Exposure-response relationships of brensocatib in patients with non-cystic fibrosis bronchiectasis (NCFBE)

Abstract

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 (AUC_0-24) 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 AUC_0-24 quartile (4845–9466 ng·h/mL) compared with 77.5% in the lowest AUC_0-24 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 AUC_0-24 increased the probability of achieving NE LLOQ.