A Pilot Clinical Study in Acute STEMI

描述（由申请人提供）：经皮冠状动脉介入治疗（PCI）已成为ST段抬高型心肌梗死（STEMI）的主要治疗方法。早期再通无疑可以挽救心肌组织，而长期缺血后的再灌注也会加重损伤。由于急性心肌梗死（AMI）患者未死于院外心律失常，因此需要限制心室尺寸，并优化有利于适应性心室愈合和重塑的条件，长期预后取决于心肌丢失量和心室重塑的结果。分散因子/肝细胞生长因子（SF/HGF）是一种内源性细胞存活因子，具有急性和慢性心脏保护作用，可用于挽救缺血心肌。然而，SF/HGF作为基因或蛋白质治疗的可行性受到与腺病毒蛋白引起的免疫和炎症反应、蛋白质在溶液中的固有不稳定性、其有限的组织半衰期和与这种治疗相关的过高成本有关的问题的限制。在美国国立卫生研究院（NIH）小企业创新研究（SBIR）和快速介入发展（RAID）计划的支持下，我们鉴定并开发了一种新型小分子SF/HGF模拟物BB 3。BB 3在迄今为止测试的每个测定中重复天然蛋白质的生物活性。在模拟缺血再灌注损伤的单个心脏细胞模型中，BB 3减轻细胞凋亡和坏死死亡。在分离的灌注心脏中，BB 3改善缺血后功能，并且在体内实验性常温心肌缺血-再灌注中，当在再灌注开始后24小时施用时，全身性BB 3施用减弱梗塞大小。我们发现延迟给予BB 3也能减轻大鼠和猪的梗死后心室功能障碍，这在临床上具有重要意义。此外，延迟的BB 3给药在缺血性和/或创伤性损伤的肾、肝和脑模型中赋予功能和梗塞保留益处，防止这些器官转变为衰竭。在SBIR计划的支持下，已经完成了一系列全面的临床前监管研究，包括BB 3的遗传毒理学、体内毒理学和安全药理学研究。美国食品药品监督管理局（FDA）批准了BB 3的研究性新药（IND）申请，并且已经完成了在健康受试者中注射BB 3的I期、随机化、单盲、安慰剂对照、单剂量、剂量递增研究;未报告严重不良事件。该项目的总体目标是评价BB 3在急性ST段抬高型心肌梗死（A-STEMI）患者中成功接受经皮再灌注的临床疗效。 公共卫生相关性：小分子器官保护剂在ST段抬高型心肌梗死（STEMI）的治疗中具有重要的临床潜力。

DESCRIPTION (provided by applicant): Percutaneous coronary intervention (PCI) has become the mainstay for treatment of ST-segment elevation myocardial infarction (STEMI). Whereas early recanalization undoubtedly salvages myocardial tissue, reperfusion following prolonged ischemia can also exacerbate injury. Infarct size needs to be limited, and the conditions favoring adaptive ventricular healing and remodeling optimized because in patients with acute myocardial infarction (AMI) who do not die of out-of-hospital arrhythmias, long-term prognosis is dependent on the amount of myocardium that is lost, and the outcome of ventricular remodeling. Scatter factor / hepatocyte growth factor (SF/HGF) is an endogenous cell survival factor that exerts both acute and chronic cardioprotective effects and can potentially be harnessed for salvaging the ischemic myocardium. The feasibility of SF/HGF as gene or protein therapy however is limited by issues relating to immune and inflammatory responses evoked by adenoviral proteins, inherent instability of proteins in solution, their limited tissue half-life and the exorbitant costs associated with such therapy. Supported by the National Institutes of Health (NIH) Small Business Innovative Research (SBIR) and Rapid Access to Interventional Development (RAID) programs, we have identified and developed BB3, a novel small molecule SF/HGF mimetic. BB3 duplicates the bioactivities of the native protein in every assay tested to date. In single cardiocyte models simulating ischemia-reperfusion injury, BB3 attenuates apoptotic and necrotic death. In the isolated perfused heart, BB3 improves postischemic function and in in vivo experimental normothermic myocardial ischemia- reperfusion, systemic BB3 administration attenuates infarct size when administered 24 hours following onset of reperfusion. Of significant clinical interest is our finding that delayed BB3 administration also attenuates post-infarct ventricular dysfunction in both rat and pig. Furthermore, delayed BB3 administration confers functional and infarct-sparing benefit in renal, hepatic and cerebral models of ischemic and/or traumatic injury, preventing transition of these organs to failure. Supported by the SBIR program, a comprehensive panel of preclinical regulatory studies comprising genotoxicology, in vivo toxicology and safety pharmacology studies for BB3 has been completed. Food and Drug Administration (FDA) approved an Investigational New Drug (IND) application for BB3 and a Phase I, Randomized, Single-Blind, Placebo-Controlled, Single Dose, Dose- Escalating Study of BB3 Injected Intravenously in Healthy Subjects has been completed; no serious adverse events have been reported. The overall objective of this program is to evaluate clinical efficacy of BB3 in patients presenting with acute ST segment elevation myocardial infarction (A-STEMI) who undergo successful percutaneous reperfusion. PUBLIC HEALTH RELEVANCE: A small molecule organ protective agent has significant clinical potential in treatment of ST-segment elevation myocardial infarction (STEMI).