Preclinical Development of an Anti-Mucus Drug

抗粘液药物的临床前开发

基本信息

批准号：
8748733
负责人：
Michael J Holtzman
金额：
$ 151.34万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-22 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8748733
关键词：
Address Animal Model Asthma Attenuated Benchmarking Biological Assay Biological Markers Breathing Businesses Calcium Calcium Channel Cells Chemicals Chloride Channels Chronic Chronic Obstructive Airway Disease Clinical Clinical Trials Coughing Development Disease Dose Drug Design Drug Targeting Drug usage Epithelial Cells Experimental Models Family suidae Funding Future Human In Vitro Infection Inflammation Inflammatory Interleukin-13 Lead Legal patent Life Link Lung Lung diseases MUC5AC gene Marketing Mitogen-Activated Protein Kinase 13 Modeling Morbidity - disease rate Mucins Mucous body substance Oral Pathway interactions Patients Performance Permeability Pharmaceutical Preparations Phase Production Property Protocols documentation Public Health Rattus Resources Safety Secure Shortness of Breath Signal Pathway Specificity Stimulus Structure Testing Therapeutic TimeLine Toxic effect Tracheobronchial United States National Institutes of Health Universities Washington abstracting airway obstruction analog attenuation base commercialization cytokine design drug candidate effective therapy fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether in vitro Assay in vivo in vivo Model inhibitor/antagonist meetings mortality novel pre-clinical respiratory safety study scale up screening small molecule stem

项目摘要

DESCRIPTION (provided by applicant): This project is designed to deliver an anti-mucus drug for the treatment of respiratory airway disease. Airway diseases such as COPD and asthma are leading causes of morbidity and mortality in the U.S. and worldwide and serious forms of these diseases are linked to excess production of inflammatory mucus that obstructs the airway. However, there are no specific and effective therapies to attenuate airway mucus production. The cytokine IL-13 is implicated as a potent stimulus of airway mucus production in both asthma and COPD, and there are ongoing clinical trials of anti-IL-13 biologics. We reasoned that a small molecule to attenuate IL-13- stimulated (but not baseline) mucus production would address a major need for therapy of airway disease. Moreover, a drug targeted to airway epithelial cells themselves could offer significant advantages of specificity and efficacy. We discovered a novel pathway for mucus production that includes IL-13-induction of chloride channel calcium activated 1 (CLCA1) and then activation of mitogen activated protein kinase 13 (MAPK13). This CLCA1-MAPK13 signaling pathway was defined in experimental models but is also active in patients with excess mucus production due to COPD and likely asthma as well. Structure-based drug design led to the development of the first potent MAPK13 inhibitors, which safely attenuated IL-13-stimulated (but not baseline) mucus production in human airway epithelial cells and now appear effective in vitro and in vivo in a pig model of inflammatory airway mucus production. This Project therefore aims to deliver a safe and effective MAPK13 inhibitor for the treatment of excess mucus production found in COPD and related hypersecretory conditions. The UH2 Phase will accomplish two aims. Aim 1 will optimize lead MAPK13 inhibitors to attenuate IL-13- stimulated mucus production in human airway epithelial cells and will secure standardized in vitro ADMET evidence required for selection of a preclinical development candidate. Aim 2 will finalize conditions for IL-13- dependent airway mucus production in a large animal model that is suitable for testing anti-mucus drugs in vitro and in vivo. The UH3 Phase will advance three Aims. Aim 1 will formulate oral and inhaled candidate compounds and complete standardized in vivo ADMET-PK/PD studies. Aim 2 will proceed to safety and efficacy of candidate drugs in a large animal model of mucus production. Aim 3 will develop a protocol for use of candidate drug in humans, including safety, regulatory, and scale-up requirements for IND status. Each Aim has a defined timeline and benchmark. Together, we expect to arrive at a clinical candidate for a MAPK13 inhibitor as the first small-molecule therapeutic to control excess inflammatory mucus production. The projected market for our anti-mucus drug is hypersecretory conditions such as COPD and asthma. The Project will operate under a business plan that includes a patent filed by Washington University for proprietary anti-mucus compounds and eventual clinical trials in humans to achieve FDA approval of a MAPK13 inhibitor as an anti-mucus drug. (End of Abstract)

描述（由申请人提供）：该项目旨在提供一种用于治疗呼吸道疾病的抗粘液药物。慢性阻塞性肺病和哮喘等气道疾病是美国和全世界发病和死亡的主要原因，这些疾病的严重形式与阻塞气道的炎症粘液的过量产生有关。然而，没有具体有效的疗法来减少气道粘液的产生。细胞因子 IL-13 被认为是哮喘和慢性阻塞性肺病中气道粘液产生的有效刺激物，并且抗 IL-13 生物制剂的临床试验正在进行中。我们推断，减弱 IL-13 刺激（但不是基线）粘液产生的小分子将满足治疗气道疾病的主要需求。此外，针对气道上皮细胞本身的药物可以提供显着的特异性和功效优势。我们发现了一种新的粘液产生途径，包括 IL-13 诱导氯通道钙激活 1 (CLCA1)，然后激活丝裂原激活蛋白激酶 13 (MAPK13)。这种 CLCA1-MAPK13 信号通路是在实验模型中定义的，但在因慢性阻塞性肺病和可能的哮喘导致粘液分泌过多的患者中也很活跃。基于结构的药物设计导致了第一个有效的 MAPK13 抑制剂的开发，该抑制剂可以安全地减弱人呼吸道上皮细胞中 IL-13 刺激的（但不是基线）粘液产生，现在在猪模型中在体外和体内表现出有效的效果。炎症性气道粘液产生。因此，该项目旨在提供一种安全有效的 MAPK13 抑制剂，用于治疗 COPD 和相关分泌过多病症中发现的粘液分泌过多。 UH2 阶段将实现两个目标。目标 1 将优化先导 MAPK13 抑制剂，以减弱人气道上皮细胞中 IL-13 刺激的粘液产生，并确保选择临床前开发候选药物所需的标准化体外 ADMET 证据。目标 2 将最终确定大型动物模型中 IL-13 依赖性气道粘液产生的条件，该模型适合体外和体内测试抗粘液药物。 UH3 阶段将推进三个目标。目标 1 将制定口服和吸入候选化合物并完成标准化体内 ADMET-PK/PD 研究。目标 2 将继续研究候选药物在粘液产生的大型动物模型中的安全性和有效性。目标 3 将制定候选药物在人体中使用的方案，包括 IND 状态的安全性、监管和扩大要求。每个目标都有明确的时间表和基准。我们共同期望找到 MAPK13 抑制剂的临床候选药物，作为第一个控制炎症粘液过多产生的小分子治疗药物。我们的抗粘液药物的预计市场是慢性阻塞性肺病和哮喘等分泌过多的疾病。该项目将根据一项商业计划运作，其中包括华盛顿大学为专有抗粘液化合物申请的专利以及最终的人体临床试验，以获得 FDA 批准 MAPK13 抑制剂作为抗粘液药物。（摘要完）