Mitigating Taxol-Induced Neuropathy through Modulation of the NMDA Receptor



 DESCRIPTION (provided by applicant): Taxol (paclitaxel) is the one of the most widely used chemotherapy agents, and is a first-line treatment for ovarian, breast, lung, and colon cancer. Despite its well-documented anti-cancer properties, taxol is known to cause chemotherapy-induced peripheral neuropathy (CIPN). CIPN affects approximately 30% - 50% of all chemotherapy patients, and the neuropathic pain can be so severe that in some cases, chemotherapy treatments must be discontinued. Therapeutic options for patients with CIPN are currently very limited, and so a new approach for mitigating the effects of CIPN could have a significant clinical impact. Naurex is investigating a new approach to addressing CIPN. The company has developed a novel class of non-toxic, orally bioavailable compounds that modulate the N-methyl D-aspartate receptor (NMDAR) within the glutamatergic system. The NMDAR is involved in regulation of synaptic plasticity, and it is known that neuropathic pain results in the dysregulation of synaptic plasticity. Our preliminary data shows that Naurex's NMDAR partial agonists display a dose-dependent analgesic effect in a rat Taxol model of CIPN. A lead compound, NRX-2922, was identified from these initial studies that displays desirable pharmaceutical properties in addition to excellent activity in the rat Taxol model. The scope of this Phase I SBIR project is to conduct pre-clinical studies to further evaluate the therapeutic potential of NRX-2922 for mitigating CIPN. To this end, our Specific Aims are: Aim #1 Establish dose response of NRX-2922. Aim #2 Evaluate NRX-2922's therapeutic potential for prevention and treatment of CIPN. Aim #3 Evaluate pharmacokinetics and toxicity of NRX-2922 in combination with Taxol. Successful completion of this Phase I project will establish effective dosing regimens of NRX-2922 that will inform follow-on IND enabling studies as well as clinical trial protocols. Given the widespread use of taxol, and its proven effectiveness as a chemotherapeutic agent, the potential to reduce the main side-effect associated with its usage would be highly significant in the field of oncology.