TREATMENT OF LIVER INJURY AND FIBROSIS: SAFETY PHARMACOLOGY AND TOXICOLOGY

肝损伤和纤维化的治疗：安全药理学和毒理学

基本信息

批准号：
10095347
负责人：
MARTINA BUCK
金额：
$ 113.61万
依托单位：
XFIBRA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10095347
关键词：
Agreement Albumins Alcoholism Animal Model Animals Apoptosis Ascites Basic Science Biological Assay Biological Availability Biotechnology CASP8 gene CCL4 gene Cachexia Cardiac Myocytes Cardiotoxicity Cell Death Cells Chronic Chronic Hepatitis B Cicatrix Circadian Rhythms Cirrhosis Clinical Clinical Research Clinical Trials Data Development Dose Drug Kinetics FDA approved Factor V Fatty Liver Financial Hardship Funding Genes Genetic Diseases Genetic Models Genetic Transcription Goals Hepatitis C Hepatitis C virus Hepatocyte Hepatology Homologous Gene Human Hypertension Inflammation Injury Isoenzymes Knowledge Leucine Zippers Libraries Liver Liver Cirrhosis Liver Failure Liver Fibrosis Liver Microsomes Liver diseases Medical Modeling Mus Myofibroblast Names National Institute of Diabetes and Digestive and Kidney Diseases Nature No-Observed-Adverse-Effect Level Obesity Organizational Innovation Paper Patients Pattern Peptides Peritoneal Fluid Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology and Toxicology Phase Phosphorylation Phosphorylation Inhibition Physiological Plasma Portal Hypertension Primary Malignant Neoplasm of Liver Primary carcinoma of the liver cells Proteins Publishing Pulmonary Hypertension Recovery Reporting Research Personnel Research Support Safety San Francisco Serum Site Small Business Innovation Research Grant Small Business Technology Transfer Research Solubility Stress Subcutaneous Injections System T-Lymphocyte Technology Therapeutic Tissues Toxicology Transactivation Transgenes United States National Institutes of Health Water Work analog animal mortality cellular targeting chronic liver disease clinically significant comorbidity design diabetes mellitus genetics differential expression drug candidate drug development fibrogenesis first-in-human genotoxicity hepatocyte injury hexokinase human stem cells immunogenicity improved inhibitor/antagonist liver development liver injury mortality nonhuman primate novel peptide drug phase 2 study pre-clinical preclinical development preclinical study prevent programs research and development therapeutic development ward

项目摘要

Activation of liver myofibroblasts (LMF) of different origins is responsible for the development of liver fibrosis in chronic liver diseases of all causes and remarkably, LMF clearance by apoptosis may prevent development of liver fibrosis and liver injury, and possibly allow recovery from reversal of liver fibrosis. Inhibiting o reversing myofibroblast activation (the therapeutic cellular target) is critical for the treatment of liver fibrosis. Both preventing progression of liver fibrosis as well as possibly, regression of liver fibrosis despite continued liver injury, as we documented in our pre-clinical studies, are considered important clinical targets for patients with advanced liver fibrosis and cirrhosis. Finally, blocking the progression of liver fibrosis would decrease development of primary liver cancer since most hepatocellular carcinomas arise in cirrhotic livers. The basis for our Research and Development is the development of a novel ‘humanized’ therapeutic peptide (XFB-19). We created a library using analog synthesis to improve potential pitfalls for human therapy. We have performed in a step-wise manner assays to select the safest and most efficient ‘humanized’ peptide (including medicinal chemistry, stability assays in human plasma and human liver microsomes, apoptosis assays in activated primary human liver myofibroblasts, cell-free caspase 8 activation assays, liver injury/fibrogenesis models, pharmacokinetics, bioassay, CYP-450 inhibition studies, immunogenicity assays in human T-cells and in mice, cardiotoxicity assays in human stem cell-derived cardiomyocytes, and toxicology assays in HCV-infected primary human hepatocytes and in normal and cirrhotic mice). In an animal model of decompensated cirrhosis, the XFB-19 peptide rescues hepatocyte cell death and liver failure, and remarkably prevents by 45 % animal mortality from week-16 to week-32. We have developed a novel (first-in-class inhibitor of a site-specific phosphorylation) and highly effective anti- fibrotic peptide in animal models, with no evidences of immunogenicity, and with exceptional stability in human microsomal systems and human plasma. XFB-19 has excellent solubility in water. These features should facilitate administration by subcutaneous injection with excellent bioavailability during clinical trials judging by the steady-state release in plasma of XFB-19 from the PEG-XFB-19. The PEG-XFB-19 was not toxic to mice at 100-fold the therapeutic dose. There was no evidence of cardiotoxicity or inhibition of CYP-450 isoenzymes. The aims that are proposed for this SBIR are to complete IND-enabling, FDA-mandated studies. There is no FDA-approved medication for the treatment of liver fibrosis, and none of the drugs currently in Clinical Studies target directly activated myofibroblasts.

不同来源的肝肌成纤维细胞（LMF）的激活是肝纤维化发生的原因所有原因引起的慢性肝病，可怕的是，通过细胞凋亡清除 LMF 可能会阻止慢性肝病的发展肝纤维化和肝损伤，并可能使肝纤维化逆转恢复。肌成纤维细胞激活（治疗细胞靶点）对于肝纤维化的治疗至关重要。预防肝纤维化的进展，并可能在持续肝脏治疗的情况下使肝纤维化消退正如我们在临床前研究中记录的那样，损伤被认为是患有以下疾病的患者的重要临床目标：最后，阻止肝纤维化的进展会减少肝纤维化和肝硬化。由于大多数肝细胞癌发生于肝硬化，因此原发性肝癌的发展是其基础。我们的研发是开发一种新型“人源化”治疗肽（XFB-19）。使用模拟合成创建了一个库，以改善我们在人类治疗中的潜在缺陷。逐步进行分析，以选择最安全、最有效的“人源化”肽（包括药用肽）化学、人血浆和人肝微粒体的稳定性测定、活化的细胞凋亡测定原代人肝肌成纤维细胞、无细胞 caspase 8 激活测定、肝损伤/纤维发生模型、药代动力学、生物测定、CYP-450 抑制研究、人类 T 细胞和小鼠免疫原性测定，人类干细胞来源的心肌细胞的心脏毒性测定以及 HCV 感染的毒理学测定原代人肝细胞以及正常和肝硬化小鼠）。在失代偿性肝硬化动物模型中，XFB-19 肽可挽救肝细胞死亡和肝脏损伤失败，并且在第 16 周到第 32 周期间异常地减少了 45% 的动物死亡率。我们开发了一种新型（首创的位点特异性磷酸化抑制剂）和高效抗- 动物模型中的纤维化肽，没有免疫原性的证据，并且在人体中具有出色的稳定性 XFB-19 具有极好的水溶性。促进皮下注射给药，在临床试验中具有优异的生物利用度 PEG-XFB-19 在血浆中稳态释放的 XFB-19 对小鼠没有毒性。在 100 倍治疗剂量下，没有证据表明存在心脏毒性或 CYP-450 同工酶抑制作用。本 SBIR 提议的目标是完成 FDA 授权的 IND 授权研究。 FDA批准用于治疗肝纤维化的药物，目前尚无药物处于临床研究阶段靶向直接激活的肌成纤维细胞。