title: 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.
authors.affiliation: Kadmon Corporation, LLC, New York, NY 10016; alexandra.zanin-zhorov@kadmon.com.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zanin-Zhorov
authors.affiliation: Kadmon Corporation, LLC, New York, NY 10016.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Weiss
authors.affiliation: Kadmon Corporation, LLC, New York, NY 10016.
authors.forename: Alissa
authors.identifier: 0000-0002-4518-0098
authors.initials: A
authors.lastname: Trzeciak
authors.affiliation: Kadmon Corporation, LLC, New York, NY 10016.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Kadmon Corporation, LLC, New York, NY 10016.
authors.forename: Jingya
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Kadmon Corporation, LLC, New York, NY 10016.
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Nyuydzefe
authors.affiliation: Kadmon Corporation, LLC, New York, NY 10016.
authors.forename: Carmen
authors.initials: C
authors.lastname: Arencibia
authors.affiliation: Kadmon Corporation, LLC, New York, NY 10016.
authors.forename: Seetharam
authors.initials: S
authors.lastname: Polimera
authors.affiliation: Kadmon Corporation, LLC, New York, NY 10016.
authors.forename: Olivier
authors.initials: O
authors.lastname: Schueller
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY 10065.
authors.forename: Judilyn
authors.identifier: 0000-0001-8022-1302
authors.initials: J
authors.lastname: Fuentes-Duculan
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY 10065.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Bonifacio
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY 10065.
authors.forename: Norma
authors.initials: N
authors.lastname: Kunjravia
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY 10065.
authors.forename: Inna
authors.initials: I
authors.lastname: Cueto
authors.affiliation: Southern California Dermatology, Inc., Santa Ana, CA 92701.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Soung
authors.affiliation: Metroplex Clinical Research Center, Dallas, TX 75231.
authors.forename: Roy M
authors.initials: RM
authors.lastname: Fleischmann
authors.affiliation: Altoona Center for Clinical Research, Duncanville, PA 16635.
authors.forename: Alan
authors.initials: A
authors.lastname: Kivitz
authors.affiliation: Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Mark
authors.initials: M
authors.lastname: Lebwohl
authors.affiliation: High Point Clinical Trials Center, High Point, NC 27265.
authors.forename: Margarita
authors.identifier: 0000-0001-8295-3398
authors.initials: M
authors.lastname: Nunez
authors.affiliation: Clinical Studies Group, LLC, Henderson, NV 89074.
authors.forename: Johnnie
authors.initials: J
authors.lastname: Woodson
authors.affiliation: Dermatology & Advanced Aesthetics, Lake Charles, LA 70605; and.
authors.forename: Shondra L
authors.initials: SL
authors.lastname: Smith
authors.affiliation: Arrowhead Health Centers, Glendale, AZ 85306.
authors.forename: Robert F
authors.initials: RF
authors.lastname: West
authors.affiliation: Kadmon Corporation, LLC, New York, NY 10016.
authors.forename: Mark
authors.initials: M
authors.lastname: Berger
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY 10065.
authors.forename: James G
authors.initials: JG
authors.lastname: Krueger
authors.affiliation: Kadmon Corporation, LLC, New York, NY 10016.
authors.forename: John L
authors.initials: JL
authors.lastname: Ryan
authors.affiliation: Kadmon Corporation, LLC, New York, NY 10016.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Waksal
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D015551:Autoimmunity / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D016753:Interleukin-10 / Q000097:blood* / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000097:blood* / Q000235:genetics / Q000276:immunology; D015603:Keratinocytes / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011565:Psoriasis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D012720:Severity of Illness Index; D012867:Skin / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology; D055815:Young Adult; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D016207:Cytokines; D006576:Heterocyclic Compounds, 4 or More Rings; C508609:IL10 protein, human; C508717:IL17A protein, human; D020381:Interleukin-17; C000619755:KD025; D016753:Interleukin-10; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases