Treatment-naïve, early stage
Our isoflavone-based mitochondrial inhibitor drug candidate, ME-344, displays a novel mechanism of action, targeting a mitochondrial component of the terminal respiratory chain complex in rapidly proliferating cells. Treatment of tumor cells with these compounds 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 pre-clinical studies, ME-344 has been shown to cause cell death in multiple human tumor cell lines, including ovarian cancer stem cells, by interfering with mitochondrial energy generation. In April 2013, data were presented at the American Association for Cancer Research (AACR) Annual Meeting showing the ability of ME-344 to decrease tumor burden and delay recurrence in a pre-clinical in vivo model of recurrent epithelial ovarian cancer.
Results from our first-in-human Phase I clinical study of intravenous 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, 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 in the study at doses equal to or less than 10 mg/kg delivered on a weekly schedule for extended durations. Treatment-related adverse events included nausea, dizziness and fatigue. Dose limiting toxicities were observed at both the 15 mg/kg and 20 mg/kg dose levels, consisting primarily of Grade 3 peripheral neuropathy.
In May 2015, we announced new pre-clinical data showing mitochondrial-specific effects of ME-344 in cancer cells, including substantially enhanced anti-tumor activity when combined with agents that inhibit the activity of vascular endothelial growth factor (VEGF). Using a well-characterized spontaneous breast tumor model, researchers at the Spanish National Cancer Research Centre in Madrid found that chronic treatment with the small molecule VEGFr nintedanib significantly diminished tumor cell glycolysis, however the growing tumor shifted to reliance on mitochondrial metabolism as its primary energy source. Subsequently, tumors primed by treatment with nintedanib showed substantially enhanced sensitivity to the mitochondrial inhibitor ME-344, with synergistic anti-tumor activity. These findings were published in the June 2016 issue of Cell Reports.
These new data demonstrate that the anti-cancer effects when combining ME-344 with a VEGF inhibitor are due to an inhibition of both mitochondrial and glycolytic metabolism. An investigator-sponsored study of ME-344 in combination with the VEGF inhibitor bevacizumab (marketed as Avastin®) in HER2-negative breast cancer opened for enrollment in August 2016. This study is now actively dosing patients and interim data are expected in the second half of 2017.