Rapid Magnetomotive Thrombolysis for Stroke

描述(申请人提供)：急性缺血性中风(AIS)是脑动脉血栓形成的结果。它仍然是头号杀手和长期致残的主要原因，每年影响超过70万美国人[10]。由于脑组织迅速死亡，再灌注时间对于防止死亡和改善神经预后都至关重要。虽然目前美国每年与缺血性中风相关的费用很高，但预计到2030年，这些费用将从2013年的70亿美元增加到1830亿美元[14]。静脉注射组织纤溶酶原激活剂(TPA)仍然是AIS的标准治疗方法[15]，尽管完全恢复的几率很小，只有10%，死亡或严重残疾的几率为65%[16]。虽然tPA已被证明在AIS[11][12][13]中提供了统计上显著的好处，尽管很低，但 与tPA相关的剂量依赖性出血在美国导致了低~8%的给药率。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。由于流体动力学差，所有溶栓药物的有效性是因为它们不能迅速扩散到闭塞血管中的凝块[17]。脉搏 治疗公司的S(PTI)的专利和临床研究技术克服了这一限制，通过使用受外部磁体控制的非tPA附着的磁铁矿颗粒，显著加快了tPA向血栓的输送速度。这项技术在基线CT后部署在急诊科。然而，通过将FDA批准的药物tPA附着到PTI的磁铁矿颗粒上，该技术承诺以显著较低的tPA剂量(允许扩展到几乎所有缺血性中风)更快地溶解血栓(推动更好的神经系统结果)。PTI的目标是通过将tPA连接到该公司的磁性颗粒来证明在溶栓方面的显著改善。在第一阶段，PTI将尝试1)开发性能最好的tPA涂层结合到表面的最佳磁铁矿颗粒，2)收集候选颗粒的凝块溶解率和体外适当剂量的数据，3)优化自动颗粒收集的软件算法，以及4)与FDA举行提交前会议。对于第二阶段，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包衣颗粒，以及7)组装数据包，为后续FDA IDE提交做准备。这项拟议的技术对AIS的治疗具有戏剧性的影响。通过附着在磁性颗粒上将tPA直接输送到血栓表面，血栓溶解将更快地发生，并导致更好的神经预后，同时药物相关的毒性效应可能被消除，从而将溶栓治疗从目前符合条件的最高中风患者的30%扩大到潜在的所有缺血性中风患者。

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.