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

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

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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/计划主任（最后，第一，中间：陈，里登抽象的双重抗血小板疗法（阿司匹林 + P2Y12拮抗剂）加上辅助抗血栓治疗抗凝剂（肝素或双伏丁素）是一种已建立的经皮冠状动脉介入治疗方案（PCI）患者。尽管有积极的抗血栓疗法，但PCI后的心肌灌注仍然不足在许多患者中。复发性血栓形成和限制剂量的出血并发症继续发生大量患者。尝试进一步改善临床结果的尝试导致了更有效的血小板P2Y12抑制剂，包括Prasugrel和Ticagrelor，以及直接因子XA抑制剂， Rivaroxaban和Apixaban（未批准用于PCI），但会增加出血并发症。而且，没有当前的抗血栓形成可有效保护冠状动脉微血管阻塞。这导致伴有炎症的微吸收，这是患者预后的决定因素，独立于梗塞大小。显然，急性AMI治疗的下一个里程碑是打破抗血栓形成之间的联系效力和出血风险，并保护心肌和冠状动脉微循环免受再灌注损伤这会导致慢性不良左心室重塑和心力衰竭。 APT402是一种新型的治疗性融合蛋白，可提供优化的人apyrase和Annexin V 抗血小板，抗凝剂和心脏保护活动。我们假设融合将针对对冠状动脉血栓形成部位的抗血栓形成效应，并协同减弱血栓形成和再灌注受伤的风险最小。在兔颈动脉电损伤模型中，APT402优选与受伤的部位和血栓。用氯吡格雷，ticagrelor，低分子量肝素或仅双伐鲁丁就无法完全防止闭塞，而出血显着增加。相反，APT402 保持100％通畅，而不会增加出血时间，PT或APTT。令人惊讶的是，APT402更有效衰减的动脉血栓形成比ticagrelor和bivalirudin。在此直接II阶段SBIR应用中，我们提出了确定使用APT402的急性治疗是否更有效地保护微血管循环和在临床相关的血栓形成性心肌梗塞模型中改善心脏功能，同时还原与Ticagrelor Plus肝素相比，出血风险是PCI期间的PCI标准治疗径向通道的当代时代。我们还组建了一个经验丰富的药物开发团队，将提前启用IND申请所需的关键活动。具体目标1。使用血栓形成冠状动脉微栓塞的猪模型，确定是否是否 APT402更有效地减少冠状动脉微血管阻塞，并在60天后提高LV功能与Ticagrelor Plus肝素相比，再灌注较少。特定目标2。制造CGMP APT402。特定目标3。评估APT402的非临床安全性。成功完成拟议的研究将强烈支持IND提交和临床试验以改进数百万急性心肌梗塞和其他血栓性疾病的患者的结局。