Phase I Clinical Study Using an Antifibrotic Drug

描述（由申请人提供）：肝纤维化是一种影响全球数千万人的疾病，是过度饮酒、病毒感染（乙型和丙型肝炎）、铁超载或肝外梗阻引起的慢性损伤的肝脏瘢痕反应，可发展为肝硬化、肝功能衰竭和死亡。事实上，由于丙型肝炎流行以及与非酒精性脂肪性肝炎相关的肝脏疾病发病率不断上升，预计未来十年因肝纤维化/肝硬化并发症死亡的人数将增加两倍。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），也被称为散点因子（SF），已被证明在减少肝纤维化方面有效。然而，HGF作为基因或蛋白质治疗的可行性受到以下问题的限制：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、它们有限的组织半衰期以及与此类治疗相关的高昂费用。在美国国立卫生研究院（NIH）小企业创新研究（SBIR）和快速介入发展（RAID）项目的支持下，我们已经确定并开发了BB3，一种新型的小分子HGF模拟物。BB3在迄今为止测试的每个实验中都复制了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，具有减轻肝纤维化的功效。我们项目的总体目标是推进BB3作为肝纤维化的一流抗纤维化药物进入临床。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，并且发现BB3具有良好的耐受性。此外，一项静脉给药BB3对肾透析患者安全性和PK的临床研究已经完成。虽然静脉注射BB3正在开发用于急性适应症，但我们也在开发用于慢性适应症的口服BB3。在这项快速通道SBIR拨款申请中，我们建议开展一项评估健康志愿者口服BB3的安全性和PK的i期临床研究。

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.