Our most advanced program is a family of NADH oxidase inhibitors that 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 introduced into hundreds of patients via oral or intravenous routes and appears to be well tolerated with low toxicity. In June 2010, we unblinded the results of our randomized OVATURE trial of orally administered Phenoxodiol in combination with platinum-based chemotherapy in women with recurrent ovarian cancer. The trial was closed in April 2009 with only 142 out of a planned 340 patients enrolled. The final analysis determined that the trial did not show a statistically significant improvement in either its primary (progression-free survival) or secondary (overall survival) endpoints.
Data from a comparable Phase II clinical trial of Phenoxodiol suggest that the OVATURE trial’s fundamental error was in its design, specifically the route of administration. In the Phase II trial, six out of 20 patients (30%) responded to intravenously administered Phenoxodiol in combination with platinum-based chemotherapy. By contrast, only one out of 142 patients (<1%) enrolled in OVATURE achieved a clinical response in either arm, indicating that Phenoxodiol does not synergize with platinum-based drugs when administered orally.
Furthermore, pharmacokinetic studies confirm that significantly higher levels of free drug are measured when this class of compounds is administered intravenously versus the oral route. In these studies, levels of free drug were detected at or below the lower limit of quantitation following oral administration – likely due to a mechanism of inactivation called glucuronidation and/or sulfation, the body’s attempt to remove an agent from circulation through the addition of a sugar or a sulfate group. As a result, we intend to pursue the clinical development of our next-generation compound, NV-143, using an intravenous formulation.
ME-143 is the primary active metabolite that is produced when Triphendiol, a second-generation derivative of Phenoxodiol, is introduced in vivo. Pre-clinical studies show that ME-143 demonstrates superior anti-tumor activity against a broad range of tumor cell lines compared to both Phenoxodiol and Triphendiol.
In addition to being more active as a single agent, ME-143 is far superior in its ability to synergize with platinum-based chemotherapy, making ME-143 the straightforward choice as the lead product candidate for this program. The U.S. Food and Drug Administration (FDA) has approved our Investigational New Drug (IND) application for ME-143 and we initiated a Phase I clinical trial of intravenous ME-143 in September 2011.