title: Downmodulation of key inflammatory cell markers with a topical Janus kinase 1/2 inhibitor.
abstract: BACKGROUND
  INCB018424 is a novel, potent Janus kinase (JAK)1/JAK2 inhibitor that blocks signal transduction of multiple proinflammatory cytokines.
  
  
  OBJECTIVE
  To evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of topical INCB018424 phosphate cream in patients with plaque psoriasis.
  
  
  METHODS
  Topical INCB018424 phosphate 1·0% or 1·5% cream was applied once daily (QD) or twice daily (BID) for 4 weeks to 2-20% body surface area in five sequential cohorts of five patients aged 18-65 years. Target lesions were scored on a scale of 0-4 for erythema, scaling and thickness. Additionally, the overall disease activity in each patient was measured using Physician's Global Assessment. INCB018424 concentrations were measured in plasma, and cytokine stimulated phosphorylated signal transducer and activator of transcription 3 phosphorylation (pSTAT3) levels in peripheral blood cells were evaluated. Pretreatment and post-treatment skin biopsies were compared with healthy skin, including evaluation of histopathology, immunohistochemistry and mRNA expression.
  
  
  RESULTS
  Treatment with INCB018424 phosphate cream either 1·0% QD or 1·5% BID resulted in improvements in lesion scores. No significant inhibition of pSTAT3 in peripheral blood cells was observed following topical application, consistent with the generally low steady-state plasma concentrations of INCB018424 measured. Transcriptional markers of immune cell lineage/activation in lesional skin were reduced by topical INCB018424, with correlations observed between clinical improvement and decreases in markers of T helper 17 lymphocyte activation, dendritic-cell activation and epidermal hyperplasia. INCB018424 treatment reduced epidermal hyperplasia and dermal inflammation in most patient samples, with reductions in CD3, CD11c, Ki67 and keratin 16 observed by immunohistochemical analysis.
  
  
  CONCLUSIONS
  Topical INCB018424 dosed for 28 days QD or BID is pharmacologically active in patients with active psoriasis and modulates proinflammatory cytokines in the pathogenesis of psoriatic lesions.
authors.affiliation: Drug Development, Incyte Corporation, Rt. 141 and Henry Clay Road, Wilmington, DE, 19880, U.S.A.
authors.forename: N
authors.initials: N
authors.lastname: Punwani
authors.affiliation: Drug Discovery, Incyte Corporation, Rt. 141 and Henry Clay Road, Wilmington, DE, 19880, U.S.A.
authors.forename: T
authors.initials: T
authors.lastname: Burn
authors.affiliation: Drug Discovery, Incyte Corporation, Rt. 141 and Henry Clay Road, Wilmington, DE, 19880, U.S.A.
authors.forename: P
authors.initials: P
authors.lastname: Scherle
authors.affiliation: Drug Development, Incyte Corporation, Rt. 141 and Henry Clay Road, Wilmington, DE, 19880, U.S.A.
authors.forename: R
authors.initials: R
authors.lastname: Flores
authors.affiliation: Drug Discovery, Incyte Corporation, Rt. 141 and Henry Clay Road, Wilmington, DE, 19880, U.S.A.
authors.forename: J
authors.initials: J
authors.lastname: Shi
authors.affiliation: Drug Discovery, Incyte Corporation, Rt. 141 and Henry Clay Road, Wilmington, DE, 19880, U.S.A.
authors.forename: P
authors.initials: P
authors.lastname: Collier
authors.affiliation: Drug Discovery, Incyte Corporation, Rt. 141 and Henry Clay Road, Wilmington, DE, 19880, U.S.A.
authors.forename: D
authors.initials: D
authors.lastname: Hertel
authors.affiliation: Drug Discovery, Incyte Corporation, Rt. 141 and Henry Clay Road, Wilmington, DE, 19880, U.S.A.
authors.forename: P
authors.initials: P
authors.lastname: Haley
authors.affiliation: Drug Discovery, Incyte Corporation, Rt. 141 and Henry Clay Road, Wilmington, DE, 19880, U.S.A.
authors.forename: Y
authors.initials: Y
authors.lastname: Lo
authors.affiliation: Drug Discovery, Incyte Corporation, Rt. 141 and Henry Clay Road, Wilmington, DE, 19880, U.S.A.
authors.forename: P
authors.initials: P
authors.lastname: Waeltz
authors.affiliation: Drug Discovery, Incyte Corporation, Rt. 141 and Henry Clay Road, Wilmington, DE, 19880, U.S.A.
authors.forename: J
authors.initials: J
authors.lastname: Rodgers
authors.affiliation: Drug Discovery, Incyte Corporation, Rt. 141 and Henry Clay Road, Wilmington, DE, 19880, U.S.A.
authors.forename: S
authors.initials: S
authors.lastname: Shepard
authors.affiliation: Drug Discovery, Incyte Corporation, Rt. 141 and Henry Clay Road, Wilmington, DE, 19880, U.S.A.
authors.forename: K
authors.initials: K
authors.lastname: Vaddi
authors.affiliation: Drug Discovery, Incyte Corporation, Rt. 141 and Henry Clay Road, Wilmington, DE, 19880, U.S.A.
authors.forename: S
authors.initials: S
authors.lastname: Yeleswaram
authors.affiliation: Drug Development, Incyte Corporation, Rt. 141 and Henry Clay Road, Wilmington, DE, 19880, U.S.A.
authors.forename: R
authors.initials: R
authors.lastname: Levy
authors.affiliation: Drug Development, Incyte Corporation, Rt. 141 and Henry Clay Road, Wilmington, DE, 19880, U.S.A.
authors.forename: W
authors.initials: W
authors.lastname: Williams
authors.affiliation: Department of Dermatology, Tufts Medical Center, Boston, MA, U.S.A.
authors.forename: A B
authors.initials: AB
authors.lastname: Gottlieb
mesh_terms: D000279:Administration, Cutaneous; D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003879:Dermatologic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D009824:Ointments; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011565:Psoriasis / Q000188:drug therapy*; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines; D050796:STAT3 Transcription Factor / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism; D058504:Th17 Cells / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D016207:Cytokines; D003879:Dermatologic Agents; D009570:Nitriles; D009824:Ointments; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C540383:ruxolitinib; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2