Brensocatib Does More Than Block Proteases — It Broadly Rebalances Lung Inflammation in Bronchiectasis

What the researchers found

The dipeptidyl peptidase-1 (DPP-1) inhibitor brensocatib — which blocks the enzyme that activates destructive neutrophil proteins — had broad immunomodulatory effects beyond its known impact on serine proteases in bronchiectasis patients. Treatment increased the antimicrobial peptides SLPI and α-defensin-3 in sputum, reduced the inflammatory mucin MUC5AC, and significantly altered 15 cytokines and chemokines including CXCL10, CCL8, CCL7, CCL3, and IL-6. These changes were consistent across both doses (10 mg and 25 mg) and validated in an independent European bronchiectasis cohort. The findings reveal that brensocatib rebalances the inflammatory environment in the airways much more broadly than just reducing protease activity.

Why it matters

Bronchiectasis is a chronic lung condition driven by a vicious cycle of infection, neutrophilic inflammation, and airway damage. Most treatments target infection (antibiotics) or mucus clearance, but none effectively break the inflammatory cycle. Brensocatib's ability to simultaneously reduce destructive proteases, increase protective antimicrobial peptides, decrease mucin overproduction, and modulate multiple inflammatory pathways suggests it could be the first therapy to comprehensively address the underlying pathology rather than just managing symptoms.

The numbers in context

n=256 (82 brensocatib 10mg, 87 brensocatib 25mg, 87 placebo) · 215 with sputum for analysis · SLPI and α-defensin-3↑ · MUC5AC↓ · 15 cytokines/chemokines significantly changed · 24-week treatment + 4-week follow-up

How the study worked

Biomarker analysis from the WILLOW phase 2 trial (double-blind, placebo-controlled, randomized). Sputum was collected at baseline, 4 weeks, 24 weeks (end of treatment), and 28 weeks (4 weeks post-treatment). Antimicrobial peptides (SLPI, α-defensin-3) were measured by ELISA, mucin MUC5AC by mass spectrometry, myeloperoxidase by immunoassay, and 45 inflammatory cytokines using the Olink Target 48 assay. Findings were validated against the European BRIDGE bronchiectasis cohort.

Who was studied

256 patients with non-cystic fibrosis bronchiectasis randomized in the WILLOW phase 2 trial; 215 with sputum samples for biomarker analysis

What this study cannot tell us

This is a biomarker sub-analysis of a phase 2 trial, not the primary efficacy endpoint. Changes in biomarkers don't necessarily translate to clinical improvement. The study population had non-cystic fibrosis bronchiectasis, so results may not apply to CF bronchiectasis. Sputum analysis was available for only a subset of randomized patients (215 of 256). The relationship between individual biomarker changes and clinical outcomes (exacerbations, lung function) is not fully characterized in this analysis.

How to read the evidence

This is a biomarker analysis from a well-designed phase 2 RCT with validation in an independent cohort. The trial design (double-blind, placebo-controlled, randomized) is rigorous, and the validation strengthens the findings. However, this is a mechanistic sub-analysis, not a clinical efficacy study.

When this study was published

Published in 2025 in the American Journal of Respiratory and Critical Care Medicine, this is a very recent and clinically relevant analysis. Brensocatib is in late-stage development, and understanding its full mechanism of action is critical for regulatory approval and clinical use.

The bigger picture

Brensocatib is being developed as a potentially first-in-class treatment for bronchiectasis, a condition with no approved anti-inflammatory therapies. The original WILLOW trial showed it reduced exacerbation risk, but the mechanism was assumed to be simply reducing neutrophil elastase. This biomarker analysis reveals a much more complex and comprehensive anti-inflammatory action, involving antimicrobial peptide enhancement, mucin modulation, and broad cytokine rebalancing. Understanding these broader effects is crucial for optimizing the drug's use and identifying which patients might benefit most.

Questions still open

• Which of the multiple immunomodulatory effects of brensocatib — protease reduction, antimicrobial peptide increase, or cytokine modulation — contributes most to the clinical benefit?
• Could brensocatib's broad anti-inflammatory effects be beneficial in other neutrophil-driven lung diseases like COPD or cystic fibrosis?
• Does the increase in antimicrobial peptides like SLPI and α-defensin-3 translate to improved control of bacterial infections in bronchiectasis?

Common questions

Read the original research

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

American journal of respiratory and critical care medicine, 211(5), 770-778

Citation

Johnson, Emma D; Long, Merete B; Perea, Lidia; Shih, Vivian H; Fernandez, Carlos; Teper, Ariel; Cipolla, David; McIntosh, Eve; Galloway, Rachel; Eke, Zsofia; Shuttleworth, Morven; Hull, Rebecca; Spinou, Arietta; De Soyza, Anthony; Ringshausen, Felix C; Goeminne, Pieter; Lorent, Natalie; Haworth, Charles; Loebinger, Michael R; Blasi, Francesco; Shteinberg, Michal; Aliberti, Stefano; Polverino, Eva; Sibila, Oriol; Shoemark, Amelia; Mange, Kevin; Huang, Jeffrey T J; Stobo, Jamie; Chalmers, James D. (2025). Broad Immunomodulatory Effects of the Dipeptidyl Peptidase-1 Inhibitor Brensocatib in Bronchiectasis: Data from the Phase 2, Double-Blind, Placebo-controlled WILLOW Trial.. American journal of respiratory and critical care medicine, 211(5), 770-778. https://doi.org/10.1164/rccm.202408-1545OC