Pharmacokinetic/Pharmacodynamic Evaluation of the Dipeptidyl Peptidase 1 Inhibitor Brensocatib for Non-cystic Fibrosis Bronchiectasis

Abstract

Background and objective: Brensocatib is an investigational, first-in-class, selective, and reversible dipeptidyl peptidase 1 inhibitor that blocks activation of neutrophil serine proteases (NSPs). The NSPs neutrophil elastase, cathepsin G, and proteinase 3 are believed to be central to the pathogenesis of several chronic inflammatory diseases, including bronchiectasis. In a phase II study, oral brensocatib 10 mg and 25 mg reduced sputum neutrophil elastase activity and prolonged the time to pulmonary exacerbation in patients with non-cystic fibrosis bronchiectasis (NCFBE). A population pharmacokinetic (PPK) model was developed to characterize brensocatib exposure, determine potential relationships between brensocatib exposure and efficacy and safety measures, and inform dose selection in clinical studies.

Methods: Pharmacokinetic (PK) data pooled from a phase I study of once-daily brensocatib (10, 25, and 40 mg) in healthy adults and a phase II study of once-daily brensocatib (10 mg and 25 mg) in adults with NCFBE were used to develop a PPK model and to evaluate potential covariate effects on brensocatib pharmacokinetics. PK-efficacy relationships for sputum neutrophil elastase below the level of quantification (BLQ) and reduction in pulmonary exacerbation and PK-safety relationships for adverse events of special interest (AESIs; periodontal disease, hyperkeratosis, and infections other than pulmonary infections) were evaluated based on model-predicted brensocatib exposure. A total of 1284 steady-state brensocatib concentrations from 225 individuals were included in the PPK data set; 241 patients with NCFBE from the phase II study were included in the pharmacodynamic (PD) population for the PK/PD analyses.

Results: The PPK model that best described the observed data consisted of two distributional compartments and linear clearance. Two significant covariates were found: age on volume of distribution and renal function on apparent oral clearance. PK-efficacy analysis revealed a threshold brensocatib exposure (area under the concentration-time curve) effect for attaining sputum neutrophil elastase BLQ and a strong relationship between sputum neutrophil elastase BLQ and reduction in pulmonary exacerbations. A PK-safety evaluation showed no noticeable trends between brensocatib exposure and the incidence of AESIs. Based on the predicted likelihood of clinical outcomes for sputum neutrophil elastase BLQ and pulmonary exacerbations, brensocatib doses of 10 mg and 25 mg once daily were selected for a phase III clinical trial in patients with NCFBE (ClinicalTrials.gov identifier: NCT04594369).

Conclusions: PPK results revealed that age and renal function have a moderate effect on brensocatib exposure. However, this finding does not warrant dose adjustments based on age or in those with mild or moderate renal impairment. The PK/PD evaluation demonstrated the clinically meaningful relationship between suppression of neutrophil elastase activity and reduction in exacerbations in brensocatib-treated patients with NCFBE, supporting further development of brensocatib for bronchiectasis.

Fig. 1

Steady-state brensocatib plasma concentrations. Open circles are observed concentrations, normalized based on dose administered. Solid lines are LOESS smoothers through the data. When normalized by dose, brensocatib plasma concentrations were consistent across doses and between the two studies, except for slightly lower concentrations observed in the 10-mg group in the phase 1 study. LOESS locally weighted scatterplot smoothing

Fig. 2

Final pooled pharmacokinetic model compared with observed data. The simulation-based diagnostics (pc-VPC plots) indicate that the final model adequately described both the central tendency and the variability in observed brensocatib concentrations over time in healthy participants (top) and in patients with NCFBE (bottom). Dots indicate observed concentrations; solid black lines indicate median observed concentrations; dashed black lines indicate 5th and 95th percentiles of the observed concentrations; blue-shaded regions indicate 90% CIs for the median and 5th and 95th percentiles from the simulations. NCFBE non-cystic fibrosis bronchiectasis, pc-VPC prediction-corrected visual predictive check

Fig. 3

Time to pulmonary exacerbation by post-baseline sputum neutrophil elastase concentration. All patients (a) and brensocatib-treated patients (b) with neutrophil elastase BLQ post-baseline experienced significantly fewer exacerbations than those with detectable neutrophil elastase. BLQ below the level of quantification

Fig. 4

Distribution of steady-state AUC by incidence of AESIs. No significant relationships between brensocatib exposure and the incidence of AESIs were evident. AESI adverse event of special interest, AUC area under the concentration-time curve