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.

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.