Treatment-naïve, early stage
|INDICATION||COMBINATION||CLINICAL PROOF OF CONCEPT||MARKETING APPROVAL STUDY||COMMERCIAL RIGHTS|
Treatment-naive, early stage
4 Investigator-initiated trial
ME-344 is our novel and tumor selective mitochondrial inhibitor drug candidate. ME-344 has been investigated clinically in patients with solid tumors. Most recently, data was reported at ASCO 2019 from an investigator-initiated, multi-center, randomized study in combination with the VEGF inhibitor bevacizumab (marketed as Avastin ®) in a total of 42 patients with HER2 negative breast cancer.
MEI holds worldwide rights to ME-344.
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 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.
In addition to monotherapy activity, ME-344 has demonstrated potential in combination with antiangiogenic therapeutics. In pre-clinical studies, it was shown that one outcome of anti-angiogenics was to reduce the rate of glycolysis in tumors as a mechanism to slow tumor growth. However, tumor metabolism was able to shift to mitochondrial metabolism for energy production to support continued tumor proliferation. In such cases of tumor plasticity, simultaneously targeting the mitochondria as the alternative metabolic source for ATP with ME-344 may open an important therapeutic opportunity.
ME-344 has been evaluated clinically in early stage clinical studies in patients with solid tumors. Most recently, clinical data was presented at ASCO 2019 from an investigator-initiated study evaluating ME-344 in combination with bevacizumab (marketed as Avastin®) in patients with early HER2-negative breast cancer demonstrating proof of biologic anti-tumor activity.
The clinical study was a multicenter, investigator-initiated, randomized, open-label trial evaluating ME-344 in a total of 42 patients with early HER2-negative breast cancer in combination with the vascular endothelial growth factor inhibitor bevacizumab. Patients were randomized one-to-one to either ME-344 plus bevacizumab or saline plus bevacizumab. The primary objective of the study was to show proof of ME-344 biologic activity as measured by Ki67 – a marker of cellular proliferation -reductions from day 0 to 28 compared to placebo. 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; two Grade 3 adverse events of high blood pressure were reported, 1 in each arm. Results from an earlier, first-in-human, monotherapy 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.