Investigating the impact of dipeptidyl peptidase-1 inhibition in humans using multi-omics

Background

Dipeptidyl peptidase-1 (DPP-1/Cathepsin C) processes and activates neutrophil serine proteases. Brensocatib (an oral, reversible, competitive DPP-1 inhibitor) is a novel therapy for bronchiectasis previously shown to reduce sputum protease activity and prevent exacerbations. Broader effects of DPP-1 inhibition on the immune response have not been investigated. Objective This study aimed to profile the effects of DPP-1 inhibition using a secondary analysis of the STOP-COVID19 trial.

Methods

The STOP-COVID19 trial was a randomized placebo-controlled trial of brensocatib 25mg in patients hospitalised for severe COVID-19 in the UK. In the primary analysis Brensocatib did not improve clinical outcomes at day 29. In a pre-specified sub-study at two UK hospitals was performed to explore the effects of DPP1 inhibition in the immune response.. blood samples were obtained at baseline and days 8, 15 and 29. Analyses included peripheral blood neutrophil mass spectrometry, neutrophil functional testing, serum cytokine analysis, whole blood mRNAseq and measurement of circulating neutrophil-associated markers.

Results

161 patients were enrolled June 2020‒January 2021 (brensocatib, n=80; placebo, n=81). Neutrophil proteomics showed significant alterations in 15 proteins (FDR p<0.01) including reductions in cathepsin G and the pseudoenzyme azurocidin-1 (FDR p<0.0001) by day 29. In serum, azurocidin-1 levels, but not total elastase or proteinase 3, were significantly reduced (p<0.0001). Neutrophil surface expression of protease-cleavable C5aR1/CD88 was significantly increased by day 29 (p<0.05). There were no differences in neutrophil extracellular traps, phagocytosis, circulating immune cell proportions or gene expression between treatment groups.

Conclusions

Brensocatib treatment in COVID-19 altered multiple neutrophil proteins including profound effects on azurocidin-1, identifying this as a key DPP-1 target and potentially highly sensitive biomarker of treatment efficacy.