DPP-1 inhibitors / Cathepsin C inhibitors

Introduction

dipeptidyl peptidase-1 (DPP-1) inhibitors (aka Cathepsin C inhibitors) are the first disease-specific therapy shown to be effective in non-cystic fibrosis bronchiectasis
DPP-1 plays a crucial role in activating various granular serine proteases including cathepsin G (CatG), neutrophil elastase (NE) and proteinase 3 (PR3)

suppression of activity of neutrophil serine proteases (NSPs) by preventing them from being activated during neutrophil maturation in the bone marrow.
NSPs exert multiple directly damaging effects and contribute to ongoing dysregulated airway inflammation
high airway levels of NSPs are linked to bronchiectasis disease severity
brensocatib treatment in COVID-19 altered multiple neutrophil proteins including profound effects on Azu-1, identifying this as a key DPP-1 target and potentially highly sensitive biomarker of treatment efficacy¹⁾

brensocatib (Brinsupri)
- an oral small-molecule inhibitor of dipeptidyl peptidase 1 (DPP1) — approved for Rx of non-cystic fibrosis bronchiectasis by FDA in 2025 but not yet approved in Australia as of Jan 2026
- did not improve clinical status at day 29 in patients hospitalised with COVID-19, in fact, these patients were clinically worse²⁾

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