ME-344 is a tumor selective mitochondrial inhibitor drug candidate in clinical development to treat solid tumors.
ME-344 is our novel and tumor selective mitochondrial inhibitor drug candidate. It targets the OXPHOS 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.
ME-344 is a novel and tumor selective, isoflavone-derived mitochondrial inhibitor drug candidate. It targets the OXPHOS pathway involved in the production of adenosine triphosphate, or ATP, in the mitochondria.
Tumor cells often exhibit 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, whereby a cell consumes itself.
ME-344 has demonstrated evidence of single agent activity against refractory solid tumors both preclinically and in Phase 1 clinical studies, mitochondrial inhibition may present a promising therapeutic modality in combination with anti-angiogenic therapeutics, which inhibit tumors from growing their own blood vessels.
It is understood that anti-angiogenics may reduce the rate of glycolysis in tumors as a mechanism to slow tumor growth, but tumor metabolism may then shift to mitochondrial metabolism for energy production to support continued tumor proliferation. In such cases of tumor plasticity in the presence of treatment with anti-angiogenics, targeting the alternative metabolic source with by inhibiting ATP production with the mitochondrial drug inhibitor ME-344, may open an important therapeutic opportunity.
ME-344 has been evaluated in multiple clinical studies, including a multicenter, investigator-initiated, randomized, open-label, clinical trial that evaluated the combination of ME-344 and bevacizumab, (marketed as Avastin®), an anti-angiogenic therapy, in 42 women with early HER2-negative breast cancer. Results the study were published in the November 2019 issue of Clinical Cancer Research.
The primary objective of the trial was to show proof of ME-344 biologic activity as measured by Ki67 reductions in the presence of the nuclear protein Ki67 (expression of which is strongly associated with tumor cell proliferation and growth) from days 0 to 28 compared to the control group who received bevacizumab alone. Secondary objectives included determining whether ME-344 biologic activity correlates with vascular normalization. The data demonstrate significant biologic activity in the ME-344 treatment group:
- In ME-344 treated patients, mean absolute Ki67 decreases were 13.3 compared to an increase of 1.1 in the bevacizumab monotherapy group (P=0.01).
- In ME-344 treated patients, mean relative Ki67 decreases were 23% compared to an increase of 186% in the bevacizumab monotherapy group (P < 0.01).
- The mean relative Ki67 reduction in patients experiencing vascular normalization in the ME-344 treated patients was 33%, compared to an increase of 11.8% in normalized patients from the bevacizumab monotherapy group (P=0.09). Approximately one-third of patients in each arm had vascular normalization.
Treatment was generally well tolerated; three grade 3 adverse events of high blood pressure were reported, two in the ME-344 arm and one in the bevacizumab monotherapy arm.
Results from our 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 trial. 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 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.
ME-344 has been evaluated in patients with solid tumors, which represent the most common type of cancer. Most solid tumors are carcinomas, which usually begin in the skin or the surface of internal organs and glands.
ME-344 is being evaluated in combination with bevacizumab, (marketed as Avastin®) in a Phase 1b study in patients with with previously treated metastatic colorectal cancer.