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

项目摘要 特发性肺纤维化（IPF）是一种慢性、进行性和最终致命的疾病， 纤维化药物，最近已经被批准。不幸的是，这两种药物都没有疗效，而临床试验 表明这两种药物减缓肺功能下降的速度，反应是可变的，副作用 在第一年中，导致高达40%的患者停止药物治疗。因此，IPF仍然是 慢性致命疾病降低生活质量，提高医疗保健利用率和成本。更有效 迫切需要安全有效地改变IPF病程并恢复生活质量的治疗。 博士Joel达德利和他的团队使用数据驱动的方法来确定 IPF疾病中的转录组学扰动和saracatinib诱导的转录组学扰动，saracatinib是一种2期就绪Src激酶， hipitor。有了这些计算机数据，达德利博士与格雷戈里唐尼博士（国家犹太人健康）合作 和Naftali Kaminski（耶鲁大学）验证并将这些发现应用于临床。唐尼医生 和卡明斯基都是 转化研究和IPF患者的临床护理。 基于trans- 脚本研究结果，已发表的文献，以及博来霉素临床前模型的初步证据， 疾病，我们假设saracatinib，Src激酶抑制剂，代表了一种新的，有针对性的，更有效的， 并且比现有药物更安全的治疗IPF。在本提案的UG 3部分，我们将审查 Saracatinib干扰与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预后不良相关的PBMC特征、IPF疾病特征，以及 saracatinib药物特征，以确定进一步研究的候选生物标志物。这些生物标志物将被 在临床前体外和体内模型中进行实验测试。UG 3向UH 3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和saracatinib活性， 移植临床研究。这些数据将被快速整合到临床研究（UH 3）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供Sup. 具有良好耐受性特征和快速转化潜力的Saracatinib长期给药途径 进了诊所UH 3部分包括一项基于生物标志物的适应性设计综合1b/2a期试验 在新诊断的IPF患者（共100例患者; 50例药物和50例对照）中使用saracatinib， 在前15名受试者达到治疗4周和12周后检查生物标志物， 根据需要从这一点进行设计（例如，增加样本量或改变药物剂量）。的主要终点 该试验将改变风险比（基于血液白细胞中的52个基因签名）。次级 终点将包括HRCT胸部扫描定量纤维化的变化; FVC斜率; DLCO; 6分钟 步行试验;另外的血清生物标志物，包括KL-6、MMP-7、骨桥蛋白、胶原蛋白肽和另外的 UG 3中确定的血清生物标志物;至首次急性加重的时间和生活质量问卷。

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.