Verducatib (BI 1291583) is an orally active inhibitor of cathepsin C (also known as DPP1 ). Verducatib restores the protease-inhibitor balance by inhibiting the activation of neutrophil serine proteases, thereby alleviating pulmonary inflammation and regulating infection responses. Verducatib significantly reduces the risk (including severe exacerbations) and frequency of acute exacerbations in bronchiectasis ( BE ). Verducatib also improves lung function and quality of life, and shortens the duration of antibiotic use. The overall incidence of adverse events of Verducatib is comparable to that of placebo, with only slightly more mild-to-moderate cutaneous adverse events observed in the high-dose group, demonstrating promising clinical application potential [1] [2].
In Vivo, Verducatib (BI 1291583) (0.005-5 mg/kg; p.o.; twice daily) dose-dependently inhibits the production of active neutrophil elastase (NE) and cathepsin G (CatG) in neutrophils within bronchoalveolar lavage fluid (BALF) in a lipopolysaccharide (LPS)-induced pulmonary neutrophil infiltration model of female Crl:NMRI mice, with maximum inhibition rates reaching 97% and 99%, respectively. The ED99 for NE inhibition is 1.5 mg/kg[3]. Verducatib (single dose; p.o.) exhibits rapid distribution to the target tissue bone marrow and slow clearance in the pharmacokinetic models of healthy mice and rats. Even at low doses, it achieves a distribution profile where bone marrow exposure is significantly higher than plasma exposure, and this property shows no obvious interspecies difference between the two species[3].
In Vitro, Verducatib (BI 1291583) (0.08, 0.4, 2, 10, 50 nM, pH 4.5) binds to recombinant human cathepsin C (CatC) in a reversible covalent manner, with binding kinetic parameters of kon 6.36×106 M-1s-1, koff 2.29×10-3 s-1, an equilibrium dissociation constant KD of 0.43 nM, and a binding half-life t1/2 of 5.19 min[3]. Verducatib (0.064-1000 nM; 48 h) concentration-dependently inhibits the production of active neutrophil elastase (NE) in human neutrophil progenitor U937 cells, with an IC50 of 0.7 nM. It shows no obvious cytotoxicity against U937 cells, with cell viability higher than 93% at all tested concentrations and an average cell viability of 98% at the highest concentration of 1000 nM[3].
References:
[1]. Chalmers J D, et al. Study design of a Phase III study (AIRTIVITY) of the novel dipeptidyl peptidase 1 (cathepsin C) inhibitor verducatib in people with bronchiectasis[J]. Pneumologie, 2026, 80(S 01): P 2026-464.
[2]. Kreideweiss S, et al. BI 1291583: a novel selective inhibitor of cathepsin C with superior in vivo profile for the treatment of bronchiectasis[J]. Inflammation Research, 2023, 72(8): 1709-1717.
[3]. Chalmers J D, et al. AIRLEAF®–a study of verducatib as a new kind of treatment for bronchiectasis: a plain language summary[J]. Future Rare Diseases, 2025, 5(1): 2580913.
In Vivo, Verducatib (BI 1291583) (0.005-5 mg/kg; p.o.; twice daily) dose-dependently inhibits the production of active neutrophil elastase (NE) and cathepsin G (CatG) in neutrophils within bronchoalveolar lavage fluid (BALF) in a lipopolysaccharide (LPS)-induced pulmonary neutrophil infiltration model of female Crl:NMRI mice, with maximum inhibition rates reaching 97% and 99%, respectively. The ED99 for NE inhibition is 1.5 mg/kg[3]. Verducatib (single dose; p.o.) exhibits rapid distribution to the target tissue bone marrow and slow clearance in the pharmacokinetic models of healthy mice and rats. Even at low doses, it achieves a distribution profile where bone marrow exposure is significantly higher than plasma exposure, and this property shows no obvious interspecies difference between the two species[3].
In Vitro, Verducatib (BI 1291583) (0.08, 0.4, 2, 10, 50 nM, pH 4.5) binds to recombinant human cathepsin C (CatC) in a reversible covalent manner, with binding kinetic parameters of kon 6.36×106 M-1s-1, koff 2.29×10-3 s-1, an equilibrium dissociation constant KD of 0.43 nM, and a binding half-life t1/2 of 5.19 min[3]. Verducatib (0.064-1000 nM; 48 h) concentration-dependently inhibits the production of active neutrophil elastase (NE) in human neutrophil progenitor U937 cells, with an IC50 of 0.7 nM. It shows no obvious cytotoxicity against U937 cells, with cell viability higher than 93% at all tested concentrations and an average cell viability of 98% at the highest concentration of 1000 nM[3].
References:
[1]. Chalmers J D, et al. Study design of a Phase III study (AIRTIVITY) of the novel dipeptidyl peptidase 1 (cathepsin C) inhibitor verducatib in people with bronchiectasis[J]. Pneumologie, 2026, 80(S 01): P 2026-464.
[2]. Kreideweiss S, et al. BI 1291583: a novel selective inhibitor of cathepsin C with superior in vivo profile for the treatment of bronchiectasis[J]. Inflammation Research, 2023, 72(8): 1709-1717.
[3]. Chalmers J D, et al. AIRLEAF®–a study of verducatib as a new kind of treatment for bronchiectasis: a plain language summary[J]. Future Rare Diseases, 2025, 5(1): 2580913.