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Sputum was collected at baseline, Week 4, Week 24 (end of treatment), and Week 28 (4 wk after treatment). The antimicrobial peptides secretory leukoproteinase inhibitor (SLPI) and \u03b1-defensin-3 were measured using ELISA, MUC5AC (mucin-5AC) using liquid chromatography\u2013mass spectrometry, myeloperoxidase using immunoassay, and 45 inflammatory cytokines using the Olink Target 48 assay. The relationship between these markers and sputum neutrophil elastase was validated using the European Multicentre Bronchiectasis Audit and Research Collaboration BRIDGE (Bronchiectasis Research Involving Databases, Genomics and Endotyping) bronchiectasis cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Of 82 patients randomized to 10 mg brensocatib, 87 to 25 mg brensocatib, and 87 to placebo, 71, 71, and 73 with sputum available for at least two time points were included. SLPI and \u03b1-defensin-3 increased significantly with brensocatib compared with placebo at both Week 4 and Week 24. MUC5AC was reduced in response to treatment. Subanalysis showed that this was primarily among patients with high baseline neutrophil elastase. Myeloperoxidase did not change. Fifteen cytokines and chemokines increased significantly compared with placebo at Week 4 or 28. CXCL10, CCL8, CCL7, CCL3, and IL-6 increased at both doses at both time points. In the BRIDGE cohort, neutrophil elastase correlated inversely with SLPI, CCL13, IL-7, CCL11, CXCL10, CCL8, and CCL7, all markers increased by brensocatib.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Brensocatib exerts broad antiinflammatory effects beyond its known effects on serine proteases.<\/jats:p>\n                    <jats:p>Clinical trial registered with www.clinicaltrials.gov (NCT 03218917).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.202408-1545oc","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T16:38:36Z","timestamp":1739378316000},"page":"770-778","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":31,"title":["Broad Immunomodulatory Effects of the Dipeptidyl Peptidase-1 Inhibitor Brensocatib in Bronchiectasis: Data from the Phase 2, Double-Blind, Placebo-controlled WILLOW Trial"],"prefix":"10.1093","volume":"211","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0155-6476","authenticated-orcid":false,"given":"Emma D.","family":"Johnson","sequence":"first","affiliation":[{"name":"Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merete B.","family":"Long","sequence":"additional","affiliation":[{"name":"Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidia","family":"Perea","sequence":"additional","affiliation":[{"name":"Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom"},{"name":"Servicio de Neumolog\u0131a, Instituto Cl\u0131nico de Respiratorio, Instituto de Investigaciones Biomedicas August Pi i Sunyer, Hospital Cl\u0131nic, Universitat de Barcelona, Barcelona, Espa\u00f1a"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0853-4210","authenticated-orcid":false,"given":"Vivian H.","family":"Shih","sequence":"additional","affiliation":[{"name":"Insmed, Bridgewater, New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Fernandez","sequence":"additional","affiliation":[{"name":"Insmed, Bridgewater, New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariel","family":"Teper","sequence":"additional","affiliation":[{"name":"Insmed, Bridgewater, New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Cipolla","sequence":"additional","affiliation":[{"name":"Insmed, Bridgewater, New 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