.
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"Understanding mechanisms of resistance to targeted therapies such as the BCL-2 inhibitor venetoclax is essential to improve current treatment strategies and may provide key insights to personalize treatment for chronic lymphocytic leukemia (CLL) patients" said Romina Gamberale, PhD, Independent Researcher at CONICET from the Institute of Experimental Medicine (IMEX, CONICET-National Academy of Medicine) in Buenos Aires, Argentina, who led the study. "Our previous ex vivo work has shown that sphingosine kinase 2 (SPHK2) is overexpressed in venetoclax-resistant CLL cells and that inhibiting SPHK2 may reduce T-cell-induced resistance and resensitize previously resistant cells. The results of this in vivo study in mice indicate that adding opaganib, a potent SPHK2 inhibitor, to venetoclax reduced CLL cell counts by 50% compared to controls, showing that opaganib may have a significant role to play in mitigating BCL-2 inhibitor resistance."
Dr. Mark Levitt, Chief Scientific Officer at RedHill said: "Venetoclax is a key CLL therapy and finding ways to maintain its effectiveness, and to reduce the potential for resistance-related treatment failure, could represent a breakthrough in the ability to treat CLL patients. This promising data supports the hypothesis that opaganib, as a potent inhibitor of SPHK2, provides a potential route to maintaining venetoclax effects in treating CLL. Opaganib has shown potential as add-on therapy in several preclinical oncology models and is currently undergoing a Phase 2 clinical trial in combination with darolutamide in advanced prostate cancer. This new data now adds CLL to the list of potential cancer indications where opaganib has shown potential to bring additive therapeutic value."
Opaganib has a safety and tolerability profile shown in more than 470 clinical trials / expanded access participants. It targets multiple oncology, virology, inflammation, medical countermeasures, diabetes and obesity indications, with several U.S. government partnerships, including BARDA funding, in place.
Approved by the FDA in 2016, venetoclax (Venclexta and Venclyxto, Abbvie / Genentech), is a first-in-class BCL-2 inhibitor that has become a mainstay of CLL therapy, achieving sales of approximately $2.5 billion in 2024. Venetoclax works by blocking a protein called BCL-2, which is often overproduced in certain cancer cells and prevents the process of apoptosis (programmed cell death) – helping to keep the cancer cells alive and growing. By binding to, and inhibiting, the BCL-2 protein, venetoclax enables the cancer cells to undergo apoptosis and die.
About Chronic Lymphocytic Leukemia (CLL)
CLL is a slow-growing blood and bone marrow cancer that affects a type of white blood cell called lymphocytes. It is the most common type of leukemia in adults and has a highly variable clinical course. It is generally not considered to be curable.
About Opaganib (ABC294640)
Opaganib is a first-in-class, proprietary investigational host-directed and potentially broad-acting orally administered drug with anticancer, anti-inflammatory and antiviral activity. Opaganib is targeted at multiple potential oncology, radioprotection, viral, inflammatory, and gastrointestinal indications, including several cancers, diabetes and obesity-related disorders, gastrointestinal acute radiation syndrome (GI-ARS), COVID-19, Ebola and other viruses as part of pandemic preparedness. Opaganib has also shown positive preclinical results in renal fibrosis.
Opaganib has received orphan-drug designations from the FDA in cholangiocarcinoma and neuroblastoma. It is currently undergoing a Phase 2 clinical trial in combination with darolutamide in advanced prostate cancer and has previously undergone studies in advanced cholangiocarcinoma (Phase 2a). Opaganib also has a Phase 1 chemoradiotherapy study protocol ready for FDA-IND submission.
Opaganib 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 medical countermeasures and pandemic preparedness programs have selected opaganib for evaluation for multiple indications, including GI-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.
(Press release, RedHill Biopharma, DEC 15, 2025, View Source [SID1234661428])