Phase I Clinical Trial for BB3

描述（由申请人提供）：经皮冠状动脉介入治疗已成为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，而长期缺血后再灌注则会加重损伤。需要限制心肌梗死的大小，因为在没有死于院外心律失常的急性心肌梗死（AMI）患者中，长期预后取决于心肌丢失的量。这些患者可能受益于再通过程中辅助心脏保护策略的使用。 肝细胞生长因子（HGF），也称为散射因子（SF），是一种内源性细胞存活因子，具有心脏保护作用，并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。我们已经确定并开发了BB 3，一种新的小分子HGF模拟物。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。在离体灌注心脏中，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3小时施用时，全身性BB 3施用减弱梗塞面积。BB 3还在缺血性和/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。提交了包含疗效和安全性数据的IND申请，并获得FDA批准。基于这些数据，本申请被设计为确定BB 3（一种小分子分散因子/肝细胞生长因子模拟物）在健康受试者中的I期、随机化、单盲、安慰剂对照、单剂量、剂量递增研究中的作用。

DESCRIPTION (provided by applicant): Percutaneous coronary intervention has become the mainstay for treatment of ST-segment elevation myocardial infarction (STEMI). Whereas early recanalization undoubtedly salvages myocardial tissue, reperfusion following prolonged ischemia exacerbates injury. Infarct size needs to be limited, 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. These patients could potentially benefit from use of adjuvant cardioprotective strategies during recanalization. Hepatocyte growth factor (HGF), also know as scatter factor (SF), is an endogenous cell survival factor that exerts 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. We have identified and developed BB3, a novel small molecule 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 3 hours following onset of reperfusion. BB3 also 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. An IND application incorporating the efficacy and safety data was submitted and approved by FDA. Based on these data, the present application is designed to determine the effects of BB3, a small molecule scatter factor/hepatocyte growth factor mimetic in a Phase I, Randomized, Single-Blind, Placebo-Controlled, Single Dose, Dose-Escalating Study in Healthy Subjects.