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

• 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
• 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

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.

主要研究者/项目负责人（末、中、首：陈日东 摘要 双联抗血小板治疗（阿司匹林+P2Y12拮抗剂）加辅助抗血栓治疗 抗凝剂（肝素或比伐卢定）是经皮冠状动脉介入治疗的既定治疗方案 (PCI)患者尽管进行了积极的抗血栓治疗，PCI术后的心肌灌注仍然不足 在许多患者中。复发性血栓形成和剂量限制性出血并发症继续发生， 大量患者。进一步改善临床结果的尝试导致了以下方面的发展： 更有效的血小板P2Y12抑制剂，包括普拉格雷和替格瑞洛，以及直接因子Xa抑制剂， 利伐沙班和阿哌沙班（未批准用于PCI），但会增加出血并发症。此外， 目前的抗血栓形成剂提供了有效的保护以防止冠状动脉微血管阻塞。这导致 伴有炎症的微梗死，这是患者预后的决定因素，独立于 梗死面积。显然，急性心肌梗死治疗的下一个里程碑是打破抗血栓药物与抗血栓药物之间的联系。 保护心肌和冠脉微循环免受再灌注损伤 导致慢性左心室重塑和心力衰竭 APT402是优化的人腺苷三磷酸双磷酸酶和膜联蛋白V的新型治疗性融合蛋白， 抗血小板、抗凝血和心脏保护活性。我们假设核聚变将针对 对冠状动脉血栓形成部位的抗血栓形成作用，并协同减弱血栓形成和再灌注 出血风险最小的创伤。在兔颈动脉电损伤模型中，APT402优选结合至 损伤部位和血栓。使用氯吡格雷、替格瑞洛、低分子量肝素或 单独的比伐卢定不能完全防止阻塞，出血显著增加。APT402 保持100%通畅，不增加出血时间、PT或aPTT。令人惊讶的是，APT 402更有效地 比替格瑞洛加比伐卢定更能减少动脉血栓形成。在这个直接的第二阶段SBIR应用中，我们建议 确定用APT402进行急性治疗是否更有效地保护微血管循环， 在血栓形成性心肌梗死的临床相关模型中改善心脏功能， 出血风险与替格瑞洛加肝素相比，替格瑞洛加肝素是PCI期间的标准治疗， 放射状通路的当代时代。我们还组建了一支经验丰富的药物开发团队， 推进必要的关键活动，以实现IND申报。 具体目标1.使用血栓形成性冠状动脉微栓塞的猪模型，确定是否 APT402更有效地减少冠状动脉微血管阻塞，并改善LV功能60天后 与替格瑞洛加肝素相比，再灌注出血更少。 具体目标2。生产cGMP级APT 402。 具体目标3。评估APT402的非临床安全性。 成功完成拟议的研究将有力地支持IND申报和临床试验，以改善 数百万急性心肌梗死和其他血栓性疾病患者的结局。