Multi-functional anti-thrombotic therapy for coronary microvascular obstruction

首席调查员/项目主任(最后、第一、中间：陈日东 摘要 双重抗血小板疗法(阿司匹林+P2Y12拮抗剂)联合应用辅助抗血栓治疗 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。尽管积极的抗血栓治疗，但经皮冠状动脉介入治疗后心肌灌注仍然不足。 在很多病人身上。反复血栓形成和限制剂量的出血并发症继续发生在 数量可观的病人。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，包括普拉格雷和替卡格雷，以及直接因子Xa抑制剂， 利伐沙班和阿皮沙班(非经皮冠状动脉介入治疗)，但增加出血并发症。此外，没有一个人 目前的抗血栓药物对冠状动脉微血管阻塞提供了有效的保护。这将导致 微梗塞伴有炎症，这是患者预后的决定因素，独立于 心肌梗死面积。显然，急性心肌梗死治疗的下一个里程碑是打破抗血栓治疗之间的联系 效力和出血风险以及保护心肌和冠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，它是优化的人apyrase和Annexin V的融合蛋白，可以提供 抗血小板、抗凝血剂和心脏保护活性。我们假设聚变的目标是 对冠状动脉血栓形成部位的抗血栓作用及协同减轻血栓形成和再灌流作用 受伤，出血风险最小。在兔颈动脉电损伤模型中，APT402最好结合到 受伤的部位和血栓。使用氯吡格雷、替卡格雷、低分子肝素或 单用比伐卢定不能完全预防闭塞，并显著增加出血。相比之下，APT402 保持100%通畅，不增加出血时间、PT或aPTT。令人惊讶的是，APT402更有效 比替卡格雷加比伐卢定更能减轻动脉血栓形成。在这个直接的第二阶段SBIR应用中，我们建议 为了确定APT402急性治疗是否更有效地保护微血管循环和 改善临床相关血栓性心肌梗死模型的心功能，同时降低 与替卡格雷加肝素的出血风险比较，在冠状动脉介入治疗中的标准护理治疗 当代的径向通道时代。我们还组建了一支经验丰富的药物开发团队，并将 推进启用IND备案所需的关键活动。 具体目的1.使用猪血栓形成冠脉微栓塞术模型，确定 APT402能更有效地减少冠脉微血管阻塞，改善左心功能 与替卡格雷加肝素相比，再灌注出血更少。 具体目标2.生产cGMP级APT402。 具体目的3.评价APT402的非临床安全性。 拟议研究的成功完成将有力地支持IND申请和临床试验的改进 数百万急性心肌梗死和其他血栓性疾病患者的预后。

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.