Use of the Src Family Kinase Inhibitor Saracatinib in the Treatment of Pulmonary Fibrosis

Src 家族激酶抑制剂 Saracatinib 在治疗肺纤维化中的应用

基本信息

批准号：
10001075
负责人：
Gregory Paul Downey
金额：
$ 172.63万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-10 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10001075
关键词：
Acute Adenoviruses Attenuated Automobile Driving Benchmarking Bioinformatics Biological Markers Bleomycin Blood Bronchoalveolar Lavage Caring Chest Chronic Cicatrix Clinic Clinical Clinical Research Clinical Trials Collagen Computer Analysis Data Deposition Development Diagnosis Disease Disease model Distal Doctor of Philosophy Dose Double-Blind Method Exposure to Extracellular Matrix FDA approved Fibroblasts Fibrosis Gold Health High Resolution Computed Tomography Human In Vitro Injury Institution Lead Leukocytes Link Literature Lung Matrilysin Mediator of activation protein Modeling Molecular Mus Newly Diagnosed Odds Ratio Outcome Measure Pathogenesis Patients Peptides Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pharmacogenomics Pharmacology Pharmacotherapy Phase Phosphorylation Physicians Physiology Pirfenidone Placebos Platelet-Derived Growth Factor Pre-Clinical Model Production Publishing Pulmonary Fibrosis Quality of life Quality-of-Life Assessment Questionnaires Randomized Research Respiratory physiology Rodent Safety Sample Size Scanning Scientist Serum Signal Pathway Skin Slice Structure of parenchyma of lung Testing Time Tissues Transforming Growth Factors Translational Research Translations Treatment Efficacy Universities Walking X-Ray Computed Tomography base biomarker development biomarker discovery biomarker panel cancer type candidate marker clinical application clinical care clinically relevant cost design drug discovery effective therapy experience follower of religion Jewish gastrointestinal genetic signature genomic biomarker health care service utilization idiopathic pulmonary fibrosis in silico in vivo in vivo Model indium-bleomycin inhibitor/antagonist injury and repair kinase inhibitor lung injury medical schools multidisciplinary novel marker osteopontin outcome forecast patient subsets pre-clinical primary endpoint programs response secondary endpoint secondary outcome side effect small molecule inhibitor src-Family Kinases transcriptome sequencing transcriptomics translational scientist

项目摘要

Project Summary Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and ultimately fatal disorder for which two anti- fibrotic drugs, have recently been approved. Unfortunately, neither drug is curative While clinical trials have demonstrated that both drugs slow the rate of decline in lung function, responses are variable and side effects lead to discontinuation of drug treatment in up to 40% of patients in the first year. IPF therefore remains a chronic, fatal disease driving down quality of life and driving up health care utilization and costs. More effective therapies that will safely and effectively modify the course of IPF and restore quality of life are urgently needed. Dr. Joel Dudley and his team have used a data-driven approach to identify a robust connection between the transcriptomic perturbations in IPF disease and those induced by saracatinib, a Phase 2-ready Src kinase in- hibitor. With this in silico data, Dr. Dudley has partnered with Drs. Gregory Downey (National Jewish Health) and Naftali Kaminski (Yale University) to validate and bring these findings to clinical application. Drs. Downey and Kaminski are each leaders in translational research and clinical care for IPF patients. Based on the tran- scriptomic findings, published literature, and preliminary evidence in the bleomycin preclinical model of this disease, we hypothesize that saracatinib, a Src kinase inhibitor, represents a new, targeted, more effective, and safer therapy for IPF than existing medications. In the UG3 segment of this proposal, we will examine the ability of saracatinib to perturb candidate biomarkers relevant to IPF pathogenesis. Computational analysis will be used to overlay the PBMC signature associated with poor prognosis in IPF, the IPF disease signature, and the saracatinib drug signature to identify candidate biomarkers for further study. These biomarkers will then be experimentally tested in preclinical in vitro and in vivo models. The key milestone for the UG3 to UH3 transition is identification of a panel of biomarkers associated with rapid IPF progression and saracatinib activity to sup- port the clinical study. These data will be rapidly integrated into a clinical study (UH3) designed to establish proof of concept and mechanism data in IPF patients. Full pharmacology and safety data are available to sup- port long-term administration of saracatinib with a favorable tolerability profile and potential for rapid translation into the clinic. The UH3 segment comprises a biomarker-based, adaptive design, integrated Phase 1b/2a trial of saracatinib in newly diagnosed IPF patients (100 patients total; 50 drug and 50 control) with an interim anal- ysis to check the biomarkers after the first 15 subjects reach 4 weeks and 12 weeks of treatment and adapt the design as necessary from that point (e.g. increase sample size or change drug dose). The primary endpoint for the trial will be change in the risk ratio (based on the 52-gene signature in blood leukocytes). The secondary end points will include change in HRCT chest scan quantification of fibrosis; slope of FVC; DLCO; 6-minute walk test; additional serum biomarkers including KL-6, MMP-7, osteopontin, collagen peptides, and additional serum biomarkers identified in the UG3; time to the first acute exacerbation, and quality of life questionnaires.

