On April 8, 2022 MEI Pharma, Inc. (NASDAQ: MEIP), a late-stage pharmaceutical company focused on advancing new therapies for cancer, reported that two posters presenting preclinical data will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 for zandelisib, an orally administered phosphatidylinositol-3-kinase (PI3K) inhibitor, and ME-344, a tumor selective mitochondrial inhibitor (Press release, MEI Pharma, APR 8, 2022, View Source [SID1234611767]).
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"The preclinical data presented at AACR (Free AACR Whitepaper) is supportive of the promise of our pipeline and we look forward to continuing to advance our clinical candidates in an effort to provide new therapeutic options for patients with cancer," said Daniel P. Gold, Ph.D., president and chief executive officer of MEI Pharma.
To view the posters click here.
Title: Efficacy and immune profiling of the PI3K delta inhibitor zandelisib (ME-401) in a preclinical model of chronic lymphocytic leukemia (CLL)
Authors: Dr. Maharaj, et. al.
Date: Friday, April 8, 2022, 8:30 AM ET
AbstractID: 5496
Summary: Data from preclinical studies with zandelisib ex vivo in normal human T cells and in vivo in a murine CLL model suggest that zandelisib has immunomodulatory properties on human T cells. Zandelisib in combination with ibrutinib further reduced normal human T cell proliferation and inducible regulatory T cells (Tregs), while zandelisib alone decreased activation and expression of suppressive markers, such as PD-1 and CTLA-4 on inducible regulatory (Tregs) and CD4+ T cells, comparably to zandelisib/ibrutinib combination. In the murine CLL model, a reduction in Treg numbers, markers of terminal memory differentiation and T-cell exhaustion on CD4+ and CD8+ T cells – all of which are features that have been shown to permit CLL immune evasion – as well as improvement in overall survival was observed.
Title: ME-344, a novel isoflavone mitochondrial inhibitor, in combination with venetoclax constitutes a new metabolism-targeted approach to overcome resistance to Bcl-2 inhibition and standard of care treatment in AML
Authors: Katie Hurrish, et. al.
Date: Wednesday, April 13, 2022, 10:00 AM – 1:30 PM ET
AbstractID: 3785
Summary: ME-344 is an investigational isoflavone that has been shown to suppress OXPHOS in solid tumor cells. However, it has not been tested extensively in hematologic malignancies. This study analyzes the ability of ME-344 to enhance the activity of venetoclax against acute myeloid leukemia (AML). Data from the presented in vitro and in vivo preclinical studies evaluating the combination of ME-344 with venetoclax in standard-of-care-resistant AML cell lines and relapsed or refractory AML patient samples suggest that ME-344, both alone and in combination with venetoclax, inhibits purine biosynthesis, suppresses oxidative phosphorylation, induces apoptosis and decreases Mcl-1, which together target metabolic vulnerabilities of AML cells. The data demonstrated that ME-344 and venetoclax prolong survival in MV4-11- and MV4-11/AraC-R-derived xenograft AML models. Overall, it’s concluded that ME-344 enhances venetoclax activity against AML cells including resistant AML.
About Zandelisib
Zandelisib, a selective PI3Kδ inhibitor, is an investigational cancer treatment being developed as an oral, once-daily, treatment for patients with B-cell malignancies. Clinical trials are investigating the efficacy and safety of zandelisib as a single agent and in combination with other modalities while administered on an Intermittent Dosing Regimen (IDT). The IDT leverages molecular and biologic properties specific to zandelisib.
Ongoing zandelisib studies include the Phase 2 TIDAL study (NCT03768505) evaluating patients with relapsed or refractory follicular and marginal zone lymphomas. Also ongoing is the Phase 3 COASTAL study (NCT04745832) comparing zandelisib plus rituximab to standard of care chemotherapy plus rituximab, in patients with relapsed or refractory follicular or marginal zone lymphomas who received more than one prior line of therapy, which must have included an anti-CD20 antibody in combination with chemotherapy or lenalidomide. COASTAL is intended to support marketing applications in the U.S. and globally.
About ME-344
ME-344 is a novel and tumor selective mitochondrial inhibitor drug candidate. It directly targets the OXPHOS complex 1, a pathway involved in the production of adenosine triphosphate, or ATP, in the mitochondria. Treatment of tumor cells with ME-344 as a single-agent results in a rapid loss of ATP and cancer cell death.
Although clinical investigation of ME-344 has demonstrated single agent activity in patients with solid tumors, using it in combination with other cancers therapies is thought to hold more significant potential for patients. Data reported from an investigator-initiated, multi-center, randomized study of ME-344 in combination with the VEGF inhibitor bevacizumab (Avastin) demonstrated biologic activity in the ME-344 treatment group supporting further clinical investigation.
A Phase 2 study of ME-344 plus Avastin in patients with relapsed colorectal cancer is planned to start towards the end of 2022.