J Michael Wells,Ingrid L Titlestad,Hanan Tanash,Alice M Turner,Kenneth R Chapman,Umur Ş Hatipoğlu,Monica P Goldklang,Jeanine M D'Armiento,Cheryl S Pirozzi,M Bradley Drummond,Igor Z Barjaktarevic,Wissam M Chatila,Megan S Devine,Charlie Strange,Robert A Sandhaus,Jacqueline M Parkin,Elizabeth Westfall,Vivian Y Lin,Robin Parks,Hui-Chien Kuo,Adzoa Ekue,Kelly L Moffitt,Jamie Inshaw,Inmaculada Aban,Mark T Dransfield,Robert A Stockley
{"title":"口服中性粒细胞弹性酶抑制剂alvelestat治疗α -1抗胰蛋白酶缺乏症的两项随机对照2期研究。","authors":"J Michael Wells,Ingrid L Titlestad,Hanan Tanash,Alice M Turner,Kenneth R Chapman,Umur Ş Hatipoğlu,Monica P Goldklang,Jeanine M D'Armiento,Cheryl S Pirozzi,M Bradley Drummond,Igor Z Barjaktarevic,Wissam M Chatila,Megan S Devine,Charlie Strange,Robert A Sandhaus,Jacqueline M Parkin,Elizabeth Westfall,Vivian Y Lin,Robin Parks,Hui-Chien Kuo,Adzoa Ekue,Kelly L Moffitt,Jamie Inshaw,Inmaculada Aban,Mark T Dransfield,Robert A Stockley","doi":"10.1183/13993003.01019-2025","DOIUrl":null,"url":null,"abstract":"BACKGROUND\r\nAlpha-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.\r\n\r\nMETHODS\r\nWe 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.\r\n\r\nRESULTS\r\nWe 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.\r\n\r\nCONCLUSIONS\r\nAlvelestat 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.","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"56 1","pages":""},"PeriodicalIF":21.0000,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Two randomized controlled Phase 2 studies of the oral neutrophil elastase inhibitor alvelestat in alpha-1 antitrypsin deficiency.\",\"authors\":\"J Michael Wells,Ingrid L Titlestad,Hanan Tanash,Alice M Turner,Kenneth R Chapman,Umur Ş Hatipoğlu,Monica P Goldklang,Jeanine M D'Armiento,Cheryl S Pirozzi,M Bradley Drummond,Igor Z Barjaktarevic,Wissam M Chatila,Megan S Devine,Charlie Strange,Robert A Sandhaus,Jacqueline M Parkin,Elizabeth Westfall,Vivian Y Lin,Robin Parks,Hui-Chien Kuo,Adzoa Ekue,Kelly L Moffitt,Jamie Inshaw,Inmaculada Aban,Mark T Dransfield,Robert A Stockley\",\"doi\":\"10.1183/13993003.01019-2025\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"BACKGROUND\\r\\nAlpha-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.\\r\\n\\r\\nMETHODS\\r\\nWe 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.\\r\\n\\r\\nRESULTS\\r\\nWe 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.\\r\\n\\r\\nCONCLUSIONS\\r\\nAlvelestat 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.\",\"PeriodicalId\":12265,\"journal\":{\"name\":\"European Respiratory Journal\",\"volume\":\"56 1\",\"pages\":\"\"},\"PeriodicalIF\":21.0000,\"publicationDate\":\"2025-09-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Respiratory Journal\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1183/13993003.01019-2025\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"RESPIRATORY SYSTEM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Respiratory Journal","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1183/13993003.01019-2025","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RESPIRATORY SYSTEM","Score":null,"Total":0}
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.
期刊介绍:
The European Respiratory Journal (ERJ) is the flagship journal of the European Respiratory Society. It has a current impact factor of 24.9. The journal covers various aspects of adult and paediatric respiratory medicine, including cell biology, epidemiology, immunology, oncology, pathophysiology, imaging, occupational medicine, intensive care, sleep medicine, and thoracic surgery. In addition to original research material, the ERJ publishes editorial commentaries, reviews, short research letters, and correspondence to the editor. The articles are published continuously and collected into 12 monthly issues in two volumes per year.