Rapid Magnetomotive Thrombolysis for Stroke

快速磁动力溶栓治疗中风

• 批准号: 8833670
• 负责人: Francis Milton Creighton
• 金额: $ 21.88万
• 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 2015-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8833670
• 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; 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; public health relevance; 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）：急性缺血性卒中（AIS）是脑动脉中的血块所致。它仍然是一个主要的杀手和长期残疾的主要原因，每年影响超过70万美国人[10]。由于脑组织迅速死亡，再灌注时间对于预防死亡和改善神经功能结局至关重要。虽然目前美国（US）与缺血性卒中相关的年度成本较高，但预计到2030年将从2013年的720亿美元增加到1830亿美元[14]。组织纤溶酶原激活剂（tPA）静脉（IV）给药仍然是AIS的标准治疗[15]，尽管完全恢复的可能性很小，约为10%，死亡或重度残疾的可能性>65%[16]。虽然tPA已被证明在AIS中提供了显著的益处，尽管很低[11] [12] [13]， 与tPA相关的剂量依赖性出血导致美国的给药率较低，约为8%。因此，尽管努力提高护理标准，但绝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都是因为它们无法快速扩散到闭塞血管中的凝块[17]。脉冲 治疗公司的（PTI的）专利和临床研究的技术已经克服了这种限制，其方式是通过使用由外部磁体控制的非tPA附着的磁铁矿颗粒来显著加速tPA向凝块的递送。该技术在基线CT后部署在急诊科。然而，通过将FDA批准的药物tPA连接到PTI的磁铁矿颗粒上，该技术有望以更低的tPA剂量（允许扩展到几乎所有的缺血性中风）更快地溶解凝块（驱动更好的神经学结果）。PTI的目标是通过将tPA附着在该公司的磁性颗粒上来证明溶栓的显著改善。在第一阶段，PTI将尝试1）开发最佳的磁铁矿颗粒，其表面结合有性能最佳的tPA涂层，2）收集候选颗粒的凝块溶解速率和体外适当剂量的数据，3）优化自动颗粒收集的软件算法，以及4）与FDA进行预提交会议。对于II期，PTI将5）修改适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tPA涂层颗粒，以及7）收集数据包，为后续FDA IDE提交做准备。该技术对AIS的治疗具有重大意义。通过将tPA直接递送到凝块的表面，凝块溶解将发生得更快，并导致更好的神经学结果，同时可以消除药物相关的毒性作用，从而将溶栓治疗从目前约30%的最大中风患者扩展到潜在的所有缺血性中风患者。