Reducing Stroke by a Novel, Clot-dissolving Antibody

描述（由申请人提供）：中风是第三大死亡原因，也是严重、长期残疾的主要原因。每年有79.5万美国人中风，每年给经济造成的损失为579亿美元。绝大多数急性缺血性中风是由血栓（血凝块）引起的，血栓阻塞血管并阻止血液流向大脑。组织纤溶酶原激活剂（TPA）是一种催化血栓溶解的药物，是FDA批准的唯一有效的缺血性卒中治疗方法。不幸的是，TPA与显著的风险、治疗延迟相关，并且高达70%的患者在足够的时间内溶解血栓以保护大脑是不成功的。需要一种更安全、更有效的治疗方法，以促进早期治疗、挽救生命、减少残疾并降低医疗保健成本。在临床前研究中，我们已经表明，这些目标可以通过使纤溶酶的主要抑制剂失活的分子来实现，并且通过避免与TPA治疗相关的出血和神经毒性风险的独特机制来溶解凝块。根据FDA的指导，我们将这种分子转化为一种用于中风的生物候选药物（stroumab），可以有效地加速人体血栓的溶解。该快速通道申请的目标是通过遵循FDA指南将stroumab进一步推向人体试验：1）确定治疗的最佳制剂和治疗时间窗，2）在GLP条件下生产和纯化stroumab，3）研究stroumab的安全性，药代动力学和药效学，4）向FDA提交IND。

DESCRIPTION (provided by applicant): Stroke is the 3rd leading cause of death and the primary cause of severe, long term disability. Each year 795,000 Americans have a stroke and the annual costs to the economy are $57.9 billion. The vast majority of acute ischemic strokes are caused by a thrombus (blood clot) which occludes the blood vessel and stops blood flow to the brain. Tissue plasminogen activator (TPA), an agent that catalyzes the dissolution of blood clots, is the only effective, FDA-approved treatment for ischemic stroke. Unfortunately, TPA is associated with significant risks, delays in treatment, and is unsuccessful in up to 70% of patients at dissolving blood clots in sufficient time to protect the brain. There is a need for a safer, more effective therapy that facilitates early treatment, saves lives, reduces disability and lowers health care costs. In pre-clinical studies, we have shown that these goals might be achieved by a molecule that inactivates the major inhibitor of plasmin and, dissolves clots through a unique mechanism that avoids the risk of hemorrhage and neurotoxicity associated with TPA therapy. Following FDA guidance, we converted this molecule into a biologic drug candidate for stroke (stromab) that potently accelerates the dissolution of human clots. The goal of this Fast Track application is to move stromab further towards human trials by following FDA guidance to: 1) determine the optimal formulation and therapeutic time window for treatment, 2) produce and purify stromab under GLP conditions, 3) investigate the safety, pharmacokinetics and pharmacodynamics of stromab and, 4) submit an IND to the FDA.