Factor XI Inhibition for the Treatment of Ischemic Stroke

XI 因子抑制治疗缺血性中风

• 批准号: 8312324
• 负责人: Philberta Yuenhui Leung
• 金额: $ 31.57万
• 依托单位: ARONORA, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8312324
• 关键词: Activase; Acute; Adverse effects; Alteplase; Antibodies; Anticoagulants; Anticoagulation; Bleeding time procedure; Blood Vessels; Blood coagulation; Brain; Cause of Death; Cerebral Ischemia; Cerebrum; Chronic; Clinical; Coagulation Process; Data; Deterioration; Development; Event; FDA approved; FXII deficiency; Factor XI; Factor XI Deficiency; Factor XIIa; Fibrinolysis; Generations; Hemorrhage; Hemostatic Agents; Hemostatic function; Hour; Human; Immunoglobulin G; Impairment; Incidence; Infarction; Intracranial Hemorrhages; Ischemic Stroke; Maintenance; Marketing; Medical; Middle Cerebral Artery Occlusion; Modeling; Monoclonal Antibodies; Mus; Nervous System Trauma; Neurologic; Neurological outcome; Outcome; Papio; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Phase; Play; Reperfusion Therapy; Research; Risk Factors; Role; Safety; Serine Protease; Small Business Innovation Research Grant; Stroke; Testing; Therapeutic; Therapeutic antibodies; Thrombin; Thrombus; Time; Treatment Efficacy; United States; cerebral artery; combat; disability; drug candidate; high risk; improved; mortality; mouse model; novel; pre-clinical; preclinical study; prevent; success; thrombolysis

DESCRIPTION (provided by applicant): One of the underlying causes of acute ischemic stroke (AIS) is the thrombotic-thromboembolic occlusion of cerebral blood vessels. Early use of tissue-type plasminogen activator (tPA, Activase(R)), currently the only FDA-approved treatment for AIS, can promote reperfusion via thrombolysis. However, tPA treatment carries a high risk of fatal intracranial hemorrhage, which is a safety concern that limits the number of stroke victims who receive tPA treatment and achieve reperfusion. In addition, re-occlusion occurs in one third of tPA-treated AIS patients, alongside clinical deterioration following the initial improvement. Thus, there is a major unmet medical need for the development of a safe and effective antithrombotic treatment that is suitable for use in AIS patients, either alone or in combination with tPA. We propose that the ideal therapeutic strategy is to block the prothrombotic activation of coagulation factor XI (FXI). In humans, elevated FXI levels are an independent risk factor for AIS, while FXI deficiency is associated with protection from AIS both in humans and in mice. Our preliminary studies suggest that using our product candidate, anti-mammalian FXI antibody 14E11, to inhibit prothrombotic FXI activation by the contact factor XIIa (FXIIa) will protect mice from AIS. Since FXII deficiency does not cause bleeding, we hypothesize that 14E11, which does not inhibit hemostatic FXI activation, has great potential for the safe treatment of AIS. In addition, we hypothesize that 14E11 can increase the long-term efficacy of tPA by enhancing its efficacy and reducing the incidence of re-occlusion. Our research objective is to determine the therapeutic potential of 14E11 to treat AIS using a mouse model of AIS. Thus, the Specific Aims for this Phase I application are to: 1) Determine the efficacy of 14E11 for improving the outcome of experimental AIS; 2) Determine the efficacy of 14E11 in combination with fibrinolytic tPA to improve the outcome of experimental AIS; and 3) Determine the hemostatic safety of 14E11 alone and in combination with tPA. If successful, this Phase I project will provide evidence that the inhibition of FXI is a safe and promising therapeutic strategy to combat thrombotic AIS. Reaching our milestones will propel our project into Phase II, with the intent to initiate formal preclinical development of 14E11 for the safe treatment of AIS patients. PUBLIC HEALTH RELEVANCE: Treatment of acute ischemic stroke with the "clotbuster" drug tPA (Activase(R)) has serious bleeding complications, which limits its usage to less than 10% of patients. The proposed research evaluates our unique therapeutic antibody (14E11) that blocks pathological clot-promoting activation of coagulation factor XI (FXI) as a novel drug candidate for the treatment of stroke, which remains a leading cause of death and chronic disability. Since 14E11 is not expected to produce bleeding side-effects, this approach has the potential to provide a safe alternative or addition to other more dangerous antithrombotic treatments.

描述（由申请人提供）：急性缺血性卒中（AIS）的潜在原因之一是血栓-血栓栓塞性脑血管闭塞。早期使用组织型纤溶酶原激活剂（tPA, Activase(R)）是目前fda批准的唯一治疗AIS的药物，可通过溶栓促进再灌注。然而，tPA治疗具有致死性颅内出血的高风险，这是一个安全问题，限制了接受tPA治疗并实现再灌注的中风患者人数。此外，三分之一接受tpa治疗的AIS患者出现再闭塞，同时在最初改善后出现临床恶化。因此，开发一种安全有效的抗血栓治疗方法，适用于AIS患者，无论是单独使用还是合并使用，这是一个重大的未满足的医学需求