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

摘要 蛛网膜下腔出血（SAH）仍然是神经系统疾病的严重来源， 美国每年报告的病例为5万例。尽管在治疗初始和后续出血方面取得了进展， 动脉瘤的术后夹闭与迟发性脑缺血（DCI）的显著风险相关。 这些事件通常发生在脑出血后的前5-14天内，DCI仍然是唯一的 是初次出血后存活的患者发病和死亡的最重要原因。额外 药物是必需的，因为尼莫地平，唯一批准的干预条件，提供只有30-40%， 从神经和认知缺陷中拯救，使SAH成为一个重要的未满足的临床需求。临床前 有证据表明，神经元长时间暴露于脑缺血时释放的谷氨酸， 导致细胞死亡，其主要通过N-甲基-D-天冬氨酸受体（NMDAR）介导。抑制 包括GluN 2B亚型的NMDA受体大大减少了脑缺血引起的神经元损伤。 NP 10679是NMDAR的GluN 2B亚型的高度选择性pH依赖性抑制剂， 其他NMDAR亚型的活性。pH依赖性的性质提高了实现 剂量水平的有效性限制了不良反应。NP 10679的选择性和特异性允许 在有缺血性事件风险的患者中的预防性使用（即，SAH后）。这很重要因为 广泛的数据显示，当NMDAR阻滞剂在给药前给药时， 缺血性损伤预期的干预策略利用NP 10679的预防性使用， SAH驱动DCI以避免可能部分导致先前临床治疗失败的给药警告时间 在中风和头部创伤中测试神经递质。8月，FDA审查了NeurOp的NP 10679 IND 申请并通知NeurOp，它已经打开了IND，但将其置于临床暂停状态，直到最终药物 产品将被生产。安全性/耐受性包装沿着临床计划和使用的方案 用于支持临床开发，未加评论。目前补助金中建议的研究 应用可能导致脑缺血的药理学神经保护剂治疗的验证， NP 10679用于未来II期和III期疗效研究。我们建议生产足够的NP 10679药物 产品完成I期临床研究，以消除IND的临床搁置。我们将 在正常健康志愿者中进行单次和多次递增剂量研究，目的是收集 所有的数据和文件，以继续在SAH患者中进行II期研究。

Abstract Subarachnoid hemorrhage (SAH) remains a serious source of neurological morbidity, with approximately 50,000 cases reported in the US each year. Despite advances in treating the initial and subsequent bleeds, post-surgical clipping of the aneurysm is associated with a significant risk of delayed cerebral ischemia (DCI). These events typically occur within the first 5-14 days after aneurysmal rupture and DCI remains the single most important cause of morbidity and mortality in those patients who survive the initial bleed. Additional medicines are needed since nimodipine, the only intervention approved for the condition, provides only 30-40% rescue from neurological and cognitive deficits, rendering SAH an important unmet clinical need. Preclinical 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 receptors (NMDARs). Inhibition of NMDA receptors including the GluN2B subtype greatly reduces neuronal damage due to brain ischemia. NP10679 is a highly selective, pH dependent inhibitor of the GluN2B subtype of the NMDAR with negligible activity at the other NMDAR subtypes. The property of pH dependence improves the chances of achieving efficacy at dose levels that limit untoward effects. The selectivity and specificity of NP10679 allows for prophylactic use in patients at risk for an ischemic event (i.e., following SAH). This is important because extensive data reveal most robust neuroprotection when NMDAR blockers are administered prior to the ischemic insult. The intended intervention strategy takes advantage of the prophylactic use of NP10679 in SAH driven DCI to avoid a time of dosing caveat that might, in part, have led to previous failures of clinical tests glutamatergic agents in stroke and head trauma. In August, FDA reviewed NeurOp's NP10679 IND application and informed NeurOp that it had opened the IND but placed it on clinical hold until final drug product would be manufactured. The safety/tolerability package along with the clinical plan and protocols used to support clinical development were accepted without comment. The studies proposed in the current grant application could lead to validation of pharmacologic neuroprotectant therapy in brain ischemia by qualifying NP10679 for future efficacy studies in phase II and III. We propose to manufacture enough NP10679 drug product to complete phase I clinical studies in order to remove the clinical hold on the IND. We 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.