Dipeptidyl peptidase-1 inhibition with brensocatib reduces the activity of all major neutrophil serine proteases in patients with bronchiectasis: results from the WILLOW trial

Abstract

Background: Brensocatib is an oral, selective, reversible inhibitor of dipeptidyl peptidase-1 (DPP-1), responsible for activating neutrophil serine proteases (NSPs) including neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (CatG). In chronic inflammatory lung diseases such as non-cystic fibrosis bronchiectasis (NCFBE), neutrophils accumulate in the airways resulting in excess active NSPs that cause damaging inflammation and lung destruction.

Methods: The 24-week WILLOW trial (NCT03218917) was a randomized, double-blind, placebo-controlled, parallel-group trial in patients with NCFBE conducted at 116 sites across 14 countries. In this trial, treatment with brensocatib was associated with improvements in clinical outcomes including time to first exacerbation, reduction in exacerbation frequency and a reduction in NE activity in sputum. An exploratory analysis of NE activity in white blood cell (WBC) extracts and NE, PR3 and CatG activity in sputum was conducted to further characterize brensocatib's effect and identify potential correlated effects.

Results: NE, PR3 and CatG activities were reduced in sputum and NE activity was reduced in WBC extracts in a dose-dependent manner after four weeks of brensocatib treatment, with a return to baseline four weeks after the end of treatment. Brensocatib produced the greatest reduction in the sputum activity of CatG, followed by NE and then PR3. Positive correlations among the sputum NSPs were observed both at baseline and in response to treatment, with the strongest correlation among the sputum NSPs for NE and CatG.

Conclusions: These results suggest a broad anti-inflammatory effect of brensocatib underlying its clinical efficacy observed in NCFBE patients.

Trial registration: The study was approved by the corresponding ethical review boards of all participating centers. The trial was approved by the Food and Drug Administration and registered at clinicaltrials.gov (NCT03218917) on July 17, 2017 and approved by the European Medicines Agency and registered at the European Union Clinical trials Register (EudraCT No. 2017-002533-32). An independent, external data and safety monitoring committee (comprising physicians with pulmonary expertise, a statistician experienced in the evaluation of clinical safety, and experts in periodontal disease and dermatology) reviewed all adverse events.

Keywords: Brensocatib; Cathepsin G; Dipeptidyl peptidase-1 inhibitor; Neutrophil elastase; Neutrophil serine protease; Non-cystic fibrosis bronchiectasis; Proteinase 3; Sputum biomarkers.

Fig. 1

NSP activity in sputum on study. Change from baseline is presented as mean (± SEM) for (a) NE, (b) PR3 and (c) Cat G. *, P < 0.05 vs placebo at the same timepoint. Figure a is from [New England Journal of Medicine, Chalmers, J.D. Haworth, C.S.; Metersky, M.L. et al. Phase 2 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis, 383, 2135. Copyright © (2020) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society]

Fig. 2

NE activity in WBCs on study. Change from baseline is presented as mean (± SEM) for NE. * P < 0.05 vs placebo at the same timepoint

Fig. 3

Correlation of sputum NSP activities from all treatment arms. Pearson correlation analysis within sputum NSPs at (a) all timepoints, (b) at baseline and (c) at only post-baseline time points. (d) Summaries of the Pearson correlation coefficients (r) between each sputum NSP activity from baseline values and from values at all timepoints. Simple linear regression was plotted with the best-fit line plus 95% confidence intervals. The total number of paired data points from baseline through week 28 are: NE and PR3 (n = 1073), NE and CatG (n = 1085) and PR3 and CatG (n = 1070)

Fig. 4

Correlation of sputum NSPs in separate dosing arms at baseline only. NSP sputum correlation analysis was performed for placebo, 10 mg brensocatib and 25 mg brensocatib. Simple linear regression was plotted with the best-fit line plus 95% confidence intervals

Fig. 5

Correlation of sputum NSPs in separate dosing arms at Week 2. NSP sputum correlation analysis was performed for placebo, 10 mg brensocatib and 25 mg brensocatib. Simple linear regression was plotted with the best-fit line plus 95% confidence intervals

Fig. 6

Correlation of sputum NSPs in separate dosing arms at Week 4. NSP sputum correlation analysis was performed for placebo, 10 mg brensocatib and 25 mg brensocatib. Simple linear regression was plotted with the best-fit line plus 95% confidence intervals

Fig. 7

Correlation of sputum NSPs in separate dosing arms at Week 12. NSP sputum correlation analysis was performed for placebo, 10 mg brensocatib and 25 mg brensocatib. Simple linear regression was plotted with the best-fit line plus 95% confidence intervals

Fig. 8

Correlation of sputum NSPs in separate dosing arms at Week 24. NSP sputum correlation analysis was performed for placebo, 10 mg brensocatib and 25 mg brensocatib. Simple linear regression was plotted with the best-fit line plus 95% confidence intervals

Fig. 9

Correlation of sputum NSPs in separate dosing arms at Week 28. NSP sputum correlation analysis was performed for placebo, 10 mg brensocatib and 25 mg brensocatib. Simple linear regression was plotted with the best-fit line plus 95% confidence intervals

Fig. 10

Pearson correlation coefficients (r) for each pair of sputum NSP activities over the trial duration. Pearson correlation coefficients (r) are presented as mean for (a) PR3 vs NE, (b) CatG vs NE and (c) Cat G vs PR3