Phase I Clinical Study Using an Antifibrotic Drug

描述(申请人提供)：肝纤维化是一种影响全球数千万人的疾病，是由于过量饮酒、病毒感染(乙肝和丙型肝炎)、铁超载或肝外梗阻造成的慢性损伤导致的肝脏疤痕反应，可发展为肝硬化、肝功能衰竭和死亡。事实上，由于丙型肝炎流行和与非酒精性脂肪性肝炎相关的肝病发病率上升，预计未来十年死于肝纤维化/肝硬变并发症的人数将增加两倍。目前可用的治疗方法，包括抗病毒药物，在治疗潜在的纤维化方面基本上无效，在大多数情况下，肝移植是唯一有效的治疗方法。肝生长因子(HGF)，也被称为散射因子(SF)，已被证明在减轻肝纤维化方面有效。然而，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，以及与这种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HGF模拟物BB3。到目前为止，BB3在每一项测试中都复制了HGF的生物活性。特别是，BB3具有细胞保护、抗纤维化和再生活性，并显示出减少肝纤维化的效果。我们计划的总体目标是将BB3作为一种一流的抗肝纤维化药物推向临床。从临床角度来看，静脉注射BB3的I期安全性和药代动力学(PK)试验已经在健康志愿者中成功完成，BB3被发现耐受性良好。此外，静脉注射BB3对肾透析患者的安全性和PK的临床研究已经完成。在开发静脉注射BB3用于急性适应症的同时，我们也正在开发用于慢性适应症的口服BB3。在这项快速通道SBIR赠款申请中，我们建议进行一项第一阶段临床研究，评估健康志愿者口服BB3的安全性和PK。 公共卫生相关性：一种小分子、保护肝脏和抗纤维化的药物具有显著的临床潜力，可对抗这两种肝纤维化。

DESCRIPTION (provided by applicant): Liver fibrosis, a disease affecting tens of millions of people worldwide, is the liver scarring response to chronic injury from excessive alcohol use, virus infection (hepatitis B and C), iron overload or extrahepatic obstructions and can progress to liver cirrhosis, liver failure and death. In fact, deaths from complications of liver fibrosis/cirrhosis are expected to triple over the next decade as a result of the hepatitis C epidemic and the growing incidence of liver disease associated with non-alcoholic steatohepatitis. Currently available therapies, including antivirals, are largely ineffective in treating the underlying fibrosis, and in the majority of cases, liver transplantation is the only effective cure. Hepatic growth factor (HGF), also known as scatter factor (SF), has been shown to be efficacious in reducing liver fibrosis. The feasibility of 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 HGF mimetic. BB3 duplicates the bioactivities of HGF in every assay tested to date. Particularly, BB3 possesses cell protective, anti-fibrotic, and regenerative activities and shows efficacy in reducing liver fibrosis. The overall objective of our program is to advance BB3 to the clinic as a first-in-class antifibrotic for liver fibrosis. From a clinical perspective, a Phase I safety and pharmacokinetic (PK) trial of intravenously administered BB3 has been completed successfully in healthy volunteers and BB3 was found to be well tolerated. In addition, a clinical study of intravenously administered BB3 for safety and PK in renal dialysis patients has been completed. While intravenous BB3 is being developed for acute indications, we are also developing oral BB3 for chronic indications. In this fast-track SBIR grant application, we propose to conduct a Phase 1 clinical study evaluating safety and PK of BB3 administered orally in healthy volunteers. PUBLIC HEALTH RELEVANCE: A small-molecule, hepatically protective and anti-fibrotic agent has significant clinical potential against both liver fibrosis.