Late Breaking Abstract - Efficacy of DPP1 inhibition with brensocatib in subgroups of patients with bronchiectasis- the WILLOW study

<b>Background:</b> Neutrophil elastase (NE) activity is increased in bronchiectasis and correlated with exacerbations. Brensocatib is an oral, selective, reversible dipeptidyl peptidase 1 inhibitor that blocks activation of neutrophil serine proteases and reduces NE activity. <b>Aims:</b> To evaluate the efficacy of brensocatib compared to placebo in subgroups of patients with bronchiectasis. <b>Methods:</b> WILLOW (NCT03218917) was a phase 2, randomized, double-blind, placebo-controlled study. Adults were randomized 1:1:1 to brensocatib 10 or 25 mg or placebo once daily. The primary endpoint was time to first bronchiectasis exacerbation over 24-weeks. Time to, and rate of, exacerbations were further analyzed in subgroups based on patient characteristics, medical history, disease severity, and baseline sputum NE. Safety and tolerability were assessed. <b>Results:</b> Brensocatib prolonged time to exacerbation vs placebo (brensocatib 10 mg, P=0.027; brensocatib 25 mg, P=0.044). Point estimates for time to, and rate of, exacerbation favored both brensocatib doses (hazard ratios &lt;1; rate ratios &lt;1) vs placebo in nearly all subgroups, including the subgroup without detectable sputum NE at baseline. Exacerbation-related hospitalization rates were 5.9% with brensocatib (pooled) and 8.0% with placebo. Brensocatib reduced sputum activity of NE, proteinase 3, and cathepsin G in a dose-dependent manner. Adverse events in ≥10% of brensocatib-treated patients were cough, headache, increased sputum, and dyspnea. <b>Conclusions:</b> Among patient subgroups (including analysis by baseline sputum NE, medical history, and disease severity), brensocatib consistently prolonged time to first exacerbation and reduced rates of exacerbation.