Adjunctive Use of Apyrase to Fibrinolytic Therapy

腺苷三磷酸双磷酸酶辅助纤溶治疗

基本信息

批准号：
8315704
负责人：
RIDONG CHEN
金额：
$ 72.96万
依托单位：
APT THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-07 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8315704
关键词：
Accounting Acute Acute myocardial infarction Adenosine Adverse event Aftercare Alteplase Amino Acid Substitution Anti-Inflammatory Agents Anti-inflammatory Applications Grants Apyrase Aspirin Attenuated Award Bleeding time procedure Blood Platelets Blood Vessels Blood flow Canis familiaris Cardiac Cause of Death Cell Line Chinese Hamster Ovary Cell Clinical Coronary Data Developed Countries Disease Dose Endotoxins Enzymes Event Exhibits Fibrinolysis Fibrinolytic Agents Goals Hemorrhage Hemostatic function Heparin Homeostasis Hour Human Hypoxia Incidence Infarction Injury Investigational New Drug Application Left Ventricular Function Licensing Maintenance Marketing Modeling Morbidity - disease rate Myocardial Infarction Myocardial Reperfusion Myocardial perfusion Oryctolagus cuniculus Outcome Patients Perfusion Phase Platelet Activation Preparation Procedures Proteins Recurrence Regimen Reperfusion Injury Reporting Risk Safety Site Small Business Innovation Research Grant Therapeutic Thrombolytic Therapy Thrombosis Tissues Toxic effect adverse outcome attenuation clinically relevant clopidogrel commercial application cost effective desensitization drug development experience extracellular follow-up immunogenicity improved mortality myocardial infarct sizing prevent programs research clinical testing thrombolysis vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Acute myocardial infarction is the leading cause of death in most industrialized nations. The estimated annual incidence in the US is 865,000 events, with ST-segment elevation myocardial infarction (STEMI, severe AMI) comprising an estimated 500,000 events per year. Fibrinolytic therapy is widely utilized to restore coronary blood flow due to its widespread availability to the broad cross-section of patients. The current regimen, including tissue plasminogen activator, aspirin, clopidogrel and heparin, still induces inadequate coronary reperfusion in 30-40% of patients and early thrombotic reocclusion in 5-10% patients. Moreover, successful recanalization causes detrimental reperfusion injury that accounts for up to 50% of the final size of a myocardial infarct. Net clinical adverse outcomes remain 10-12% at 30 days after treatment and 16-17% STEMI patients die during 1-year follow-up. Moreover, both morbidity and mortality are dramatically increased in patients experiencing peri-procedure bleeding. Importantly, most of the recurrent MI and major bleeding events occur in the first hours and days after treatment. Consequently, the search for more efficacious and safer acute antithrombotic agents with effective attenuation of reperfusion injury remains the "holy grail' of drug development. APT102 is an optimized human apyrase with two amino acid substitution that has significantly higher activity than the wild-type apyrases. This enzyme inhibits platelet activation and limits vascular inflammation by enzymatically hydrolyzing extracellular ADP and ATP. Adenosine is further generated by CD73 which prevents tissue damage during hypoxia and in the setting of cardiac reperfusion injury. In addition, APT102 prevents platelet desensitization and maintains homeostasis. With the Phase I award, we demonstrated that in the r-tPA induced fibrinolysis model in dogs, treatment of APT102 completely prevented re-occlusion, maintained normal blood flow, and profoundly reduced infarct size of hearts by 80% compared with clopidogrel. Meanwhile, APT102 did not prolong bleeding time, as did clopidogrel. The goal of this Phase II SBIR grant application is to rigorously determine whether in the coronary fibrinolysis model in dogs, APT102 promotes improved myocardial perfusion and left ventricular function with minimal bleeding compared with clopidogrel. The long-term goal is to develop APT102 as a highly effective antithrombotic and anti-inflammatory therapy with minimal bleeding risk that will profoundly improve efficacy and safety of acute treatment for AMI and other thrombotic patients. PUBLIC HEALTH RELEVANCE: The goal of this Phase II SBIR grant application is to rigorously determine whether in the coronary fibrinolysis model in dogs, APT102 promotes improved myocardial perfusion and left ventricular function with minimal bleeding compared with clopidogrel.

描述（由申请人提供）：急性心肌梗塞是大多数工业化国家的主要原因。美国估计每年发生 865,000 起事件，其中 ST 段抬高型心肌梗死（STEMI，严重 AMI）每年估计有 500,000 起事件。由于纤溶疗法广泛适用于广大患者，因此被广泛用于恢复冠状动脉血流。目前的治疗方案，包括组织纤溶酶原激活剂、阿司匹林、氯吡格雷和肝素，仍然会导致 30-40% 的患者冠状动脉再灌注不足，并导致 5-10% 的患者出现早期血栓再闭塞。此外，成功的再通会导致有害的再灌注损伤，这种损伤占心肌梗塞最终面积的 50%。治疗后 30 天的净临床不良结果仍为 10-12%，16-17% 的 STEMI 患者在 1 年随访期间死亡。此外，经历围手术期出血的患者的发病率和死亡率均显着增加。重要的是，大多数复发性心肌梗死和大出血事件发生在治疗后的最初几小时和几天内。因此，寻找更有效、更安全、能有效减轻再灌注损伤的急性抗血栓药物仍然是药物开发的“圣杯”。APT102是一种优化的人腺苷三磷酸双磷酸酶，具有两个氨基酸取代，其活性显着高于野生型腺苷三磷酸双磷酸酶这种酶通过酶水解细胞外 ADP 和 ATP 来抑制血小板活化并限制血管炎症，CD73 进一步生成腺苷，从而防止组织损伤。此外，在缺氧和心脏再灌注损伤的情况下，APT102 可以防止血小板脱敏并维持稳态。通过 I 期试验，我们证明在狗的 r-tPA 诱导的纤维蛋白溶解模型中，APT102 的治疗完全防止了再闭塞。与氯吡格雷相比，APT102 维持了正常的血流，并且使心脏梗塞面积大大减少了 80%。同时，APT102 并没有像氯吡格雷那样延长出血时间。这项 II 期 SBIR 拨款申请的目标是严格确定在狗的冠状纤维蛋白溶解模型中，与氯吡格雷相比，APT102 是否能改善心肌灌注和左心室功能，同时出血最少。长期目标是将APT102开发为出血风险最小的高效抗血栓和抗炎疗法，将深刻提高AMI和其他血栓患者急性治疗的疗效和安全性。公共健康相关性：本次 SBIR 资助申请的第二阶段目标是严格确定在犬冠状动脉纤溶模型中，与氯吡格雷相比，APT102 是否能改善心肌灌注和左心室功能，同时出血最少。