A Pilot Clinical Study in Acute STEMI

描述（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）的主流治疗手段。早期再通无疑能挽救心肌组织，但长时间缺血后的再灌注也会加重损伤。由于急性心肌梗死（AMI）患者没有死于院外心律失常，长期预后取决于心肌损失的数量和心室重构的结果，因此需要限制梗死面积，并优化有利于心室适应性愈合和重构的条件。散点因子/肝细胞生长因子（SF/HGF）是一种内源性细胞生存因子，具有急性和慢性心脏保护作用，可能被用于挽救缺血心肌。然而，由于腺病毒蛋白引起的免疫和炎症反应、溶液中蛋白质的固有不稳定性、有限的组织半衰期以及与此类治疗相关的高昂费用等问题，SF/HGF作为基因或蛋白质治疗的可行性受到限制。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）项目的支持下，我们已经确定并开发了BB3，一种新型的小分子SF/HGF模拟物。迄今为止，BB3在每一项检测中都复制了天然蛋白的生物活性。在模拟缺血再灌注损伤的单心肌模型中，BB3可减轻细胞凋亡和坏死死亡。在离体灌注心脏中，BB3可改善缺血后功能；在体内实验常温心肌缺血-再灌注中，在再灌注开始24小时后，全身给药BB3可减轻梗死面积。具有重要临床意义的是，我们发现延迟给药BB3也能减轻大鼠和猪的梗死后心室功能障碍。此外，延迟给药BB3可在缺血和/或创伤性损伤的肾、肝和脑模型中提供功能和梗死保护，防止这些器官向衰竭过渡。在SBIR项目的支持下，一组包括基因毒理学、体内毒理学和安全药理学在内的BB3临床前研究已经完成。美国食品和药物管理局（FDA）批准了BB3的研究新药（IND）申请，并完成了健康受试者静脉注射BB3的随机、单盲、安慰剂对照、单剂量、剂量递增的一期研究；未见严重不良事件的报道。该项目的总体目标是评估BB3在经皮再灌注成功的急性ST段抬高型心肌梗死（A-STEMI）患者中的临床疗效。

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).