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Multi-functional anti-thrombotic therapy for coronary microvascular obstruction

多功能抗血栓治疗冠状动脉微血管阻塞

基本信息

批准号：
10696319
负责人：
RIDONG CHEN
金额：
$ 158.2万
依托单位：
APT THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10696319
关键词：
ANXA5 gene Activated Partial Thromboplastin Time measurement Acute Acute myocardial infarction Adenosine Anticoagulants Antiinflammatory Effect Antithrombin III Apyrase Aspirin Attenuated Autologous Benefits and Risks Binding Binding Sites Bleeding time procedure Blood Platelets Blood Vessels Blood flow Carotid Arteries Cause of Death Cell membrane Chimeric Proteins Chronic Circulation Clinical Clinical Trials Competitive Binding Coronary Coronary Occlusions Coronary Thrombosis Data Development Dose Dose Limiting EFRAC Endothelial Cells Enoxaparin Fibrinolytic Agents Functional disorder Generations Good Manufacturing Process Heart Heart failure Hemorrhage Heparin Homologous Gene Human Infarction Inflammation Inflammatory Injections Left Ventricular Remodeling Left ventricular structure Legal patent Leukocytes Life Link Low-Molecular-Weight Heparin Mediating Membrane Microcirculation Modeling Myocardial Infarction Myocardial perfusion Myocardium Obstruction Oryctolagus cuniculus Outcome Patients Phase Phosphatidylserines Platelet Activation Principal Investigator Proteins Radial Recommendation Recurrence Reperfusion Injury Reperfusion Therapy Risk Safety Site Small Business Innovation Research Grant Therapeutic Embolization Thrombin Thrombosis Thrombus Toxic effect Treatment Protocols Work antagonist attenuation bivalirudin cardioprotection clinically relevant clopidogrel drug development electrical injury experience extracellular factor IXa-factor VIIIa heart function improved improved outcome inhibitor injured innovation manufacture manufacturing process mortality myocardial damage novel novel therapeutics patient prognosis percutaneous coronary intervention pharmacologic porcine model preclinical study prevent programs protein expression prothrombinase complex research clinical testing restoration safety study standard of care thrombogenesis thrombotic vascular inflammation vascular injury

项目摘要

Principal Investigator/Program Director (Last, First, Middle: Chen, Ridong ABSTRACT Adjunctive antithrombotic treatment with dual antiplatelet therapy (aspirin + P2Y12 antagonist) plus anticoagulant (heparin or bivalirudin) is an established treatment regimen for percutaneous coronary intervention (PCI) patients. Despite aggressive antithrombotic therapy, myocardial perfusion after PCI remains inadequate in many patients. Recurrent thrombosis and dose-limiting bleeding complications continue to occur in a significant number of patients. Attempts to further improve clinical outcomes have led to the development of more potent platelet P2Y12 inhibitors including prasugrel and ticagrelor, and direct factor Xa inhibitors, rivaroxaban and apixaban (not approved for PCI), but increase bleeding complications. Moreover, none of the current antithrombotics provide effective protection against coronary microvascular obstruction. This results in microinfarcts accompanied by inflammation, which is a determinant of patient prognosis, independent from infarct size. Clearly, the next milestones for acute AMI treatment are to break the link between antithrombotic potency and bleeding risk and to protect the myocardium and coronary microcirculation against reperfusion injury that causes chronic adverse left ventricle remodeling and heart failure. APT402 is a novel therapeutic fusion protein of an optimized human apyrase and annexin V that provides antiplatelet, anticoagulant, and cardioprotective activities. We hypothesize that the fusion will target the antithrombotic effect to the site of coronary thrombosis and synergistically attenuate thrombosis and reperfusion injury with minimal bleeding risk. In a rabbit carotid artery electrical injury model, APT402 preferably bound to the injured site and to the thrombus. Treatment with clopidogrel, ticagrelor, low molecular weight heparin, or bivalirudin alone failed to fully prevent occlusion with significantly increased bleeding. In contrast, APT402 maintained 100% patency without increasing bleeding time, PT, or aPTT. Strikingly, APT402 more effectively attenuated arterial thrombosis than ticagrelor plus bivalirudin. In this direct Phase II SBIR application, we propose to determine whether acute treatment with APT402 more effectively protects microvascular circulation and improves heart function in a clinically relevant model of thrombogenic myocardial infarction, while reducing bleeding risks compared to ticagrelor plus heparin, the standard-of-care treatment during PCI in the contemporary era of radial access. We have also assembled an experienced drug development team and will advance critical activities necessary to enable IND filing. Specific Aim 1. Using a porcine model of thrombogenic coronary microembolization, determine whether APT402 more effectively reduces coronary microvascular obstruction and improves LV function 60 days after reperfusion with less bleeding compared to ticagrelor plus heparin. Specific Aim 2. Manufacture cGMP grade APT402. Specific Aim 3. Evaluate nonclinical safety of APT402. Successful completion of the proposed studies will strongly support IND filing and clinical trials to improve outcomes for millions of patients with acute myocardial infarction and other thrombotic diseases.

首席研究员/项目主任(倒数第一中：陈日东