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.

Citation

Wells JM, Titlestad IL, Tanash H, Turner AM, Chapman KR, Hatipoğlu UŞ, Goldklang MP, D'Armiento JM, Pirozzi CS, Drummond MB, Barjaktarevic IZ, Chatila WM, Devine MS, Strange C, Sandhaus RA, Parkin JM, Westfall E, Lin VY, Parks R, Kuo HC, Ekue A, Moffitt KL, Inshaw J, Aban I, Dransfield MT, Stockley RA. Two randomized controlled Phase 2 studies of the oral neutrophil elastase inhibitor alvelestat in alpha-1 antitrypsin deficiency. Eur Respir J. 2025 Sep 18:2501019. doi: 10.1183/13993003.01019-2025.

Type

Journal Article