Broad Immunomodulatory Effects of the Dipeptidyl Peptidase-1 Inhibitor Brensocatib in Bronchiectasis: Data from the Phase 2, Double-Blind, Placebo-controlled WILLOW Trial

<b>Rationale:</b> In the WILLOW (Assessment of INS1007 in Participants with Non-Cystic Fibrosis Bronchiectasis) trial, the dipeptidyl peptidase-1 inhibitor brensocatib reduced neutrophil serine protease activity and prolonged time to first exacerbation in patients with bronchiectasis. <b>Objectives:</b> We hypothesized that by reducing neutrophil serine proteases, brensocatib would affect antimicrobial peptides, mucins, and cytokines throughout the inflammatory cascade. <b>Methods:</b> The WILLOW trial was a phase 2 randomized trial of brensocatib (10 and 25 mg) versus placebo. 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 α-defensin-3 were measured using ELISA, MUC5AC (mucin-5AC) using liquid chromatography-mass 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. <b>Measurements and Main Results:</b> 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 α-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. <b>Conclusions:</b> Brensocatib exerts broad antiinflammatory effects beyond its known effects on serine proteases. Clinical trial registered with www.clinicaltrials.gov (NCT03218917).

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Journal
American Journal of Respiratory and Critical Care Medicine
Published
2025-02-12
DOI
https://doi.org/10.1164/rccm.202408-1545oc
Citations
12
Primary Topic
Cystic Fibrosis Research Advances
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article
Field-Weighted Citation Impact
18.22
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article

Broad Immunomodulatory Effects of the Dipeptidyl Peptidase-1 Inhibitor Brensocatib in Bronchiectasis: Data from the Phase 2, Double-Blind, Placebo-controlled WILLOW Trial

Vivian H. Shih, Francesco Blasi, Arietta Spinou, Jeffrey Huang et al.
12 citations
American Journal of Respiratory and Critical Care Medicine
Cystic Fibrosis Research Advances
18.22
article

Broad Immunomodulatory Effects of the Dipeptidyl Peptidase-1 Inhibitor Brensocatib in Bronchiectasis: Data from the Phase 2, Double-Blind, Placebo-controlled WILLOW Trial

Vivian H. Shih, Francesco Blasi, Arietta Spinou, Jeffrey Huang, Michael R. Loebinger, Michal Shteinberg, Lídia Perea, Oriol Sibila, Charles Haworth, Felix C. Ringshausen, Eva Polverino, Rebecca C Hull, Jamie Stobo, Pieter Goeminne, Eve Mcintosh, James Duncan Chalmers, Ariel Teper, Natalie Lorent, Amelia Shoemark, Anthony De Soyza, Carlos Fernández‐Peña, Morven Shuttleworth, Stefano Aliberti, David Cipolla, Zsofia Eke, R.B. Galloway, Kevin C. Mange, Merete Bridget Long, Emma D Johnson
article en
12 citations

Abstract

<b>Rationale:</b> In the WILLOW (Assessment of INS1007 in Participants with Non-Cystic Fibrosis Bronchiectasis) trial, the dipeptidyl peptidase-1 inhibitor brensocatib reduced neutrophil serine protease activity and prolonged time to first exacerbation in patients with bronchiectasis. <b>Objectives:</b> We hypothesized that by reducing neutrophil serine proteases, brensocatib would affect antimicrobial peptides, mucins, and cytokines throughout the inflammatory cascade. <b>Methods:</b> The WILLOW trial was a phase 2 randomized trial of brensocatib (10 and 25 mg) versus placebo. 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 α-defensin-3 were measured using ELISA, MUC5AC (mucin-5AC) using liquid chromatography-mass 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. <b>Measurements and Main Results:</b> 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 α-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. <b>Conclusions:</b> Brensocatib exerts broad antiinflammatory effects beyond its known effects on serine proteases. Clinical trial registered with www.clinicaltrials.gov (NCT03218917).

American Journal of Respiratory and Critical Care MedicineVol. 211(5)
Humanitas University (IT), University of Ulster (GB), Technion – Israel Institute of Technology (IL), University of Dundee (GB), King's College London (GB), University of Milan (IT), Royal Papworth Hospital (GB), Royal Brompton & Harefield NHS Foundation Trust (GB), Hospital de Sant Pau (ES), Freeman Hospital (GB), Ninewells Hospital (GB), Harefield Hospital (GB), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Medizinische Hochschule Hannover (DE), National Institute for Health and Care Research (GB), Royal Brompton Hospital (GB), Vall d'Hebron Institut de Recerca (ES), Insmed (United States) (US), Carmel Medical Center (IL), Vlaamse Vereniging voor Obstetrie en Gynaecolo (BE), Vall d'Hebron Hospital Universitari (ES), German Center for Lung Research (DE), Royal Victoria Hospital (GB), IRCCS Humanitas Research Hospital (IT), Imperial College London (GB), Universitat de Barcelona (ES), KU Leuven (BE)
Openalex Percentile: Top 1%
Cystic Fibrosis Research Advances
18.22
DOISourceOpenAlex
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