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)已成为治疗ST段抬高心肌梗死(STEMI)的主要手段。虽然早期再通无疑挽救了心肌组织，但长时间缺血后的再灌注也会加重损伤。需要限制梗死范围，优化有利于适应性室壁愈合和重塑的条件，因为对于没有死于院外心律失常的急性心肌梗死患者，长期预后取决于丢失的心肌量和室壁重塑的结果。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，可用于抢救缺血心肌。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有关的问题的限制，蛋白质在溶液中的固有不稳定性，其有限的组织半衰期以及与此类治疗相关的高昂成本。在美国国立卫生研究院(NIH)小企业创新研究(SBIR)和快速介入开发(RAID)计划的支持下，我们发现并开发了一种新型的小分子SF/HGF模拟物BB3。到目前为止，BB3在每一次测试中都复制了天然蛋白质的生物活性。在模拟缺血-再灌注损伤的单细胞模型中，BB3可减轻细胞凋亡和坏死性死亡。在离体灌流心脏中，BB3改善了缺血后的功能，在体内实验性常温心肌缺血-再灌流中，全身应用BB3在再灌流开始后24小时给予BB3可缩小梗塞面积。临床上值得注意的是，我们发现延迟给药BB3也可以减轻大鼠和猪脑梗塞后的心功能障碍。此外，在肾、肝和脑缺血和/或创伤性损伤模型中，延迟给药BB3可提供功能性和脑梗塞保护作用，防止这些器官向衰竭过渡。在SBIR计划的支持下，一个全面的临床前调控研究小组已经完成，其中包括BB3的遗传毒理学、体内毒理学和安全药理学研究。美国食品和药物管理局(FDA)批准了BB3的研究新药(IND)申请，并完成了一项针对健康受试者静脉注射BB3的I阶段随机、单盲、安慰剂对照、单剂量、剂量递增研究；尚未有严重不良事件的报告。该计划的总体目标是评估BB3在急性ST段抬高性心肌梗死(A-STEMI)患者中的临床疗效，这些患者成功地接受了经皮再通。 公共卫生相关性：一种小分子器官保护剂在治疗ST段抬高心肌梗死(STEMI)方面具有显著的临床潜力。

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).