Cutting Edge: 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

Abstract

Targeted inhibition of Rho-associated kinase (ROCK)2 downregulates the proinflammatory T cell response while increasing the regulatory arm of the immune response in animals models of autoimmunity and Th17-skewing human cell culture in vitro. In this study, we report that oral administration of a selective ROCK2 inhibitor, KD025, reduces psoriasis area and severity index scores by 50% from baseline in 46% of patients with psoriasis vulgaris, and it decreases epidermal thickness as well as T cell infiltration in the skin. We observed significant reductions of IL-17 and IL-23, but not IL-6 and TNF-α, whereas IL-10 levels were increased in peripheral blood of clinical responders after 12 wk of treatment with KD025. Collectively, these data demonstrate that an orally available selective ROCK2 inhibitor downregulates the Th17-driven autoimmune response and improved clinical symptoms in psoriatic patients via a defined molecular mechanism that involves concurrent modulation of cytokines without deleterious impact on the rest of the immune system.

Copyright © 2017 by The American Association of Immunologists, Inc.

Figures

FIGURE 1.

Clinical response rate (A and B) and improvement of skin pathology (C) in patients with moderate-to-severe psoriasis vulgaris treated with selective ROCK2 inhibitor. KD025 was orally administrated at three daily dosage regimens, that is, 200 mg twice a day, 400 mg once a day, and 400 mg twice a day for 12 wk, and clinical response was defined by changes in PASI scores. Percentages of patients achieving a PASI 50 response in each cohort and representative images are shown (B). Histologic evaluation of skin thickness (H&E), keratinocyte proliferation (K16), and T cell infiltrate (CD3) of nonlesional skin (NS) and lesional (LS) skin in 13 patients before (month 1 day 1 [M1D1]) and after (month 3 day 29 [M3D29]) the treatment with KD025 (C). Representative images (original magnification ×10) as well as average data ± SEM are shown. The p values were calculated by a paired t test.

FIGURE 2.

Treatment with KD025 downregulates IL-17/IL-23 while increasing IL-10 levels in psoriatic patients. Peripheral blood samples were collected from all patients on a monthly basis. IL-17, IL-23, and IL-10 levels were determined by using the Simoa immunoassay. (A and B) Average data ± SEM from 22 patients who completed the treatment and responded clinically are shown. (C and D) Percentage change was calculated as (value during treatment/predose value) × 100%. (E) Intracellular staining for FOXP3 was performed in PBMCs from 12 patients who completed the study and achieved a PASI 50 clinical response. The p values were calculated by a paired t test.

FIGURE 3.

Targeted ROCK2 inhibition downregulates the expression of Th17-associated molecules, such as ROCK2, pSTAT3, and RORγt, in lesional skin of psoriasis patients. Representative images (original magnification ×10) (A) and average data ± SEM (B) of pSTAT3, RORγt, ROCK1, and ROCK2 staining from nonlesional and lesional skin in 13 patients before and after the 12 wk treatment with KD025 are shown. The p values were calculated by a paired t test.