{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:07:20Z","timestamp":1790946440044,"version":"4.1.0"},"reference-count":35,"publisher":"European Respiratory Society (ERS)","issue":"6","license":[{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100022502","name":"Mereo BioPharma","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100022502","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["UG3\/UH3 TR002450"],"award-info":[{"award-number":["UG3\/UH3 TR002450"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["publications.ersnet.org"],"crossmark-restriction":true},"short-container-title":["Eur Respir J"],"accepted":{"date-parts":[[2025,8,22]]},"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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\u2013antiprotease 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We conducted two complementary, double-blind, randomised, placebo-controlled, 12-week trials, incorporating two doses of alvelestat in AATD. ATALANTa investigated 120\u2005mg twice daily, including a subset of participants also receiving augmentation; ASTRAEUS tested 120 and 240\u2005mg twice daily without augmentation. Primary and secondary end-points were the change in blood NE (the putative target) and its activity in AATD (A\u03b1-Val\n                      <jats:sup>360<\/jats:sup>\n                      and desmosine\/isodesmosine) as well as safety and tolerability.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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 (&gt;90% suppression) at alvelestat 240\u2005mg twice daily. There was no effect of alvelestat 120\u2005mg on disease activity biomarkers, while 240\u2005mg demonstrated significant reduction in A\u03b1-Val\n                      <jats:sup>360<\/jats:sup>\n                      and desmosine. The most common adverse event was headache, particularly at the 240\u2005mg dose. No safety signals of concern were detected.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Alvelestat effectively suppressed NE and its activity at both doses, but only the 240\u2005mg 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\u2005mg twice-daily dose into a clinical end-point study.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1183\/13993003.01019-2025","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T15:17:26Z","timestamp":1758208646000},"page":"2501019","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Two randomised controlled phase 2 studies of the oral neutrophil elastase inhibitor alvelestat in alpha-1 antitrypsin deficiency"],"prefix":"10.1183","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9612-5454","authenticated-orcid":false,"given":"J. Michael","family":"Wells","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid L.","family":"Titlestad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanan","family":"Tanash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5947-3254","authenticated-orcid":false,"given":"Alice M.","family":"Turner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2498-9859","authenticated-orcid":false,"given":"Kenneth R.","family":"Chapman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umur \u015e.","family":"Hatipo\u011flu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica P.","family":"Goldklang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanine M.","family":"D'Armiento","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheryl S.","family":"Pirozzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Bradley","family":"Drummond","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor Z.","family":"Barjaktarevic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wissam M.","family":"Chatila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan S.","family":"Devine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlie","family":"Strange","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Sandhaus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline M.","family":"Parkin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Westfall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian Y.","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Parks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Chien","family":"Kuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adzoa","family":"Ekue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly L.","family":"Moffitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"Inshaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inmaculada","family":"Aban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark T.","family":"Dransfield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Stockley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"81","published-online":{"date-parts":[[2025,9,18]]},"reference":[{"key":"2025121809152035000_66.6.2501019.1","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.arbres.2023.03.016","article-title":"Estimated worldwide prevalence of the PI*ZZ alpha-1 antitrypsin genotype in subjects with chronic obstructive pulmonary disease","volume":"59","author":"Blanco","year":"2023","journal-title":"Arch Bronconeumol"},{"key":"2025121809152035000_66.6.2501019.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1910234"},{"key":"2025121809152035000_66.6.2501019.3","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.168.7.818"},{"key":"2025121809152035000_66.6.2501019.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcp0900449"},{"key":"2025121809152035000_66.6.2501019.5","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)66781-5"},{"key":"2025121809152035000_66.6.2501019.6","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.158.1.9712017"},{"key":"2025121809152035000_66.6.2501019.7","doi-asserted-by":"crossref","first-page":"20406223211010172","DOI":"10.1177\/20406223211010172","article-title":"Management of lung disease in alpha-1 antitrypsin deficiency: what we do and what we do not know","volume":"12","author":"Barjaktarevic","year":"2021","journal-title":"Ther Adv Chronic Dis"},{"key":"2025121809152035000_66.6.2501019.8","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1164\/ajrccm.161.3.9906011","article-title":"Feasibility of a clinical trial of augmentation therapy for \u03b11-antitrypsin deficiency. The Alpha 1-Antitrypsin Deficiency Registry Study Group","volume":"161","author":"Schluchter","year":"2000","journal-title":"Am J Respir Crit Care Med"},{"key":"2025121809152035000_66.6.2501019.9","first-page":"95","article-title":"Designing clinical trials in \u201cregular\u201d COPD versus alpha-1 antitrypsin deficiency-associated COPD: \u201cmore alike than unalike?