P112 Efficacy and safety of Dipeptidyl Peptidase-1 (DPP-1) inhibition in long-term macrolide users with bronchiectasis: a post-hoc analysis of the WILLOW trial

<h3>Background</h3> Neutrophil serine proteases, such as neutrophil elastase, are activated by DPP-1 in the bone marrow. Brensocatib, a reversible DPP-1 inhibitor, prolonged time to first exacerbation vs placebo in non-cystic fibrosis bronchiectasis (NCFBE) patients in the phase 2 WILLOW trial (NCT03218917). Long-term macrolides are widely used and have been shown to reduce neutrophilic inflammation. The present post-hoc analysis compares patient characteristics and outcomes in WILLOW subgroups based on long-term macrolide use. <h3>Methods</h3> Adult bronchiectasis patients received once-daily brensocatib (10 or 25 mg) or placebo. Patients on stable long-term macrolide therapy could be included in the trial. Endpoints included time to first exacerbation, annualised rate of pulmonary exacerbations, and treatment-emergent adverse events (TEAEs). Pooled results from brensocatib arms are presented. <h3>Results</h3> Patients on long-term macrolide treatment (n=44) were more likely to have <i>P. aeruginosa</i> cultured from sputum, a higher background exacerbation rate, lower baseline FEV₁, higher baseline levels of sputum NE, higher Bronchiectasis Severity Index (BSI) scores, a medical history of asthma, and inhaled steroid use than patients without long-term macrolide treatment (n=212) (table 1). Brensocatib prolonged time to first exacerbation (hazard ratio 0.60 [95% CI: 0.25–1.45] in the macrolide subgroup; 0.60 [0.38–0.94] for the subgroup without macrolides) and reduced exacerbation rates in patients with and without long-term macrolide treatment (table 1). Similar TEAE rates were observed across all subgroups. The most common TEAEs across the pooled brensocatib arms were increased sputum, cough, and dyspnea. <h3>Conclusions</h3> Consistent with overall WILLOW results, brensocatib prolonged time to first exacerbation and reduced exacerbation rates vs placebo regardless of long-term macrolide use, and was generally well tolerated with consistent safety signals. A confirmatory phase 3 trial (ASPEN; NCT04594369) is ongoing. Please refer to page A290 for declarations of interest related to this abstract.