title: Investigation of selective JAK1 inhibitor GSK2586184 for the treatment of psoriasis in a randomized placebo-controlled phase IIa study.
abstract: BACKGROUND
  GSK2586184 is a selective oral Janus kinase (JAK)1 inhibitor being evaluated as a treatment for moderate-to-severe plaque-type psoriasis.
  
  
  OBJECTIVE
  To assess the relationship between dose of GSK2586184 and clinical response, primarily by the Psoriasis Area Severity Index (PASI).
  
  
  METHODS
  Sixty patients with moderate-to-severe plaque psoriasis were randomized to cohort A: 100 mg, 200 mg or 400 mg GSK2586184 twice daily or placebo; and eight were randomized to open-label cohort B, a small exploratory cohort treated with 400 mg GSK2586184 twice daily, to explore differential gene expression.
  
  
  RESULTS
  At week 12, a 75% reduction in PASI (PASI 75) response rates in the intent-to-treat population were 0% in the placebo group compared with 13%, 25% and 57% in the 100 mg, 200 mg and 400 mg GSK2586184 twice-daily groups, respectively. Increases in the proportion of PASI 75 responses were seen across all dose levels by week 4. Improvement in itch and quality of life were observed at all doses relative to placebo with the greatest improvement seen in the 400-mg dose group. Overall, the incidence of adverse events (AEs) was similar across treatment groups, and no relationship between frequency of AE and GSK2586184 dose was identified. Differential gene expression was observed in involved and uninvolved skin at baseline and in involved skin after 2 weeks of treatment with GSK2586184.
  
  
  CONCLUSIONS
  Our study demonstrates that 12 weeks of treatment with GSK2586184 resulted in clinical improvement and was generally well tolerated in patients with moderate-to-severe plaque-type psoriasis.
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG4 7AE, U.K.
authors.forename: V J
authors.initials: VJ
authors.lastname: Ludbrook
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG4 7AE, U.K.
authors.forename: K J
authors.initials: KJ
authors.lastname: Hicks
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG4 7AE, U.K.
authors.forename: K E
authors.initials: KE
authors.lastname: Hanrott
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG4 7AE, U.K.
authors.forename: J S
authors.initials: JS
authors.lastname: Patel
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG4 7AE, U.K.
authors.forename: M H
authors.initials: MH
authors.lastname: Binks
authors.affiliation: Stiefel, Research Triangle Park, NC, U.S.A.
authors.forename: M R
authors.initials: MR
authors.lastname: Wyres
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG4 7AE, U.K.
authors.forename: J
authors.initials: J
authors.lastname: Watson
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG4 7AE, U.K.
authors.forename: P
authors.initials: P
authors.lastname: Wilson
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG4 7AE, U.K.
authors.forename: M
authors.initials: M
authors.lastname: Simeoni
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, U.S.A.
authors.forename: L A
authors.initials: LA
authors.lastname: Schifano
authors.affiliation: Dermatologikum Hamburg and SCIderm Research Center, Hamburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Reich
authors.affiliation: Dermatology Centre, Salford Royal Hospital, The University of Manchester, Manchester Academic Health Science Centre, Manchester, M6 8HD, U.K.
authors.forename: C E M
authors.initials: CE
authors.lastname: Griffiths
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001384:Azetidines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003879:Dermatologic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D015870:Gene Expression; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D011565:Psoriasis / Q000188:drug therapy* / Q000235:genetics; D011788:Quality of Life; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D001384:Azetidines; D003879:Dermatologic Agents; C000604226:GSK2586184; D014230:Triazoles; C507904:JAK1 protein, human; D053613:Janus Kinase 1