Rapid Magnetomotive Thrombolysis for Stroke

快速磁动力溶栓治疗中风

• 批准号: 9066982
• 负责人: Francis Milton Creighton
• 金额: $ 74.63万
• 依托单位: PULSE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2017-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9066982
• 关键词: Accident and Emergency department; Acute; Address; Algorithmic Software; Algorithms; Alteplase; American; Animals; Automobile Driving; Biochemical; Biological Assay; Biological Availability; Blood coagulation; Blood flow; Brain; Caring; Cessation of life; Classification; Clinical; Clinical Trials; Coagulation Process; Collection; Cytolysis; Data; Devices; Diffuse; Diffusion; Dose; Dose-Rate; Effectiveness; Enrollment; FDA approved; Failure; Fibrinolytic Agents; Futility; Goals; Guidelines; Health; Hemorrhage; Human; Hypotension; In Vitro; International; Intravenous; Investigation; Ischemic Stroke; Kinetics; Knowledge; Lead; Legal patent; Liquid substance; Location; Magnetism; Measures; Modeling; Neurologic; Neurological outcome; Outcome; Performance; Pharmaceutical Preparations; Phase; Physiologic pulse; Pilot Projects; Population; Pre-Clinical Model; Preparation; Procedures; Recommendation; Recovery; Reperfusion Therapy; Research; Risk; Safety; Site; Small Business Innovation Research Grant; Solutions; Stroke; Surface; System; Technology; Testing; Therapeutic; Thrombolytic Therapy; Time; Toxic effect; Uncertainty; United States; Visual; base; biomaterial compatibility; brain tissue; cerebral artery; commercialization; cost; design; disability; experience; improved; intravenous administration; magnetite ferrosoferric oxide; meetings; minimally invasive; particle; pre-clinical; preclinical efficacy; preclinical safety; preclinical study; prevent; prototype; standard of care; success; thrombolysis; treatment effect

DESCRIPTION (provided by applicant): Acute ischemic stroke (AIS) is the result of a blood clot in a cerebral artery. It remains a leading killer and the leading cause of long-term disabilit, annually impacting over 700,000 Americans [10]. Because brain tissue rapidly dies, time to reperfusion is critical in both preventing death and improving neurological outcomes. While current annual costs related to ischemic stroke are high in the United States (US), they are projected to increase from $72B in 2013 to $183B by 2030 [14]. Intravenous (IV) administration of tissue plasminogen activator (tPA) remains the standard of care for AIS [15], despite a small ~10% chance for a full recovery and a >65% chance of death or severe disability [16]. While tPA has been proven to offer statistically-significant benefits, albeit low, in AIS [11] [12] [13], the dose- dependent bleeding associated with tPA has resulted in a low ~8% administration rate in the US. As a result, a large majority of stroke victims are greatly underserved despite efforts to improve standards of care. Due to poor fluid dynamics, the effectiveness of all thrombolytic drugs is because of their inability to rapidly diffuse to a clot in the occluded vessel [17]. Pulse Therapeutics, Inc.'s (PTI's) patented and clinically- investigated technology has overcome this limitation in a way that dramatically accelerates tPA delivery to a clot by using non-tPA-attached magnetite particles controlled by an external magnet. This technology is deployed in the emergency department after the baseline CT. However, by attaching the FDA-approved drug tPA to PTI's magnetite particles, the technology promises faster clot lysis (driving better neurological outcomes) at a substantially lower tPA dose (allowing expansion to nearly all ischemic strokes). PTI's objective is to demonstrate dramatic improvements in thrombolysis by attaching tPA to the company's magnetic particles. In Phase I, PTI will attempt to 1) develop optimal magnetite particles with the best- performing tPA coating conjugated to the surface, 2) collect data on the candidate particle's clot lysis rate and proper dosing in vitro, 3) optimize a software algorithm for automated particle collection, and 4) conduct a pre- submission meeting with the FDA. For Phase II, PTI will 5) modify an existing PTI magnet system suitable for use in pre-clinical animal studies, 6) identify the best tPA-coated particle from safety and efficacy GLP preclinical studies, and 7) assemble a data package in preparation for a subsequent FDA IDE submission. The proposed technology has dramatic implications for the treatment of AIS. By delivering tPA directly to the clot's surface via attachment to magnetic particles, clot lysis willto occur faster and result in better neurological outcomes, while drug-related toxicity effects may be eliminated, thereby expanding thrombolytic therapy from the ~30% maximum stroke victims eligible today, to potentially all ischemic stroke victims.

描述（由申请人提供）： 急性缺血性中风（AIS）是脑动脉血栓的结果。它仍然是主要杀手和长期残疾的主要原因，每年影响超过 70 万美国人 [10]。由于脑组织会迅速死亡，因此再灌注时间对于预防死亡和改善神经系统结果至关重要。虽然目前美国 (US) 与缺血性中风相关的年度费用很高，但预计到 2030 年将从 2013 年的 $72B 增加到 $183B [14]。静脉 (IV) 施用组织纤溶酶原激活剂 (tPA) 仍然是 AIS 的标准治疗方法 [15]，尽管完全康复的可能性很小，约为 10%，死亡或严重残疾的可能性 > 65% [16]。虽然 tPA 已被证明可以在 AIS 中提供具有统计意义的显着益处（尽管较低）[11][12][13]， 在美国，与 tPA 相关的剂量依赖性出血导致给药率低至 8%。因此，尽管努力提高护理标准，但大多数中风患者的服务严重不足。由于流体动力学较差，所有溶栓药物的有效性是因为它们无法快速扩散到闭塞血管中的凝块[17]。脉冲 Therapeutics, Inc. (PTI) 的专利和临床研究技术克服了这一限制，通过使用由外部磁铁控制的非 tPA 附着的磁铁矿颗粒，显着加速 tPA 向凝块的输送。该技术在基线 CT 之后部署在急诊科。然而，通过将 FDA 批准的药物 tPA 附着到 PTI 的磁铁矿颗粒上，该技术有望以低得多的 tPA 剂量（允许扩展到几乎所有缺血性中风）更快地溶解血栓（带来更好的神经系统结果）。 PTI 的目标是通过将 tPA 附着到公司的磁性颗粒上来证明溶栓效果的显着改善。在第一阶段，PTI 将尝试 1) 开发具有性能最佳的 tPA 涂层的最佳磁铁矿颗粒，2) 收集候选颗粒的凝块溶解率和体外适当剂量的数据，3) 优化软件算法自动颗粒收集，以及 4) 与 FDA 召开提交前会议。对于第二阶段，PTI 将 5) 修改适合用于临床前动物研究的现有 PTI 磁体系统，6) 从安全性和有效性 GLP 临床前研究中确定最佳的 tPA 涂层颗粒，以及 7) 组装准备中的数据包用于后续 FDA IDE 提交。所提出的技术对 AIS 的治疗具有重大影响。通过附着在磁性颗粒上，将 tPA 直接输送到凝块表面，凝块溶解将发生得更快，并产生更好的神经系统结果，同时可以消除药物相关的毒性作用，从而将溶栓治疗范围扩大到当今符合条件的最大中风患者的约 30% ，可能适用于所有缺血性中风患者。