RedHill's Opaganib Shows Promise in Overcoming Venetoclax Resistance in Chronic Lymphocytic Leukemia
核心洞察
RedHill Biopharma announced positive in vivo results showing opaganib combined with venetoclax reduced chronic lymphocytic leukemia cells by 50% compared to controls in mice studies.
The combination therapy targets venetoclax resistance through opaganib's inhibition of sphingosine kinase 2 (SPHK2 (搜索)), which is overexpressed in venetoclax-resistant CLL cells.
Venetoclax resistance represents a growing therapeutic challenge for the $2.5 billion blockbuster CLL therapy, with leukemic cells persisting despite combination treatments.
RedHill Biopharma Ltd. announced positive preclinical results demonstrating that opaganib, a sphingosine kinase 2 (SPHK2 (搜索)) inhibitor, may help overcome resistance to venetoclax, the widely-used chronic lymphocytic leukemia (CLL) therapy. The in vivo study showed that combining opaganib with venetoclax reduced CLL cell counts by 50% compared to controls in mice models.
Addressing Venetoclax Resistance Challenge
Resistance to venetoclax, marketed as Venclexta® and Venclyxto® by AbbVie (搜索) and Genentech, has emerged as a significant therapeutic challenge in CLL treatment. The $2.5 billion blockbuster therapy, approved by the FDA in 2016, works by blocking the BCL-2 (搜索) protein that prevents cancer cell death. However, leukemic cells can persist over time, even with combination therapy approaches.
"Understanding mechanisms of resistance to targeted therapies such as the BCL-2 (搜索) 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 in Buenos Aires, Argentina, who led the study.
SPHK2 Inhibition Mechanism
Previous research has shown that sphingosine kinase 2 (SPHK2 (搜索)) is overexpressed in venetoclax-resistant cancer cells. Studies indicate that SPHK2 inhibition may reduce T-cell-induced activation and proliferation of venetoclax-resistant CLL cancer cells and resensitize previously resistant CLL cells.
The new in vivo study demonstrated that adding opaganib, a potent SPHK2 (搜索) inhibitor, to venetoclax not only reduced CLL cell (CD19 (搜索)⁺, CD5 (搜索)⁺) counts by 50% compared to controls but also lowered CD3+, CD4+ and CD8+ T cell counts compared to controls with reduced PD1 expression (CD8+).
"The results of this in vivo study in mice indicate that adding opaganib, a potent SPHK2 (搜索) 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 (搜索) inhibitor resistance," Gamberale explained.
Clinical Development and Safety Profile
Opaganib is a first-in-class, orally administered drug with anticancer, anti-inflammatory and antiviral activity. The compound has demonstrated safety and tolerability in more than 470 clinical trials and expanded access participants across multiple indications.
Dr. Mark Levitt, Chief Scientific Officer at RedHill, emphasized the clinical significance: "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."
The drug is currently undergoing a Phase 2 clinical trial in combination with darolutamide for advanced prostate cancer. Opaganib has received orphan drug designations from the FDA for cholangiocarcinoma and neuroblastoma.
Broader Therapeutic Applications
Beyond oncology, opaganib targets multiple indications including virology, inflammation, diabetes and obesity-related disorders. The compound has several U.S. government partnerships, including funding from the Biomedical Advanced Research and Development Authority (BARDA (搜索)) for pandemic preparedness applications.
Opaganib works through the inhibition of multiple pathways, inducing autophagy and apoptosis, and disrupting viral replication through simultaneous inhibition of three sphingolipid-metabolizing enzymes in human cells (SPHK2 (搜索), DES1 and GCS).
Disease Context
Chronic lymphocytic leukemia is a slow-growing blood and bone marrow cancer affecting lymphocytes, a type of white blood cell. It represents the most common type of leukemia in adults and has a highly variable clinical course. The disease is generally not considered curable, making effective resistance-management strategies particularly important for long-term patient outcomes.