AZD9688: A First in Class Disease Modifying Therapy to Treat Alpha-1 Antitrypsin Deficiency a Genetically Linked Orphan Disease

AZD9688：一流的疾病修饰疗法，用于治疗 Alpha-1 抗胰蛋白酶缺乏症（一种与遗传相关的孤儿病）

• 批准号: 10001076
• 负责人: Inmaculada B. Aban
• 金额: $ 89.67万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-09 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001076
• 关键词: Accounting; Affect; American; Biochemical; Biological Markers; Blood; Bronchiectasis; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Buffers; Caring; Case Report Form; Cause of Death; Chronic Obstructive Airway Disease; Clinical; Clinical Drug Development; Clinical Trials; Contracts; Cystic Fibrosis; Data; Database Management Systems; Databases; Desmosine; Direct Costs; Disease; Double-Blind Method; Dyspnea; Elastin; Enzymes; Equilibrium; Extracellular Matrix; Feedback; Foundations; Gene Mutation; Genetic; Health Status; Human; Individual; Inflammation; Inflammatory; Influenza; Infusion procedures; Institution; Institutional Review Boards; Intravenous; Isodesmosine; Leukocyte Elastase; Link; Lung; Lung diseases; Manuals; Measurement; Measures; Mediating; Mediation; Mediator of activation protein; Molecular; Nature; Online Systems; Onset of illness; Oral; Patients; Peptide Hydrolases; Periodicity; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Placebos; Plasma; Play; Preparation; Procedures; Protease Inhibitor; Proteins; Proteolysis; Protocols documentation; Pulmonary Emphysema; Pulmonary Inflammation; Randomized; Rare Diseases; Reporting; Research Personnel; Respiratory Signs and Symptoms; Role; Safety; Serine Proteinase Inhibitors; Site; Streptococcus pneumoniae; Testing; Therapeutic; Training; United States; Vaccination; airway obstruction; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; base; clinical development; clinical research site; cost; early onset; efficacy evaluation; extracellular; improved; inflammatory marker; lung injury; member; neutrophil; neutrophil elastase inhibitor; novel therapeutic intervention; phase 2 study; primary endpoint; pulmonary function; pulmonary function decline; recruit; response; safety study; secondary endpoint; supplemental oxygen

Project Summary / Abstract Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause of chronic obstructive pulmonary disease (COPD) and emphysema and affects between 70,000-100,000 individuals in the United States. Individuals with AATD have extremely low plasma and lung levels of AAT, a serine protease inhibitor that inactivates neutrophil elastase (NE) and other proteases to maintain protease-antiprotease balance in the lung. In the absence of AAT, NE activity is unchecked leading to accelerated elastin degradation, progressive damage to the extracellular matrix, and causing early-onset emphysema. Desmosine and isodesmosine (DES), markers of NE-mediated elastolysis, can be measured in plasma and bronchoalveolar lavage (BAL) fluid, correlate with lung function, and can be modified by AAT augmentation therapy which currently forms the mainstay of AATD treatment. While AAT augmentation therapy may slow emphysema progression, data is not definitive and the therapy is costly and burdensome. Direct inhibition of NE, the mediator of lung injury, represents a more direct approach. AZD9668 is a potent, selective, and orally available NE inhibitor that was developed as treatment for pulmonary diseases characterized by increased protease activity. In Phase 2 clinical trials, AZD9668 improved lung function in bronchiectasis, reduced markers of elastin degradation in cystic fibrosis, and improved inflammatory markers in a subset of non-AATD COPD patients without raising any safety concerns. We hypothesize that AZD9668 will block NE activity in the lungs and plasma of AATD patients and thus reduce DES levels in both compartments and that the drug will be safe and well tolerated. We will test this through the following specific aims: UG3 Phase: 1. To finalize the study protocol and manual of procedures, establish the coordinating center and the electronic database system, execute clinical site contracts, gain IRB approvals for the phase II study, and apply for and receive approval of an investigator initiated IND for AZD9668 in AATD from the FDA. UH3 Phase: 2a. To evaluate the efficacy and safety of AZD9668 120mg bid in a 12-week randomized, double- blind, placebo-controlled Phase 2a trial in patients with AATD and COPD. The co-primary endpoints will be the reduction in elastin degradation and NE activity as measured by DES in plasma and the safety and tolerability of AZD9668. Secondary endpoints include lung function, health status, and dyspnea as well as additional measurements of NE activity, elastolysis, and inflammation in blood and BAL. 2b. To determine the utility of baseline plasma and BAL DES as a biomarker of AZD9668 response in patients with AATD. This project explores a novel therapeutic approach to target the excessive proteolysis/elastolysis in AATD and if successful will set the stage to further develop this paradigm shifting oral therapeutic strategy.

项目总结/摘要 α-1抗胰蛋白酶缺乏症（AATD）是慢性阻塞性肺疾病最常见的遗传原因， 疾病（COPD）和肺气肿，并且在美国影响70，000 - 100，000个体。 患有AATD的个体具有极低的血浆和肺AAT水平，AAT是一种丝氨酸蛋白酶抑制剂， 使中性粒细胞弹性蛋白酶（NE）和其它蛋白酶失活以维持肺中的蛋白酶-抗蛋白酶平衡。 在不存在AAT的情况下，NE活性未受抑制，导致弹性蛋白降解加速，进行性地降低。 损伤细胞外基质，并导致早发性肺气肿。锁链素和异锁链素 (DES)NE介导的弹性蛋白溶解的标志物，可以在血浆和支气管肺泡灌洗（BAL）中测量。 液体，与肺功能相关，并且可以通过AAT增强治疗进行修改，目前形成了 AATD治疗的支柱。虽然AAT增强治疗可能会减缓肺气肿的进展，但数据并非如此。 确定的，并且治疗是昂贵和繁重的。直接抑制NE，肺损伤的介质， 是一种更直接的方法。AZD 9668是一种有效的、选择性的和口服的NE抑制剂， 开发用于治疗以蛋白酶活性增加为特征的肺部疾病。在阶段2中 在临床试验中，AZD 9668改善了支气管扩张症患者的肺功能，减少了支气管扩张症患者的弹性蛋白降解标志物， 囊性纤维化，并改善非AATD COPD患者亚组的炎症标志物， 任何安全问题。我们假设AZD 9668将阻断AATD肺和血浆中的NE活性， 患者，从而降低两个隔室中的DES水平，并且药物将是安全的且耐受性良好。 我们将通过以下具体目标来检验这一点： UG 3阶段：1.完成研究方案和程序手册，建立协调中心， 电子数据库系统，执行临床研究中心合同，获得IRB对II期研究的批准，以及 向FDA申请并获得研究者发起的AZD 9668用于AATD的IND批准。UH3 阶段：2a.在一项为期12周的随机化、双盲、随机对照研究中，评价AZD 9668 120 mg bid的疗效和安全性。 在AATD和COPD患者中进行的盲态、安慰剂对照IIa期试验。协同主要终点为 通过血浆中DES测量的弹性蛋白降解和NE活性降低以及安全性和耐受性 AZD9668次要终点包括肺功能、健康状况和呼吸困难以及其他 测量血液和BAL中的NE活性、弹性蛋白溶解和炎症。2b.确定的效用 基线血浆和BAL DES作为AATD患者中AZD 9668应答的生物标志物。 该项目探索了一种新的治疗方法，以靶向AATD中的过度蛋白水解/弹性蛋白水解， 如果成功，将为进一步发展这种范式转变的口服治疗策略奠定基础。