MEI Pharma to Present Design of Ongoing Clinical Study Evaluating ME-344 at ASCO GI Cancers Symposium 2024
– Ongoing Phase 1b Study Evaluating ME-344 Plus Avastin® in Patients with Metastatic Colorectal Cancer: Combination Intended to Create Metabolic Synthetic Lethality –
Presentation Title: A Phase 1b Study of the OXPHOS Inhibitor ME-344 in Combination with Bevacizumab in Refractory Metastatic Colorectal Cancer
Session Title: Trials in Progress Poster Session C: Cancers of the Colon, Rectum, and Anus
Presenter:
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Abstract Number: TPS222
The poster can be viewed on the
https://meipharma.com/ASCO2024enocuyg.html#
About the Phase 1b Study
The ongoing Phase 1b study is evaluating ME-344 plus bevacizumab across two cohorts in patients with metastatic colorectal cancer after failure of standard therapies. The combination of ME-344 and bevacizumab is intended to create metabolic synthetic lethality by leveraging the ability of antiangiogenics like bevacizumab to reduce glycolysis, forcing tumors to switch to mitochondrial respiration via OXPHOS, which is inhibited by ME-344.
In the first cohort of approximately 20 patients ME-344 is administered at 10 mg/kg once weekly for 3 weeks in combination with bevacizumab every two weeks, with cycles repeated every 4 weeks. If the rate of non-progression in Cohort 1 reaches a predetermined progression free survival threshold, Cohort 2 will enroll an additional 20 patients. Patients will be treated until disease progression or intolerability. The primary endpoint of the study is progression free survival. Secondary endpoints include overall response rate, duration of response, overall survival and safety.
The study is being conducted at member centers of the
About ME-344
ME-344 is a novel drug candidate that inhibits mitochondrial oxidative phosphorylation (OXPHOS), a fundamental metabolic pathway involved in the production of adenosine triphosphate (ATP) in the mitochondria. ATP provides energy to drive many metabolic cell processes, including division, proliferation, and growth. By disrupting the production of ATP, ME-344 has been shown to induce cancer cell death in nonclinical models and was associated with antitumor activity in clinical studies.
The two main sources of ATP production in cells are OXPHOS and glycolysis; the latter is highly active in most tumors. Anti-angiogenics, like the vascular endothelial growth factor (VEGF) inhibitor bevacizumab (AVASTIN®), have the potential to normalize vasculature and decrease reliance on glycolysis. The resulting reduction in glycolysis may trigger an increased dependence on mitochondrial ATP production for energy to support continued tumor proliferation.
In such cases of tumor plasticity, the combination of ME-344 and bevacizumab may induce metabolic synthetic lethality, providing a novel therapeutic strategy. Specifically, leveraging the ability of antiangiogenics like bevacizumab to reduce glycolysis and force tumor cells to switch to mitochondrial respiration via OXPHOS, which is inhibited by ME-344, may reduce access to ATP needed for cell division and growth in tumors.
This approach was first clinically evaluated in a multicenter, investigator-initiated, randomized, open-label, window of opportunity clinical study, evaluating ME-344 (3 doses) plus bevacizumab (1 dose) in 42 women with early HER2-negative breast cancer. Study results demonstrated significant biological antitumor activity as measured by a reduction in the proliferative biomarker Ki-67 compared to placebo. The combination appeared to be generally well tolerated. The data from this study were consistent with preclinical data suggesting that combining ME-344 can augment anti-angiogenic therapy and provided validation for continued evaluation of the combination of ME-344 with bevacizumab and other VEGF inhibitors.
An earlier Phase 1 clinical study evaluating ME-344 as a single-agent in patients with refractory solid tumors also demonstrated anti-tumor activity, further validating the potential of mitochondrial inhibition as a promising therapeutic modality.
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