Inhaled alpha-1 antitrypsin (AAT) restores lower respiratory tract protease-antiprotease homoeostasis and reduces inflammation in AAT-deficient individuals: a randomised phase 2 study.

Background: Alpha-1 antitrypsin (AAT)-deficient individuals have a greater risk for developing COPD than individuals with normal AAT levels. Methods: This was a double-blind, randomised, parallel group, placebo-controlled trial to examine the safety and tolerability of "Kamada-AAT for Inhalation" (inhaled AAT) in subjects with AAT deficiency, and to explore its effect on AAT and biomarkers in the lung epithelial lining fluid (ELF). 36 patients with severe AAT deficiency were randomised 2:1 to receive 80 mg or 160 mg inhaled AAT or placebo once daily for 12 weeks. The primary outcomes were AAT and antineutrophil elastase capacity (ANEC) in bronchoalveolar lavage and plasma after treatment. Secondary outcomes included safety, levels of normal M-type AAT in the plasma and concentrations of AAT, neutrophil elastase (NE), AAT-NE complexes and neutrophil count in the ELF. Results: 12 weeks of active treatment significantly increased AAT, ANEC and AAT-NE complexes in the ELF. Mean antigenic AAT levels in the ELF were restored to 5.2±2.3 μM in the 80 mg arm and to 17.7±2 μM in the 160 mg arm. Both doses significantly restored AAT antiprotease activity within the lung and reduced NE levels. M-specific AAT levels in plasma increased in a dose-dependent manner. A clinically meaningful reduction in ELF neutrophil % was observed in the 80 mg arm. AAT for inhalation was well tolerated. Conclusions: Inhaled AAT restores protease-antiprotease homoeostasis and may represent a safe and effective therapy.