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).

Background Serum anti-glycopeptidolipid (GPL) core immunoglobuin A (IgA) antibody test has been proposed as a diagnostic tool for Mycobacterium avium complex pulmonary diseases. Cross-reactivity with other non-tuberculous mycobacteria (NTM), including M. abscessus, indicates that it may have a role as a broader screening test for NTM pulmonary disease (NTM-PD). NTM-PD is believed to be underdiagnosed in patients with bronchiectasis. Research Question Can the serum anti-GPL core IgA antibody test be used to screen for NTM-PD in bronchiectasis? Study Design and Methods Patients from the prospective European Bronchiectasis Registry (EMBARC-BRIDGE; NCT03791086) were enrolled. Patients from the United Kingdom, Italy, Spain, Belgium, the Netherlands, and Germany were included. A control cohort of patients without any underlying lung disease was also recruited. The levels of serum IgA antibodies against the GPL core were measured using an enzyme immunoassay kit, and receiver operating characteristics curve analysis was conducted to evaluate the accuracy of the antibody level in screening for NTM-PD. Results 282 patients were enrolled (151 [53.6%] female, median age 68 years). Median (quartile 1–3) anti-GPL-core IgA antibody levels were 0.2 (0.1–0.3) U/mL in patients without NTM isolation and NTM-PD (n=238), 0.3 (0.2–0.4) U/mL in NTM isolation that were incompatible with the diagnosis of NTM-PD (n=18) and 1.5 (0.4–6.2) U/mL in NTM-PD (n=26) (P=0.0001). Antibody levels showed excellent accuracy in identifying patients with NTM-PD (area under the curve 0.886, 95% CI 0.800–0.973) in bronchiectasis cohort and also showed excellent discrimination of patients with NTM-PD from those with NTM isolation who did not meet the diagnostic criteria for NTM-PD (0.816, 95% CI 0.687–0.945). Interpretation The anti-GPL-core IgA antibody demonstrated excellent efficacy in screening for NTM-PD in a large bronchiectasis cohort.