Rationale: The dipeptidyl peptidase-1 (DPP1) inhibitor brensocatib, prolonged the time to first exacerbation and reduced sputum neutrophil elastase (NE) activity in non-cystic fibrosis bronchiectasis (NCFBE) patients in the WILLOW (NCT03218917) trial. Secretory leukocyte peptidase inhibitor (SLPI) is an antimicrobial and anti-inflammatory host defence peptide associated with lower disease severity in NCFBE. Since NE cleaves and inactivates SLPI, we hypothesised that brensocatib treatment would increase sputum SLPI levels. 

Methods: WILLOW was a phase 2b, randomized, double-blind, placebo-controlled trial of brensocatib (10mg and 25mg). SLPI was measured by ELISA in sputum supernatant at baseline and day 169 (end of treatment). This analysis includes brensocatib 25mg vs placebo in subjects with paired samples at both timepoints. 

Results: The WILLOW trial enrolled 256 subjects. 53 and 54 subjects in 25mg brensocatib and placebo group, respectively, are included in this analysis. Median sputum SLPI levels were similar at baseline in brensocatib and placebo (50ng/ml, interquartile range 16 to 265 vs 59ng/ml IQR 22 to 237, p=0.8). After 24 weeks of treatment, the placebo group showed no statistically significant change (median 123ng/ml, p=0.3). However, median SLPI levels increased to 335ng/ml with brensocatib (p<0.001). The linear mixed effects model showed that brensocatib significantly increased SLPI levels (p=0.02). 

Conclusions: Brensocatib 25mg significantly increased sputum SLPI levels indicating downstream effects of protease inhibition on host defence.

Funded by Insmed Inc.