Our family of NADH oxidase inhibitors have demonstrated single-agent activity as well as synergy with both cytotoxic and targeted therapeutics in vitro and in vivo. NADH oxidase is a regulator of the plasma membrane quinone-quinol cation pump that is selectively expressed in rapidly proliferating tumor cells. The biochemical target of inhibition is the sphingosine kinase-Akt signaling pathway, which induces caspase-mediated apoptotic cell death.
Phenoxodiol has been administered to more than 400 patients in clinical trials via oral or intravenous routes and appears to be well tolerated with low toxicity. In a Phase II clinical trial of intravenous Phenoxodiol in combination with platinum-based chemotherapy in women with recurrent ovarian cancer, a clinical response was observed in 19% of patients (three out of 16). These results were published in the May 2011 issue of the International Journal of Gynecological Cancer.
By contrast, in a randomized, placebo-controlled Phase III clinical trial of oral Phenoxodiol in combination with platinum-based chemotherapy in women with advanced ovarian cancer resistant or refractory to platinum-based drugs, a clinical response was observed in less than 1% of patients (one out of 142).
Furthermore, pharmacokinetic studies suggest that significantly higher levels of active drug are measured when next-generation compounds of Phenoxodiol are administered intravenously versus orally. As a result of these findings and our clinical experience to date, we are developing our next-generation compound, ME-143, using an intravenous formulation.
Pre-clinical studies show that ME-143, a next-generation analogue of Phenoxodiol, demonstrates superior anti-tumor activity against a broad range of tumor cell lines when used alone or in combination with platinum-based chemotherapy when compared to Phenoxodiol. As a result, ME-143 was selected as the lead drug candidate for our NADH oxidase inhibitor program.
Our Investigational New Drug (IND) application was approved by the U.S. Food and Drug Administration (FDA) in August 2011. We initiated a Phase I clinical trial of intravenous ME-143 in patients with refractory solid tumors in September 2011. The Phase I trial was designed to evaluate the the safety and tolerability of intravenous ME-143 and characterize its pharmacokinetic profile.
Dr. Carla Kurkjian, co-investigator at the University of Oklahoma Health Sciences Center, presented results from the Phase I trial at the American Society of Clinical Oncology (ASCO) Annual Meeting in June 2012. ME-143 was generally well tolerated at all dose levels on a weekly dosing schedule and the maximum tolerated dose was defined as 20 mg/kg.
We are now preparing for a Phase II clinical trial of intravenous ME-143 in combination with standard-of-care in recurrent ovarian cancer and/or triple-negative breast cancer.