PT  - JOURNAL ARTICLE
AU  - Carlos Fernandez
AU  - Christopher M. Rubino
AU  - Ariel Teper
AU  - Helen Usansky
AU  - James D. Chalmers
AU  - Kevin C. Mange
TI  - Exposure-response relationships of brensocatib in patients with non-cystic fibrosis bronchiectasis (NCFBE)
AID  - 10.1183/13993003.congress-2021.RCT4268
DP  - 2021 Sep 05
TA  - European Respiratory Journal
PG  - RCT4268
VI  - 58
IP  - suppl 65
4099  - http://erj.ersjournals.com/content/58/suppl_65/RCT4268.short
4100  - http://erj.ersjournals.com/content/58/suppl_65/RCT4268.full
SO  - Eur Respir J2021 Sep 05; 58
AB  - Background: Neutrophil serine proteases (NSPs) including neutrophil elastase (NE) are associated with increased exacerbation risk in NCFBE. Brensocatib, a selective and reversible dipeptidyl peptidase 1 inhibitor, reduced NSP activity and prolonged time to exacerbation in patients with NCFBE in a phase 2 study (WILLOW; NCT03218917).Aims: Explore the pharmacokinetic/pharmacodynamic (PK/PD) relationships for efficacy and safety of brensocatib in patients with NCFBE in the WILLOW study.Methods: Adults with NCFBE were randomized 1:1:1 to brensocatib 10 mg (n=82) or 25 mg (n=87) or placebo (n=87) once daily for 24 weeks. Sputum NE activity was evaluated as a dichotomous variable for attaining ≥1 post-baseline level below the lower limit of quantitation [LLOQ] with brensocatib (pooled) or placebo. Exploratory analyses assessed PK/PD relationships between drug exposure (AUC0-24) and clinically dependent variables (exacerbations, NE, adverse events of special interest).Results: Brensocatib-treated patients with postbaseline sputum NELLOQ (hazard ratio [95% confidence interval]=0.32 [0.21–0.47]; P<0.0001). The greatest incidence of postbaseline NE<LLOQ in the pooled brensocatib group (86.8%) occurred among those in the highest AUC0-24 quartile (4845–9466 ng·h/mL) compared with 77.5% in the lowest AUC0-24 quartile (624-1758 ng·h/mL) and 50.0% in the placebo group. The PK/PD analyses for safety did not reveal any clinically relevant relationships.Conclusion: Achieving post-baseline sputum NE<LLOQ was a predictor for experiencing fewer exacerbations. Higher brensocatib AUC0-24 increased the probability of achieving NE LLOQ.FootnotesCite this article as: European Respiratory Journal 2021; 58: Suppl. 65, RCT4268.This abstract was presented at the 2021 ERS International Congress, in session “Prediction of exacerbations in patients with COPD”.This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).