title: Preliminary clinical activity of a topical JAK1/2 inhibitor in the treatment of psoriasis.
abstract: BACKGROUND
  Janus-associated kinases (JAKs) are involved in signal transduction from a variety of cytokines implicated in the pathogenesis of psoriasis, including interleukin (IL)-12, IL-23, and interferon-γ. INCB018424, a small molecule inhibitor of JAK1 and JAK2, inhibits cytokine-induced JAK/signal transducers and activators of transcription signaling and the resultant production of inflammatory proteins (eg, IL-17).
  
  
  OBJECTIVE
  We sought to demonstrate proof of concept in patients with stable plaque psoriasis.
  
  
  METHODS
  Patients were dosed with vehicle, 0.5% or 1.0% INCB018424 phosphate cream once a day or 1.5% twice a day for 28 days. Additional groups included two active comparators (calcipotriene 0.005% cream or betamethasone dipropionate 0.05% cream).
  
  
  RESULTS
  Both the 1% and the 1.5% cream improved lesion thickness, erythema, and scaling and reduced lesion area compared with placebo. A composite lesion score decreased by greater than 50% with the efficacious doses of INCB018424 compared with 32% for vehicle controls. Topical application of INCB018424 was well tolerated with few mild adverse events noted. Mean plasma concentrations of INCB018424 after topical application of 0.5% to 1.5% cream were in the low nanomolar range, representing a fraction (<1%) of the half maximal inhibitory concentration (IC(50)) in whole blood for inhibition of cytokine-stimulated signal transducers and activators of transcription-3 phosphorylation.
  
  
  CONCLUSIONS
  This study was limited by the relatively short study duration and small sample size.
  
  
  CONCLUSIONS
  Topical INCB018424 is safe, is well tolerated, and exhibits clinical activity in the topical treatment of psoriasis.
authors.affiliation: Incyte Corp, Wilmington, Delaware 19880, USA. npunwani@incyte.com
authors.forename: Naresh
authors.initials: N
authors.lastname: Punwani
authors.forename: Peggy
authors.initials: P
authors.lastname: Scherle
authors.forename: Robert
authors.initials: R
authors.lastname: Flores
authors.forename: Jack
authors.initials: J
authors.lastname: Shi
authors.forename: Jinjin
authors.initials: J
authors.lastname: Liang
authors.forename: Swamy
authors.initials: S
authors.lastname: Yeleswaram
authors.forename: Richard
authors.initials: R
authors.lastname: Levy
authors.forename: William
authors.initials: W
authors.lastname: Williams
authors.forename: Alice
authors.initials: A
authors.lastname: Gottlieb
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D001623:Betamethasone / Q000008:administration & dosage / Q000031:analogs & derivatives; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives; D003879:Dermatologic Agents / Q000008:administration & dosage; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D010865:Pilot Projects; D011565:Psoriasis / Q000188:drug therapy* / Q000378:metabolism*; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D003879:Dermatologic Agents; D004791:Enzyme Inhibitors; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C055085:calcipotriene; C011175:betamethasone-17,21-dipropionate; C540383:ruxolitinib; D001623:Betamethasone; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D002117:Calcitriol