Two randomized controlled Phase 2 studies of the oral neutrophil elastase inhibitor alvelestat in alpha-1 antitrypsin deficiency.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that causes emphysema from lack of the AAT serpin anti-protease, leading to protease-anti-protease imbalance. Weekly intravenous AAT therapy (augmentation) is the only specific treatment available. Alvelestat is an oral inhibitor of neutrophil elastase (NE) in development as a novel approach to AATD therapy. Here, we tested the safety and mechanistic efficacy of alvelestat in severe AATD. METHODS: We conducted two complementary, double-blind, randomized, placebo-controlled, 12-week trials, incorporating two doses of alvelestat in AATD. ATALANTa investigated 120 mg twice daily, including a subset of participants also receiving augmentation; ASTRAEUS tested 120 mg and 240 mg twice a day without augmentation. Primary and secondary endpoints were the change in blood NE (the putative target) and its activity in AATD (Aα-Val360 and desmosine/isodesmosine) as well as safety and tolerability. RESULTS: We enrolled 161 participants (63 in ATALANTa and 98 in ASTRAEUS). Blood NE was significantly suppressed in both studies at both doses, with the greatest effect (>90% suppression) at the 240 mg BID dose. There was no effect of 120 mg on disease activity biomarkers, whilst the 240 mg dose demonstrated significant reduction Aα-Val360 and desmosine. The most common adverse event was headache, particularly at the 240 mg dose. No safety signals of concern were detected. CONCLUSIONS: Alvelestat effectively suppressed NE and its activity at both doses, but only the 240 mg twice daily dose demonstrated relevant efficacy compared to placebo on disease activity biomarkers with a favourable safety profile. These findings support progression of the 240 mg twice daily dose into a clinical endpoint study.