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

TY - JOUR

T1 - Broad Immunomodulatory Effects of the Dipeptidyl-peptidase-1 Inhibitor Brensocatib in Bronchiectasis

T2 - Data from the Phase 2, Double-Blind, Placebo-controlled WILLOW Trial

AU - Johnson, Emma D

AU - Long, Merete B

AU - Perea, Lidia

AU - Shih, Vivian H

AU - Fernandez, Carlos

AU - Teper, Ariel

AU - Cipolla, David

AU - McIntosh, Eve

AU - Galloway, Rachel

AU - Eke, Zsofia

AU - Shuttleworth, Morven

AU - Hull, Rebecca

AU - Spinou, Arietta

AU - De Soyza, Anthony

AU - Ringshausen, Felix C

AU - Goeminne, Pieter

AU - Lorent, Natalie

AU - Haworth, Charles

AU - Loebinger, Michael R

AU - Blasi, Francesco

AU - Shteinberg, Michal

AU - Aliberti, Stefano

AU - Polverino, Eva

AU - Sibila, Oriol

AU - Shoemark, Amelia

AU - Mange, Kevin

AU - Huang, Jeffrey T. J.

AU - Stobo, Jamie

AU - Chalmers, James D.

PY - 2025/2/12

Y1 - 2025/2/12

N2 - RATIONALE: In 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.OBJECTIVES: We hypothesized that, by reducing NSPs, brensocatib would affect antimicrobial peptides, mucins, and cytokines throughout the inflammatory cascade.METHODS: The 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 RESULTS: Of 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.CONCLUSIONS: Brensocatib exerts broad anti-inflammatory effects beyond its known effects on serine proteases. Clinical trial registration available at www.CLINICALTRIALS: gov, ID: NCT03218917.

AB - RATIONALE: In 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.OBJECTIVES: We hypothesized that, by reducing NSPs, brensocatib would affect antimicrobial peptides, mucins, and cytokines throughout the inflammatory cascade.METHODS: The 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 RESULTS: Of 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.CONCLUSIONS: Brensocatib exerts broad anti-inflammatory effects beyond its known effects on serine proteases. Clinical trial registration available at www.CLINICALTRIALS: gov, ID: NCT03218917.

U2 - 10.1164/rccm.202408-1545OC

DO - 10.1164/rccm.202408-1545OC

M3 - Article

C2 - 39938076

SN - 1073-449X

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

ER -