What type of study is this?

This is a RCT study (also classified as: Phase 2).

September 18, 2025Open Access

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

JWJ. Michael WellsUniversity of Alabama at Birmingham ITIngrid Louise TitlestadUniversity of Southern Denmark HTHanan TanashLund University

Key Points

Alvelestat significantly suppressed neutrophil elastase levels in both trials, particularly at 240 mg twice daily.
In the Phase 2 studies, AATD biomarkers showed robust reduction only with the higher alvelestat dose, while safety was established.
Headache was the most frequent adverse event, especially at the higher dosage, but no concerning safety signals arose.
The findings provide support for advancing the 240 mg twice daily alvelestat into further clinical endpoint studies.

Abstract

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-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 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-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 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.

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