TREATMENT OF LUNG FIBROSIS : IND PHARMACOLOGY AND TOXICOLOGY

肺纤维化的治疗：IND 药理学和毒理学

• 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
• 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

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).

不同来源的肺肌成纤维细胞（LMF）的激活与肺纤维化的发展有关