Target engagement confirmed in man with a dipeptidyl peptidase 1 inhibitor

Introduction: AZD7986 is an oral dipeptidyl peptidase 1 (DPP1) inhibitor originally developed for the treatment of COPD. Neutrophil serine proteases (NSPs), such as neutrophil elastase (NE), are increased in sputum from COPD patients and further increased during disease exacerbations. A similar increase in NE has been reported in bronchiectasis patients. DPP1 inhibition blocks NSP activation during neutrophil maturation in bone marrow, preventing high local concentrations of NSPs in the lung and thus reducing their proteolytic effects on extracellular matrix and the induction of excessive mucus release and pro-inflammatory events (Korkmaz, B. et al. Pharmacol. Rev. 2010; 62:726-759). Objective: To confirm target engagement via effects on downstream protease activity with a DPP1 inhibitor in man. Methods: NE activity in blood was monitored in a multiple dose AZD7986 Ph1 trial for up to 58 days (28 days dosing in healthy individuals), using a semi-quantitative, endpoint read NE activity assay employing a fluorogenic substrate added to plasma from zymosan stimulated whole blood. Results: Following drug administration a dose and exposure related reduction in blood NE activity was observed. The rate of change in NE activity was consistent with the expected mechanism of action and with literature data on neutrophil maturation and lifespan (Bekkering S. and Torensma R. World J Hematol. 2013; 2(2):44-58). AZD7986 was well tolerated in healthy volunteers and the only notable findings were mild reversible skin effects in some subjects. Conclusion: Target engagement with the DPP1 inhibitor AZD7986 was demonstrated by a dose-, exposure- and time-dependent reduction in neutrophil elastase activity.