TREATMENT OF LUNG FIBROSIS : IND PHARMACOLOGY AND TOXICOLOGY

肺纤维化的治疗：IND 药理学和毒理学

基本信息

批准号：
10026462
负责人：
MARTINA BUCK
金额：
$ 132.7万
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/10026462
关键词：
Adverse effects American Animal Model Animals Apoptosis Area B-Lymphocytes Binding Biological Assay Biological Availability Bleomycin CASP8 gene Cardiotoxicity Cause of Death Cells Cellular Assay Chronic Cicatrix Clinical Complex Data Deposition Development Disease Progression Dose Drug Kinetics Drug usage Epithelial Epithelial Cells Epithelium Event Extracellular Matrix FDA approved Feedback Fibrosis Financial Hardship Formulation Funding Goals Health Human Immune response In Vitro Inflammation Inhalation Injury Isoenzymes Knowledge Libraries Liver Lung Lung Inflammation Lung Transplantation Macrophage Activation Medical Medical Research Mesenchymal Modeling Molecular Molecular Target Mus Myofibroblast Neuraxis Organ Pathogenesis Pathway interactions Patients Peptides Pharmaceutical Preparations Pharmacology Pharmacology and Toxicology Phase Phenotype Phosphorylation Phosphorylation Site Phosphotransferases Pirfenidone Plasma Process Proliferating Proteins Pulmonary Fibrosis Pulmonary Surfactant-Associated Protein C Recovery Research Respiratory physiology Reverse Transcriptase Polymerase Chain Reaction Route Safety Skin Small Business Innovation Research Grant Solubility Subcutaneous Injections System T-Lymphocyte Therapeutic Tissues Toxicology Validation Water alveolar epithelium analog cell injury cellular targeting clinical candidate cost design fibrogenesis idiopathic pulmonary fibrosis immunogenicity improved in vivo innovation lung development lung injury meetings mortality novel outcome forecast peptide drug pneumocyte pre-clinical preclinical development preclinical study prevent programs respiratory subcutaneous treatment duration wound healing

项目摘要

Activation of lung myofibroblasts (LMF) of different origins is responsible for the development of lung fibrosis in in IPF and remarkably, LMF clearance by apoptosis may prevent development of lung fibrosis and lung injury, and possibly allow recovery from reversal of lung fibrosis. Inhibiting or reversing myofibroblast activation and macrophage activation (the therapeutic cellular targets) may be critical for the treatment of lung fibrosis in IPF. Both preventing progression of lung fibrosis and inflammation, as well as possibly, regression of lung fibrosis despite continued lung injury, as we documented in our pre-clinical studies, are considered important clinical targets for patients with IPF. Finally, blocking the progression of lung fibrosis may decrease the demand for lung transplants. The basis for our Research is the development of a novel ‘humanized’ therapeutic peptide. We created a library using analog synthesis to prevent potential pitfalls for human therapy. We have performed in a step-wise manner assays to select the safest and most efficient ‘humanized’ peptide (including apoptosis assays in activated primary human lung myofibroblasts; cell-free caspase 8 activation assays; lung injury/fibrogenesis model; pharmacokinetics; bioassay; CYP-450 inhibition studies; cardiotoxicity assays; and preliminary toxicology assays). We have developed novel and highly effective anti-fibrotic peptides in animal models, with no evidences of immunogenicity in state-of-the-art human CD-4+ T-cell and B- cell assays, and with exceptional stability in human lung microsomal systems and human plasma. The therapeutic peptide has excellent solubility in water. These features should facilitate administration by subcutaneous injection once per week (~ 50-200 μL) with excellent bioavailability during preclinical PK studies judging by the steady-state release in plasma of the peptide from the PEG-30kDa-Peptide, achieving therapeutic lung concentrations. Xfibra will maintain the inhalation route as an alternative formulation for development. The proposed compound markedly inhibits the activation of human lung myofibroblast in culture and in vivo in mice. This compound was not toxic to mice in the preliminary toxicology studies, at least at 100- fold the therapeutic dose. We found no evidence of liver, lung or cardiac toxicity or inhibition of CYP-450 isoenzymes. The Aims of this SBIR are to complete FDA-mandated, IND-enabling studies. The available IPF medications are very expensive, and not highly effective in most patients. The FDA agreed with Xfibra to proceed with IND-enabling studies for XFB-19 (Pre-IND # 131245).

不同起源的肺肌纤维化（LMF）的激活是导致肺纤维化发展的原因在IPF和非常明显的凋亡中，LMF清除可能会阻止肺纤维化和肺损伤的发展并可能使肺纤维化逆转恢复。抑制或逆转肌纤维细胞激活和巨噬细胞激活（治疗性细胞靶标）对于治疗肺纤维化至关重要 IPF。既可以防止肺纤维化和注射的进展正如我们在临床前研究中所记录的那样，持续肺损伤造成的纤维化被认为很重要 IPF患者的临床靶标。最后，阻断肺纤维化的进展可能会减少对肺移植的需求。我们研究的基础是开发小说“人性化” 治疗性胡椒。我们使用模拟合成创建了一个文库，以防止人类治疗的潜在陷阱。我们已经以逐步的方式进行了测定，以选择最安全，最有效的“人性化”肽（包括激活的原代人肺肌纤维细胞中的凋亡测定；无细胞caspase 8激活测定；肺损伤/纤维化模型；药代动力学；生物测定； CYP-450抑制研究；心脏毒性测定；和初步毒理学测定法）。我们已经开发了新颖且高效的抗纤维化动物模型中的肽，没有任何证据表明人类CD-4+ T细胞和B-的免疫原性细胞测定，并且在人肺微粒体系统和人血浆中具有出色的稳定性。治疗性胡椒在水中具有出色的溶解度。这些功能应通过临床前PK期间，皮下注射一次（〜50-200μL），具有出色的生物利用度通过稳态释放从PEG-30KDA肽中的胡椒等离子体中判断的研究，实现治疗性肺浓度。 Xfibra将保持吸入路线作为替代公式发展。提出的复合明显抑制了培养物中人肺肌纤维细胞的激活和体内小鼠。在初步毒理学研究中，这种化合物对小鼠没有毒性，至少在100-时折叠治疗剂量。我们没有发现肝，肺或心脏毒性或CYP-450抑制的证据同工酶。该SBIR的目的是完成FDA规定的指定研究。可用的IPF药物非常昂贵，并且在大多数患者中都不有效。 FDA同意 Xfibra进行XFB-19的辅助研究（预印度＃131245）。