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

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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.