Epithelial desquamation observed in a phase I study of an oral cathepsin C inhibitor (GSK2793660)

Aims: Cathepsin C (CTSC) is necessary for the activation of several serine proteases including neutrophil Elastase (NE), Cathepsin G and proteinase 3. GSK2793660 is an oral, irreversible inhibitor of CTSC that is hypothesized to provide an alternative route to achieve NE inhibition and was tested in a Phase I study.

Methods: Single escalating oral doses of GSK2793660 from 0.5 to 20 mg or placebo were administered in a randomized crossover design to healthy male subjects; a separate cohort received once daily doses of 12 mg or placebo for 21 days. Data were collected on safety, pharmacokinetics, CTSC enzyme inhibition and blood biomarkers.

Results: Single, oral doses of GSK2793660 were able to dose-dependently inhibit whole blood CTSC activity. Once daily dosing of 12 mg GSK2793660 for 21 days achieved ≥90% inhibition (95% CI: 56, 130) of CTSC within 3 h on day 1. Only modest reductions of whole blood enzyme activity of approximately 20% were observed for NE, Cathepsin G and proteinase 3. Seven of 10 subjects receiving repeat doses of GSK2793660 manifested epidermal desquamation on palmar and plantar surfaces beginning 7-10 days after dosing commencement. There were no Other clinically important safety findings.

Conclusions: GSK2793660 inhibited CTSC activity but not the activity of downstream neutrophil serine proteases. The palmar-plantar epidermal desquamation suggests a previously unidentified role for CTSC or one of its target proteins in the maintenance and integrity of the epidermis at these sites, with some similarities to the phenotype of CTSC-deficient humans.