Phase 1 Clinical Evaluation of NP10679, a GluN2B Selective,Context-Dependent NMDA Receptor Inhibitor for Subarachnoid Hemorrhage

Abstract Subarachnoid hemorrhageSAHremains a serious source of neurological morbiditywith approximatelycases reported in the US each yearDespite advances in treating the initial and subsequent bleedspost surgical clipping of the aneurysm is associated with a significant risk of delayed cerebral ischemiaDCIThese events typically occur within the firstdays after aneurysmal rupture and DCI remains the single most important cause of morbidity and mortality in those patients who survive the initial bleedAdditional medicines are needed since nimodipinethe only intervention approved for the conditionprovides onlyrescue from neurological and cognitive deficitsrendering SAH an important unmet clinical needPreclinical evidence demonstrates that prolonged exposure of neurons to glutamate released during cerebral ischemia leads to cell death that is largely mediated through N methyl D aspartate receptorsNMDARsInhibition of NMDA receptors including the GluN B subtype greatly reduces neuronal damage due to brain ischemiaNPis a highly selectivepH dependent inhibitor of the GluN B subtype of the NMDAR with negligible activity at the other NMDAR subtypesThe property of pH dependence improves the chances of achieving efficacy at dose levels that limit untoward effectsThe selectivity and specificity of NPallows for prophylactic use in patients at risk for an ischemic eventi efollowing SAHThis is important because extensive data reveal most robust neuroprotection when NMDAR blockers are administered prior to the ischemic insultThe intended intervention strategy takes advantage of the prophylactic use of NPin SAH driven DCI to avoid a time of dosing caveat that mightin parthave led to previous failures of clinical tests glutamatergic agents in stroke and head traumaIn AugustFDA reviewed NeurOpandapos s NPIND application and informed NeurOp that it had opened the IND but placed it on clinical hold until final drug product would be manufacturedThe safety tolerability package along with the clinical plan and protocols used to support clinical development were accepted without commentThe studies proposed in the current grant application could lead to validation of pharmacologic neuroprotectant therapy in brain ischemia by qualifying NPfor future efficacy studies in phase II and IIIWe propose to manufacture enough NPdrug product to complete phase I clinical studies in order to remove the clinical hold on the INDWe will than proceed to single and multiple ascending dose studies in normal healthy volunteers with the goal of gathering all data and documentation to move on to phase II studies in SAH patients Project Narrative This grant requests support to manufacture drug product and to conduct phase I clinical trials both single and multiple ascending dose studies for NPa selective context dependent GluN B NMDA receptor inhibitorThis work is intended to support eventual phaseefficacy testing for amelioration of neurological and cognitive deficit in patients suffering a subarachnoid hemorrhage