Background/Purpose:

Rho-associated kinase 2 (ROCK2) was shown to be implicated in regulation of autoimmunity in mice and humans¹. Previous findings demonstrated that oral administration of a selective ROCK2 inhibitor (KD025) in healthy subjects decreases IL-17 and IL-21 secretion induced by ex vivo stimulation². Moreover, targeted ROCK2 inhibition shifted the balance between Th17/Tfh and Treg subsets via concurrent regulation of STAT3/STAT5 phosphorylation^2-4. We have hypothesized that targeting of ROCK2 may therefore restore disrupted immune homeostasis and has a role in the treatment of Th17-driven inflammatory disorders.Methods:

We conducted a Phase 2, open-label, dose-finding study to evaluate the safety, tolerability, and activity of KD025 in subjects with psoriasis vulgaris who failed first-line therapy (NCT02317627 at ClinicalTrials.gov). KD025 was orally administrated at three daily dose regimens for 12 weeks. Decreases in Psoriasis Area and Severity Index (PASI) scores were measured and peripheral blood samples were collected on a monthly basis. The levels of cytokines in plasma samples were determined by using the Simoa® Immunoassay. Skin punch biopsies were obtained at baseline and at the end of treatment.Results:

KD025 treatment resulted in PASI score reductions 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 12 weeks of treatment. KD025 reduced levels of both IL-17 and IL-23, but not 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 and T-cell infiltration in the skin.Conclusion:

Collectively, our results demonstrate that selective ROCK2 inhibition with KD025 down-regulates Th17-driven autoimmune response and improved clinical symptoms in psoriatic patients via concurrent modulation of cytokines without deleterious impact on the rest of the immune system.    References: 1.            Biswas, P.S. et al. Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice. J Clin Invest 120, 3280-3295 (2010). 2.            Zanin-Zhorov, A. et al. Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proc Natl Acad Sci U S A 111, 16814-16819 (2014). 3.            Flynn, R. et al. Targeted Rho-associated kinase 2 (ROCK2) inhibition decreases clinical and immune pathology of murine and human chronic GVHD through Stat3-dependent mechanism. Blood (2016). 4.            Weiss, J.M. et al. ROCK2 signaling is required to induce a subset of T follicular helper cells through opposing effects on STATs in autoimmune settings. Science signaling 9, ra73 (2016).