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

NP10679（一种治疗蛛网膜下腔出血的 GluN2B 选择性、背景依赖性 NMDA 受体抑制剂）的 1 期临床评价

• 批准号: 9345917
• 负责人: George Walter Koszalka
• 金额: $ 216.39万
• 依托单位: NEUROP, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9345917
• 关键词: Adverse effects; Aneurysm; Applications Grants; Biological Markers; Brain; Brain Injuries; Brain Ischemia; Case Study; Cell Death; Cerebral Ischemia; Cessation of life; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Cognitive deficits; Craniocerebral Trauma; Data; Dependence; Development; Documentation; Dose; Dose-Limiting; Event; Failure; Future; Glutamatergic Agents; Glutamates; Goals; Grant; Heavy Metals; Human; Impairment; Intervention; Lead; Letters; Light; Mediating; Medicine; Methods; Morbidity - disease rate; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurologic; Neurologic Deficit; Neurons; Neuroprotective Agents; Nimodipine; Operative Surgical Procedures; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Population; Property; Protocols documentation; Published Comment; Qualifying; Regimen; Risk; Rupture; Safety; Sedation procedure; Source; Specificity; Sterility; Stroke; Subarachnoid Hemorrhage; Testing; Therapeutic Intervention; Time; Traumatic Brain Injury; Validation; Work; base; clinical development; design; disability; efficacy study; efficacy testing; genotoxicity; healthy volunteer; improved; inhibitor/antagonist; mortality; neuroprotection; patient population; phase 1 study; phase 2 study; pre-clinical; preclinical study; prevent; programs; prophylactic; research clinical testing

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.

抽象的 蛛网膜下腔出血（SAH）仍然是神经系统疾病的一个严重来源，大约有 美国每年报告 50,000 例病例。尽管在治疗初次出血和后续出血方面取得了进展， 动脉瘤手术后夹闭与迟发性脑缺血（DCI）的显着风险相关。 这些事件通常发生在动脉瘤破裂后的前 5-14 天内，DCI 仍然是唯一的 对于初次出血后幸存的患者来说，这是发病和死亡的最重要原因。额外的 需要药物，因为尼莫地平是唯一被批准用于治疗该疾病的干预措施，只能提供 30-40% 的效果 拯救神经和认知缺陷，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期间释放的谷氨酸 导致细胞死亡，这主要是通过 N-甲基-D-天冬氨酸受体 (NMDAR) 介导的。抑制 包括 GluN2B 亚型在内的 NMDA 受体大大减少了脑缺血引起的神经元损伤。 NP10679 是一种高度选择性、pH 依赖性的 NMDAR GluN2B 亚型抑制剂，其抑制作用可以忽略不计。 其他 NMDAR 亚型的活性。 pH 依赖性的特性提高了实现目标的机会 在限制不良反应的剂量水平上发挥功效。 NP10679 的选择性和特异性允许 有缺血事件风险的患者（即 SAH 后）预防性使用。这很重要，因为 大量数据表明，在治疗前给予 NMDAR 阻滞剂时，神经保护作用最强。 缺血性损伤。预期的干预策略利用了 NP10679 的预防性使用 SAH 驱动 DCI 避免剂量警告时间，这可能在一定程度上导致了之前临床试验的失败 测试中风和头部创伤中的谷氨酸能药物。 8月，FDA审核NeurOp的NP10679 IND 申请并通知 NeurOp 已开放 IND，但将其置于临床搁置状态，直至最终药物上市 产品将被制造。安全性/耐受性包以及所使用的临床计划和方案 支持临床开发被接受，没有评论。当前拨款中提出的研究 应用程序可以通过资格认证来验证脑缺血的药物神经保护疗法 NP10679 用于未来 II 期和 III 期疗效研究。我们建议生产足够的 NP10679 药物 产品完成 I 期临床研究，以解除 IND 的临床搁置。我们会比 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 所有数据和文件都将进入 SAH 患者的 II 期研究。