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. 2025 Feb 12.
doi: 10.1164/rccm.202408-1545OC. Online ahead of print.

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

Emma D Johnson  1 , Merete B Long  1 , Lidia Perea  2   1 , Vivian H Shih  3 , Carlos Fernandez  3 , Ariel Teper  3 , David Cipolla  3 , Eve McIntosh  4 , Rachel Galloway  1 , Zsofia Eke  1 , Morven Shuttleworth  5 , Rebecca Hull  1 , Arietta Spinou  6   7 , Anthony De Soyza  8 , Felix C Ringshausen  9 , Pieter Goeminne  10 , Natalie Lorent  11 , Charles Haworth  12 , Michael R Loebinger  13 , Francesco Blasi  14 , Michal Shteinberg  15   16 , Stefano Aliberti  17   18 , Eva Polverino  19 , Oriol Sibila  20 , Amelia Shoemark  21   22 , Kevin Mange  23 , Jeffrey T J Huang  24 , Jamie Stobo  4 , James D Chalmers  25
Affiliations

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

Emma D Johnson et al. Am J Respir Crit Care Med. .

Abstract

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.

Keywords: brensocatib; bronchiectasis; inflammation.

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