MEI Pharma Reports Initial Data from Clinical Study Evaluating ME-344 in Combination with Bevacizumab (Avastin) in Relapsed Metastatic Colorectal Cancer Patients - Seite 3

ME-344 Plus Bevacizumab Combination: Initial Efficacy Data

Of the 23 patients enrolled in Cohort 1, three patients were not evaluable for 16-weeks disease progression analysis due to early discontinuation prior to first disease assessment on therapy. Of the 20 patients that were evaluable, 5 (25%) completed at least 16 weeks of therapy without disease progression, exceeding the predetermined threshold of 4 (20%) patients defined by the protocol as the condition to initiate enrollment in a second cohort. The median PFS was 1.9 months, the 4-month PFS rate was 31.2%, and the median overall survival was 6.7 months with 15 patients censored at the time of analysis. Nine (45%) of the 20 evaluable patients had stable disease.

About ME-344

ME-344, an investigational drug candidate, is a novel inhibitor of 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 support 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 supporting the potential of inhibition of OXHPOS by ME-344 as a promising therapeutic modality.