Resistance to venetoclax (Venclexta^® and Venclyxto^®, Abbvie / Genentech), the $2.5 billion blockbuster Chronic Lymphocytic Leukemia (CLL) therapy, is emerging as a therapeutic challenge, with leukemic cells persisting over time, even with combination therapy

Studies show that sphingosine kinase 2 (SPHK2) is overexpressed in venetoclax-resistant cancer cells and that SPHK2 inhibition may reduce T-cell-induced activation and proliferation of venetoclax-resistant CLL cancer cells and resensitize previously resistant CLL cells

New in vivo study shows adding opaganib, a potent SPHK2 inhibitor, to venetoclax reduces CLL cell (CD19⁺, CD5⁺) counts by 50% compared to controls and lowered CD3⁺, CD4⁺ and CD8⁺ T cell counts compared to controls with lowered PD1 expression (CD8⁺)

Data shows opaganib's venetoclax combination potential in CLL; builds on multiple preclinical studies demonstrating opaganib's therapeutic add-on potential in oncology; further clinical evaluation ongoing in a Phase 2 study of opaganib + darolutamide in advanced prostate cancer

Opaganib has a safety and tolerability profile shown in more than 470 clinical trials / expanded access participants. It targets multiple oncology, virology, inflammation, diabetes and obesity indications, with several U.S. government partnerships, including BARDA funding, in place

RedHill Biopharma Ltd.  a specialty biopharmaceutical company, today announced 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.

"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," saidRomina 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.