• Emma D Johnson, Merete B Long, Lidia Perea, Vivian H Shih, Carlos Fernandez, Ariel Teper, David Cipolla, Eve McIntosh, Rachel Galloway, Zsofia Eke, Morven Shuttleworth, Rebecca Hull, Arietta Spinou, Anthony De Soyza, Felix C Ringshausen, Pieter Goeminne, Natalie Lorent, Charles Haworth, Michael R Loebinger, Francesco Blasi, Michal Shteinberg, Stefano Aliberti, Eva Polverino, Oriol Sibila, Amelia Shoemark, Kevin Mange, Jeffrey T J Huang, Jamie Stobo, and James D Chalmers.
• University of Dundee, Division of Molecular and Clinical Medicine, Dundee, United Kingdom of Great Britain and Northern Ireland.
• Am. J. Respir. Crit. Care Med. 2025 Feb 12.

RationaleIn the WILLOW trial, the Dipeptidyl peptidase-1 inhibitor brensocatib reduced neutrophil serine protease (NSP) activity and prolonged time to first exacerbation in patients with bronchiectasis.ObjectivesWe hypothesized that, by reducing NSPs, brensocatib would affect antimicrobial peptides, mucins, and cytokines throughout the inflammatory cascade.MethodsThe WILLOW trial was a phase 2 randomized trial of brensocatib (10mg and 25mg) versus placebo. Sputum was collected at baseline, week 4, week 24 (end of treatment) and week 28 (4 weeks post-treatment). The antimicrobial peptides secretory leukoproteinase inhibitor (SLPI) and α-defensin-3 were measured by ELISA, mucin-5AC (MUC5AC) by liquid chromatography mass spectrometry, myeloperoxidase by immunoassay and 45 inflammatory cytokines by Olink® Target 48 assay. The relationship between these markers and sputum neutrophil elastase was validated using the EMBARC-BRIDGE bronchiectasis cohort.Measurements And Main ResultsOf 82 patients randomized to 10mg brensocatib, 87 to 25mg brensocatib, and 87 to placebo, 71, 71 and 73 with sputum available for at least two time points were included. SLPI and α-defensin-3 increased significantly with brensocatib compared to placebo at both week 4 and week 24. MUC5AC reduced in response to treatment. Sub-analysis showed this was primarily among patients with high baseline neutrophil elastase. Myeloperoxidase did not change. 15 cytokines and chemokines increased significantly compared to placebo at week 4 or 28. CXCL10, CCL8, CCL7, CCL3 and IL-6 increased at both doses at both timepoints. In the EMBARC-BRIDGE cohort neutrophil elastase correlated inversely with SLPI, CCL13, IL7, CCL11, CXCL10, CCL8, CCL7, all markers increased by brensocatib.ConclusionsBrensocatib exerts broad anti-inflammatory effects beyond its known effects on serine proteases. Clinical trial registration available at www.Clinicaltrialsgov, ID: NCT03218917.

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