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

Rationale: 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. Objectives: We hypothesized that by reducing neutrophil serine proteases, brensocatib would affect antimicrobial peptides, mucins, and cytokines throughout the inflammatory cascade. Methods: 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. Measurements and Main Results: 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. Conclusions: Brensocatib exerts broad antiinflammatory effects beyond its known effects on serine proteases. Clinical trial registered with www.clinicaltrials.gov (NCT03218917).