项目概要特发性肺纤维化（IPF）是一种慢性、进行性、最终致命的疾病，有两种抗- 纤维化药物最近已被批准。不幸的是，这两种药物都没有疗效，尽管临床试验表明证明这两种药物都能减缓肺功能下降的速度，但反应各不相同且有副作用导致高达 40% 的患者在第一年停止药物治疗。因此，IPF 仍然是慢性致命疾病会降低生活质量并提高医疗保健利用率和成本。更有效迫切需要能够安全有效地改变 IPF 病程并恢复生活质量的疗法。 Joel Dudley 博士和他的团队使用数据驱动的方法来确定 IPF 疾病中的转录组扰动以及由 saracatinib 诱导的转录组扰动，saracatinib 是一种 2 期就绪的 Src 激酶，抑制剂。凭借这一计算机数据，达德利博士与博士合作。格雷戈里·唐尼（国家犹太健康中心）和 Naftali Kaminski（耶鲁大学）验证这些发现并将其应用于临床应用。博士。唐尼和卡明斯基都是领导者从事 IPF 患者的转化研究和临床护理。基于反式博来霉素临床前模型的脚本组学发现、已发表的文献和初步证据疾病，我们假设 Src 激酶抑制剂 saracatinib 代表了一种新的、有针对性的、更有效的、比现有药物更安全的 IPF 治疗方法。在本提案的 UG3 部分，我们将研究 saracatinib 扰乱与 IPF 发病机制相关的候选生物标志物的能力。计算分析将用于覆盖与 IPF 不良预后相关的 PBMC 特征、IPF 疾病特征，以及 saracatinib 药物特征以确定候选生物标志物以供进一步研究。这些生物标志物将被在临床前体外和体内模型中进行了实验测试。 UG3 到 UH3 过渡的关键里程碑是鉴定一组与 IPF 快速进展相关的生物标志物以及 saracatinib 活性以支持移植临床研究。这些数据将被快速整合到一项临床研究（UH3）中，旨在建立 IPF 患者的概念验证和机制数据。完整的药理学和安全性数据可用于支持 saracatinib 的长期给药具有良好的耐受性和快速转化的潜力进入诊所。 UH3 部分包括基于生物标志物的自适应设计、综合 1b/2a 期试验 saracatinib 在新诊断的 IPF 患者（总共 100 名患者；50 名药物和 50 名对照）中进行了临时分析前 15 名受试者达到 4 周和 12 周治疗后检查生物标志物并调整治疗方案从那时起根据需要进行设计（例如增加样本量或改变药物剂量）。主要终点为该试验将改变风险比（基于血液白细胞中的 52 个基因特征）。二级终点将包括 HRCT 胸部扫描纤维化量化的变化； FVC 斜率； DLCO； 6分钟步行测试；其他血清生物标志物，包括 KL-6、MMP-7、骨桥蛋白、胶原蛋白肽等 UG3 中鉴定的血清生物标志物；首次急性加重时间和生活质量调查问卷。