|Type:||Late Breaking Abstract|
|Topic:||09. COPD, Emphysema, Chronic Bronchitis, Alpha-1 Antitrypsin Deficiency / Adult / Translational Science / Respiratory Cell and Molecular Biology (RCMB)|
|Authors:||M. Brantly1, J. Stocks2, F. Rouhani1, J. Lascano1, A. Jeffers2, J. Nolte1, S. Owens2, T.A. Tucker2, N. Tov3; 1Gainesville, FL/US, 2Tyler, TX/US, 3Ness-Ziona/IL|
Introduction: Alpha-1-Antitrypsin (AAT) deficient individuals are at substantially greater risk of developing COPD following exposure to cigarette or passive smoking compared to individuals with normal amounts of AAT. We hypothesize that inhaled AAT will reduce protease activity and lower respiratory tract inflammation.
Methods: Study design- 2 separate groups of 18 PI ZZ individuals were evaluated using bronchoalveolar lavage (BAL) before and following 12 weeks of inhaled Kamada-API using a dose of 80 mg once or twice a day (160 mg). The dosing groups were performed at 2 separate sites and subjects were randomized in a double blind 2:1 fashion to active API or placebo. After 12 weeks subjects received 160 mg of Kamada-API for an additional 12 weeks. BAL was performed using 100 ml of saline in 5-20 ml aliquots in 3 separate lobes. The BAL fluid was evaluated separately for all lobes. Comparisons were made in two separate ways, as paired lobes (before and after) and the total of all 3 lobes. Anti-neutrophil elastase capacity (ANEC), %PMNs, NE, AAT, NE-AAT complex and a panel of inflammatory cytokines were measured and adjusted for the epithelial lining fluid (ELF) volume using the urea method.
Results: Compared to placebo, ELF-AAT, ANEC, AAT-NE Complexes concentrations were significantly increased in subjects receiving the 80 mg and 160 mg doses. The average ELF AAT concentrations were 2-5 fold above the AAT concentration of 2500 nM found in normal individuals. Paired lobe analysis using the RML demonstrates a significant reduction in % neutrophils and NE in the 80 mg dose group. Pro-inflammatory cytokines were not significantly different in pair lobe analysis. Importantly aerosolized M AAT was detected in the plasma of all subjects receiving inhaled AAT in a dose-response relationship. All subjects tolerated inhaled Kamada-API and adverse events were very rare.
Conclusion: Inhaled AAT restored protease anti-protease homeostasis and reduced the percentage of neutrophils and NE concentration in the lower respiratory tract of AAT deficient individuals. Detection of normal M AAT in the plasma of study subjects indicates that inhaled AAT passed from the alveolar compartment and the interstitial space. Based on these findings inhaled Kamada API may be an effective therapy for the treatment of lung disease in AAT deficient individuals. A phase 3 study using clinical outcomes is in the planning stage.