Efficacy of a Novel Cathepsin C Inhibitor in MPO-ANCA Vasculitis: Preclinical Insights

MPO-ANCA-associated vasculitis (MPO-AAV) is a systemic disease characterized by the presence of MPO-ANCA in the serum, leading to kidney damage and lung hemorrhage. The pathogenesis of MPO-AAV is linked to neutrophil extracellular traps (NETs) and the role of neutrophil elastase (NE). Cathepsin C (CatC) is crucial for activating NE and other neutrophil serine proteases (NSPs) by converting their inactive forms to active ones.

The objective of this study was to evaluate the efficacy of MOD06051, a new CatC inhibitor, in treating MPO-AAV using a rat model. In vitro tests showed MOD06051's inhibitory effect on CatC and NE activity without affecting other cathepsins. In vivo studies involved immunizing rats with human MPO and administering MOD06051 orally for 42 days.

Results indicated that MOD06051 effectively reduced the percentage of affected glomeruli, NET-forming neutrophils, and glomerular neutrophil counts in a dose-dependent manner. Additionally, it decreased hematuria, urinary NGAL levels, tubular erythrocyte cast counts, and pulmonary hemorrhage foci, particularly in the group treated with the higher dose.

The study concludes that MOD06051, by inhibiting CatC activity, suppresses serine proteases activation in human neutrophils and NET formation in MPO-AAV rats. This compound has the potential to mitigate MPO-ANCA-induced tissue damage in the kidneys and lungs, making it a promising candidate for MPO-AAV treatment.

Disclosures include grant and research support from Modulus Discovery, Inc., for some authors, with others having no declared interests. Certain authors are also shareholders and employees of Modulus Discovery, Inc.