\u201d","volume":"9","author":"Stoller","year":"2022","journal-title":"Chronic Obstr Pulm Dis"},{"key":"2025121809152035000_66.6.2501019.10","doi-asserted-by":"publisher","DOI":"10.1172\/JCI110360"},{"key":"2025121809152035000_66.6.2501019.11","doi-asserted-by":"publisher","DOI":"10.1097\/MCP.0000000000000238"},{"key":"2025121809152035000_66.6.2501019.12","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.111.182139"},{"key":"2025121809152035000_66.6.2501019.13","doi-asserted-by":"crossref","first-page":"288","DOI":"10.5414\/CP201674","article-title":"Pharmacokinetics and safety of AZD9668, an oral neutrophil elastase inhibitor, in healthy volunteers and patients with COPD","volume":"51","author":"Gunawardena","year":"2013","journal-title":"Int J Clin Pharmacol Ther"},{"key":"2025121809152035000_66.6.2501019.14","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1080\/15412555.2017.1376044","article-title":"Bioequivalence of a liquid formulation of alpha1-proteinase inhibitor compared with Prolastin-C (Lyophilized Alpha1-PI) in alpha1-antitrypsin deficiency","volume":"14","author":"Barker","year":"2017","journal-title":"COPD"},{"key":"2025121809152035000_66.6.2501019.15","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2010.154690"},{"key":"2025121809152035000_66.6.2501019.16","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00197411"},{"key":"2025121809152035000_66.6.2501019.17","doi-asserted-by":"publisher","DOI":"10.4155\/bio.13.164"},{"key":"2025121809152035000_66.6.2501019.18","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2011-200279"},{"key":"2025121809152035000_66.6.2501019.19","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1164\/rccm.201901-0010OC","article-title":"The biological effects of double-dose alpha-1 antitrypsin augmentation therapy. A pilot clinical trial","volume":"200","author":"Campos","year":"2019","journal-title":"Am J Respir Crit Care Med"},{"key":"2025121809152035000_66.6.2501019.20","first-page":"34","article-title":"The effect of alpha-1 proteinase inhibitor on biomarkers of elastin degradation in alpha-1 antitrypsin deficiency: an analysis of the RAPID\/RAPID extension trials","volume":"4","author":"Ma","year":"2016","journal-title":"Chronic Obstr Pulm Dis"},{"key":"2025121809152035000_66.6.2501019.21","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1378\/chest.14-0520","article-title":"The relationship of the fibrinogen cleavage biomarker A\u03b1-Val360 with disease severity and activity in \u03b11-antitrypsin deficiency","volume":"148","author":"Carter","year":"2015","journal-title":"Chest"},{"key":"2025121809152035000_66.6.2501019.22","doi-asserted-by":"publisher","DOI":"10.3109\/15412555.2013.771163"},{"key":"2025121809152035000_66.6.2501019.23","doi-asserted-by":"publisher","DOI":"10.1081\/COPD-200050513"},{"key":"2025121809152035000_66.6.2501019.24","doi-asserted-by":"publisher","DOI":"10.1183\/23120541.00095-2019"},{"key":"2025121809152035000_66.6.2501019.25","first-page":"163","article-title":"Alpha-1 antitrypsin deficiency: have we got the right proteinase?","volume":"7","author":"Stockley","year":"2020","journal-title":"Chronic Obstr Pulm Dis"},{"key":"2025121809152035000_66.6.2501019.26","doi-asserted-by":"publisher","DOI":"10.1165\/ajrcmb.26.3.4704"},{"key":"2025121809152035000_66.6.2501019.27","doi-asserted-by":"crossref","first-page":"1421598","DOI":"10.3389\/fphar.2024.1421598","article-title":"A novel in vitro cell model of the proteinase\/antiproteinase balance observed in alpha-1 antitrypsin deficiency","volume":"15","author":"Chen","year":"2024","journal-title":"Front Pharmacol"},{"key":"2025121809152035000_66.6.2501019.28","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202305-0863OC"},{"key":"2025121809152035000_66.6.2501019.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmed.2012.12.009"},{"key":"2025121809152035000_66.6.2501019.30","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00194611"},{"key":"2025121809152035000_66.6.2501019.31","first-page":"260","article-title":"Non-invasive assessment and management of liver involvement in adults with alpha-1 antitrypsin deficiency","volume":"7","author":"Hamesch","year":"2020","journal-title":"Chronic Obstr Pulm Dis"},{"key":"2025121809152035000_66.6.2501019.32","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s10194-022-01412-0","article-title":"Involvement of adenosine signaling pathway in migraine pathophysiology: a systematic review of preclinical studies","volume":"23","author":"Thuraiaiyah","year":"2022","journal-title":"J Headache Pain"},{"key":"2025121809152035000_66.6.2501019.33","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1016\/j.tranon.2019.05.018","article-title":"Clinical implications and translation of an off-target pharmacology profiling hit: adenosine uptake inhibition in vitro","volume":"12","author":"Amouzadeh","year":"2019","journal-title":"Transl Oncol"},{"key":"2025121809152035000_66.6.2501019.34","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.2169\/internalmedicine.50.4384","article-title":"Escalation regimen of cilostazol for acute brain infarction","volume":"50","author":"Nishiyama","year":"2011","journal-title":"Intern Med"},{"key":"2025121809152035000_66.6.2501019.35","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1182\/blood-2021-151324","article-title":"Effects of alvelestat, an oral neutrophil elastase inhibitor, on elevated elastase and collagen turnover biomarkers in patients with bronchiolitis obliterans syndrome after hematopoietic cell transplantation","volume":"138","author":"Im","year":"2021","journal-title":"Blood"}],"container-title":["European Respiratory Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1183\/13993003.01019-2025","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T17:15:33Z","timestamp":1766078133000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.ersnet.org\/lookup\/doi\/10.1183\/13993003.01019-2025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,18]]},"references-count":35,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,12,18]]},"published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1183\/13993003.01019-2025"],"URL":"https:\/\/doi.org\/10.1183\/13993003.01019-2025","relation":{},"ISSN":["0903-1936","1399-3003"],"issn-type":[{"value":"0903-1936","type":"print"},{"value":"1399-3003","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,18]]}}}