Phase I Clinical Trial for BB3

BB3的I期临床试验

• 批准号: 7406556
• 负责人: WEIZHONG CAI
• 金额: $ 29.55万
• 依托单位: ANGION BIOMEDICA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2009-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7406556
• 关键词: Acute myocardial infarction; Adjuvant; Apoptotic; Applications Grants; Arrhythmia; Attenuated; Biological Assay; Businesses; Cardiac Myocytes; Cell Survival; Cerebrum; Cessation of life; Clinic; Clinical; Clinical Research; Clinical Trials; Consult; Coronary; Data; Development; Doctor of Philosophy; Dose; Drug Kinetics; Elevation; Failure; Funding; Future; Genes; Grant; Guanosine Monophosphate; Half-Life; Heart; Hepatic; Hepatocyte Growth Factor; Hospitals; Hour; Immune; Infarction; Inflammatory Response; Infusion procedures; Injury; Intervention; Ischemia; Kidney; Knowledge; Laboratories; Leadership; Letters; Liver diseases; MCC protocol; Maximum Tolerated Dose; Measures; Medicine; Modeling; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; Myocardium; Necrosis; New York; Organ; Patients; Personnel Staffing; Pharmaceutical Preparations; Pharmacists; Pharmacology; Pharmacy facility; Phase; Phase I Clinical Trials; Physiological reperfusion; Placebo Control; Positioning Attribute; Program Development; Proteins; Randomized; Reperfusion Injury; Reperfusion Therapy; Research; Safety; Simulate; Solutions; Specific qualifier value; Standards of Weights and Measures; Testing; Tissues; Toxicology; Translational Research; United States Food and Drug Administration; United States National Institutes of Health; base; blind; cost; design; experience; improved; in vivo; innovation; medical schools; mimetics; novel; outcome forecast; pre-clinical; prevent; professor; programs; prophylactic; size; small molecule

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.

描述（申请人提供）：经皮冠状动脉介入治疗已成为治疗ST段抬高型心肌梗死（STEMI）的主要手段。虽然早期再通无疑可以挽救心肌组织，但长时间缺血后的再灌注会加剧损伤。梗塞面积需要受到限制，因为对于未死于院外心律失常的急性心肌梗塞 (AMI) 患者，长期预后取决于心肌损失量。这些患者可能会从再通期间使用辅助心脏保护策略中受益。 肝细胞生长因子（HGF），也称为分散因子（SF），是一种内源性细胞存活因子，具有心脏保护作用，可用于挽救缺血的心肌。然而，SF/HGF 作为基因或蛋白质疗法的可行性受到与腺病毒蛋白质引起的免疫和炎症反应、溶液中蛋白质固有的不稳定性、其有限的组织半衰期以及与此类疗法相关的过高成本相关的问题的限制。我们已经鉴定并开发了 BB3，一种新型小分子 HGF 模拟物。 BB3 在迄今为止测试的每个测定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心肌细胞模型中，BB3 可减轻细胞凋亡和坏死。在离体灌注心脏中，BB3 改善了缺血后功能，并且在体内实验性常温心肌缺血再灌注中，在再灌注开始后 3 小时施用时，全身施用 BB3 可减轻梗塞面积。 BB3 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，BB3 的临床前监管研究综合小组已经完成，包括基因毒理学、体内毒理学和安全药理学研究。包含功效和安全性数据的 IND 申请已提交并获得 FDA 批准。基于这些数据，本申请旨在确定BB3（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、单盲、安慰剂对照、单剂量、剂量递增研究中的效果。