Two randomised controlled phase 2 studies of the oral neutrophil elastase inhibitor alvelestat in alpha-1 antitrypsin deficiency

作者：J. Michael Wells, Ingrid Louise Titlestad, Hanan Tanash, Alice Turner, Kenneth R. Chapman, Umur Hatipoğlu, Monica Goldklang, Jeanine D’Armiento, C.S. Pirozzi, Michael Drummond, Igor Barjaktarević, Wissam Chatila, Megan Devine, Charlie Strange, Robert A. Sandhaus, Jacqueline Parkin, Elizabeth Westfall, Vivian Lin, Robin J. Parks, Hui‐Chien Kuo, Adzoa Ekue, Kelly Moffitt, Jamie Inshaw, Inmaculada Aban, Mark T. Dransfield, R A Stockley · 发表于：European Respiratory Journal · 年份：2025 · DOI：10.1183/13993003.01019-2025 · 被引用次数：10 · 研究领域：Protease and Inhibitor Mechanisms、Neutrophil, Myeloperoxidase and Oxidative Mechanisms、Blood disorders and treatments

Background Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that causes emphysema from lack of the alpha-1 antitrypsin (AAT) serpin antiprotease, leading to protease–antiprotease 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, randomised, 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 and 240 mg twice daily without augmentation. Primary and secondary end-points were the change in blood NE (the putative target) and its activity in AATD (Aα-Val 360 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 alvelestat 240 mg twice daily. There was no effect of alvelestat 120 mg on disease activity biomarkers, while 240 mg demonstrated significant reduction in Aα-Val 360 and desmosine. The most common adverse event was headache, particularly at the 240 mg dose. No safety signals of concern were detected. Conclusions Alvelesta...