Selective oral ROCK2 inhibitor reduces clinical scores in patients with Psoriasis Vulgaris and normalizes skin pathology via concurrent regulation of IL-17 and IL-10 levels

Abstract

Abstract Targeted inhibition of Rho-associated kinase 2 (ROCK2) down-regulates pro-inflammatory T-cell response, while increasing the regulatory arm of immune response in animals models of autoimmunity and T helper 17 (Th17)-skewing human cell culture in vitro. We conducted a Phase 2, open-label, dose-finding study to evaluate the safety, tolerability, and activity of selective ROCK2 inhibitor, KD025, in subjects with Psoriasis Vulgaris who failed first-line therapy (NCT02317627 at ClinicalTrials.gov). Here, we report that oral administration of KD025 reduces Psoriasis Area and Severity Index (PASI) scores in 85% of patients completing the study, with minimal side effects. In the 400 mg QD and 200 mg BID cohorts 42% and 71% of patients respectively achieved at least a 50% decrease in PASI score (PASI 50) after three month of treatment. KD025 treatment reduced levels of both IL-17 and IL-23, but no IL-6 and TNF-a in the peripheral blood of clinical responders, whereas IL-10 levels were increased at the end of the study. The clinical improvement and changes in cytokine levels were associated with decreased epidermal thickness, T-cell infiltration and down-regulation of key molecules implicated in the regulation of the Th17 pathway, such as ROCK2, pSTAT3, RORgt and IRF4 in the skin. Collectively, these data demonstrate that orally available selective ROCK2 inhibitor down-regulates Th17-driven autoimmune response and improved clinical symptoms in psoriatic patients via defined molecular mechanism that involves concurrent modulation of cytokines without deleterious impact on the rest of the immune system.