Treatment-naïve, early stage
§ Investigator-initiated study
ME-344 is our novel and tumor selective, isoflavone-derived mitochondrial inhibitor drug candidate. ME-344 is currently in an ongoing investigator-initiated, multi-center, randomized study in combination with the VEGF inhibitor bevacizumab (marketed as Avastin ®) in a total of 40 patients with HER2 negative breast cancer.
MECHANISM OF ACTION
ME-344 is a novel, tumor selective, isoflavone-derived 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. Tumor cells often display a high metabolic rate to support cell division and growth. This heightened metabolism requires a continual supply of energy in the form of ATP. By disrupting the production of ATP, ME-344 has been shown to induce cancer cell death through the induction of DNA fragmentation and through a process known as destructive autophagy, wherein a cell consumes itself.
In addition to single-agent activity, ME-344 may also have potential in combination with antiangiogenic therapeutics. While antiangiogenics reduce the rate of glycolysis in tumors as a mechanism to block growth, tumor metabolism often shifts to mitochondrial metabolism to continue energy production to support continued tumor proliferation. In such cases of tumor plasticity in the presence of treatment with antiangiogenics, targeting the alternative metabolic source with ME-344 may open another important therapeutic opportunity.
We are investigating the potential of ME-344 in combination with the vascular endothelial growth factor inhibitor drug bevacizumab (marketed as Avastin®) in a multicenter, investigator-initiated, randomized, open-label, clinical trial, evaluating a total of up to 40 patients with HER2-negative breast cancer. Patients are randomized one-to-one to either ME-344 in combination with bevacizumab or saline in combination with bevacizumab. An interim data review performed after 20 patients were randomized and presented at the ASCO Annual Meeting in June 2018 demonstrate evidence of inhibition of tumor proliferation as measured by Ki-67 reductions. The treatment was generally well tolerated. These interim data are consistent with pre-clinical results indicating ME-344’s potential to reverse resistance to anti-angiogenic therapy, thereby warranting the continuation of the ongoing study.
Results from an earlier, first-in-human, single-agent Phase 1 clinical trial of ME-344 in patients with refractory solid tumors were published in the April 1, 2015 issue of Cancer. The results indicated that eight of 21 evaluable patients (38%) treated with ME-344 achieved stable disease or better, including five who experienced progression-free survival that was at least twice the duration of their last prior treatment before entry into the study. In addition, one of these patients, a heavily pre-treated patient with small cell lung cancer, achieved a confirmed partial response and remained on study for two years. ME-344 was generally well tolerated.