Phase I Study of BB3 in Dialysis Patients

描述（由申请人提供）：肾移植是终末期肾病最有效的治疗方式;它提供了更好的生活质量和更长的生存期。尽管在过去十年中手术和器官保存技术有所改进，但肾功能不全和/或衰竭仍然是移植后的一个重要问题。缺血再灌注损伤与肾脏的回收，储存和植入是一个主要的同种异体抗原无关的贡献者原发性无功能和延迟移植功能。此外，边缘肾，即来自无心跳供体、老年供体或来自患有轻度至中度高血压/糖尿病的供体的肾，对缺血-再灌注损伤高度敏感，并且通常移植失败。由于需求的增加，这种边缘肾的使用进一步增加了移植物功能障碍的发生率。目前用于减轻缺血后肾损伤的药物治疗策略经常以添加剂的形式递送到器官保存溶液中。尽管与常温再灌注相关的有害且通常延迟的影响，很少（如果有的话）策略针对移植后的肾。肝细胞生长因子（HGF），也称为分散因子，是一种肾脏营养因子，具有强大的器官保护和再生作用。然而，其在溶液中的相对不稳定性、与其体内给药相关的困难、递送的蛋白质的蛋白水解以及成本高昂的生产方案降低了SF/HGF在器官保存溶液和肾受体中使用的可行性和有效性。模拟SF/HGF活性的低分子量化合物可以克服这些后勤困难并提供有效的治疗。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复制天然蛋白质的生物活性。在几项体内研究中，BB 3在肾移植中显示出有益作用。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。在提交IND后，FDA允许该药物进入临床。BB 3在健康志愿者中的I期临床试验已经完成。本申请提出在血液透析患者中进行I期临床试验，以表征BB 3的药代动力学（PK）特性。这两项临床研究的数据为肾移植II期研究奠定了坚实的基础。公共卫生相关性：小分子器官保护剂在肾移植中具有重要的临床潜力。

DESCRIPTION (provided by applicant): Kidney transplantation is the most effective therapeutic modality for end-stage renal disease; it offers a better quality of life and a longer survival. Despite improvements in surgical and organ preservation techniques over the last decade, renal dysfunction and/or failure remains a significant problem following transplantation. Ischemia-reperfusion injury associated with the retrieval, storage and implantation of the kidney is a major alloantigen-independent contributor to primary non-function and delayed graft function. Moreover, marginal kidneys, i.e. kidneys from non-heart-beating donors, aged donors, or from donors with mild-to-moderate hypertension/diabetes, are highly susceptible to ischemia-reperfusion injury, and often fail transplantation. Increased use of such marginal kidneys because of demand further increases the incidence of graft dysfunction. Current pharmacotherapeutic strategies for attenuation of post-ischemic renal injury are frequently delivered in the form of additives to the organ preservation solution. Despite the deleterious and often delayed effects associated with normothermic reperfusion, few, if any, strategies target the kidney following transplantation. Hepatocyte growth factor (HGF), also know as scatter factor, is a renal trophic factor with potent organ protective and regenerative effects. However, its relative instability in solution, the difficulties associated with its administration in vivo, proteolysis of the delivered protein, and cost prohibitive production schemes lessen the feasibility and effectiveness of the use of SF/HGF in both the organ preservation solution and the renal recipient. Low molecular weight compounds that mimic the activity of SF/HGF could overcome these logistical difficulties and provide effective therapy. We have identified and developed BB3, a novel small molecule HGF mimetic. BB3 replicates the bioactivities of the native protein in every assay tested to date. In several in vivo studies, BB3 showed beneficial effects in renal transplantation. 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. Following the filing of an IND, FDA has allowed the drug to proceed to the clinic. BB3 in a Phase I clinical trial with healthy volunteers has been completed. The current application proposed to conduct a Phase I clinical trial in hemodialysis patients to characterize the pharmacokinetic (PK) properties of BB3. The data from these two clinical studies form a solid basis for the Phase II study in renal transplantation. PUBLIC HEALTH RELEVANCE: A small molecule organ protective agent has significant clinical potential in renal transplantation.