PARP inhibitory therapy of acute ischemic stroke

描述(申请人提供)：中风激活核酶多聚(ADP-核糖)聚合酶(“PARP”)，触发细胞发生坏死和炎症。伊诺克的超强临床PARP抑制剂(“INO-1001‘)可显著减少短暂性和永久性脑缺血大鼠中风模型中的组织坏死和神经功能障碍。我们的数据与中风小鼠的基因缺失研究一致，该研究表明在大脑中动脉闭塞模型中有80%的神经保护。我们现在提议进行一项临床研究，以证实INO-1001在急性中风人群中的耐受性、药代动力学和安全性。 基于INO-1001在健康人中的临床研究，我们预计INO-1001将是 耐受性良好且安全，并在服药后24小时内保持治疗药物的血药浓度 单次推注。我们将通过开展一项前瞻性的开放标签多中心研究来检验这一假设 30例有临床诊断和CT证实的急性非腔隙病变患者 缺血性中风。计划进行剂量递增，每个剂量水平n=10名受试者组成队列。 将持续监测和观察受试者的生命体征、体检、 心电图、代谢状态、临床化学、血液学和凝血 参数和血药浓度。虽然临床结果将被记录下来，但这不是 旨在作为一项治疗试验，而WALL包括能够同意自己的稳定患者 并报告症状，进行更详细的药代动力学和耐受性监测 在大型多中心疗效研究中具有典型性。在后续的第二阶段SBIR中，我们将进行 在900名患者中进行了一项关键研究，以确定INO-1001在急性白血病人群中的疗效 非腔隙性缺血性卒中。我们将评估INO-1001对脑梗塞的影响，因为 2)神经功能障碍，如在基线、4天、1周、2周、 I个月按(A)NIHSS修正的Rankin和Barthel评分。

DESCRIPTION (provided by applicant): Stroke activates the nuclear enzyme poly (ADP-ribose) polymerase ("PARP"), triggering cells to undergo necrosis and inflammation. Inotek's ultrapotent clinical PARP inhibitor ("INO-1001') profoundly reduces tissue necrosis and neurologic dysfunction in transient and permanent ischemic rat stroke models. Our data are in agreement with genetic deletion studies in stroked mice, which demonstrate > 80% neuroprotection in MCA occlusion models. We now propose a clinical study of INO-1001 to confirm tolerability, pharmacokinetics, and safety in a population with acute stroke. Based on clinical studies of INO-1001 in healthy subjects, we expect that INO-1001 will be Well-tolerated and safe, and maintain therapeutic drug plasma concentrations for 24 hours after a single bolus. We will test this hypothesis by carrying out a prospective, open-label multi-center study of n=30 subjects presenting with a clinical diagnosis and CT confirmation of acute non-lacunar ischemic stroke. A dose-escalation is planned, structured in cohorts of n=10 subjects per dose level. Subjects will be continuously monitored and observed for alterations in vital signs, physical exam, electrocardiogram, metabolic status, and clinical chemistries, hematologic and coagulation parameters, and plasma drug concentration. Whilst clinical outcome will be recorded, this is not intended to be a therapeutic trial, and wall include stable patients, who are able to consent themselves and report symptoms, with more detailed pharmacokinetic and tolerability monitoring than would be typical in a large multi-center investigation of efficacy. In a follow-on Phase 2 SBIR, we will carry out a pivotal study of INO-1001 in 900 patients to establish efficacy in a population with acute non-lacunar ischemic stroke. We will assess the effect of INO-1001 on 1) brain infarction, as quantitated by MRI, and 2) neurologic dysfunction, as assessed at baseline, 4 days, I week, 2 weeks, and I month by (a) NIHSS modified Rankin and Barthel score.