title: Apilimod inhibits the production of IL-12 and IL-23 and reduces dendritic cell infiltration in psoriasis.
abstract: Psoriasis is characterized by hyperplasia of the epidermis and infiltration of leukocytes into both the dermis and epidermis. IL-23, a key cytokine that induces T(H)17 cells, has been found to play a critical role in the pathogenesis of psoriasis. Apilimod is a small-molecule compound that selectively suppresses synthesis of IL-12 and IL-23. An open-label clinical study of oral administration of apilimod was conducted in patients with psoriasis. Substantial improvements in histology and clinical measurements were observed in patients receiving 70 mg QD. The expression of IL-23p19 and IL-12/IL-23p40 in skin lesions was significantly reduced in this dose group, with a simultaneous increase in IL-10 observed. A decrease in the levels of T(H)1 and T(H)17 cytokines/chemokines in skin lesions followed these p19 and p40 changes. In parallel, a reduction in skin-infiltrating CD11c(+) dendritic cells and CD3(+) T cells was seen, with a greater decrease in the CD11c(+) population. This was accompanied by increases in T and B cells, and decreases in neutrophils and eosinophils in the periphery. This study demonstrates the immunomodulatory activity of apilimod and provides clinical evidence supporting the inhibition of IL-12/IL-23 synthesis for the treatment of T(H)1- and T(H)17-mediated inflammatory diseases.
authors.affiliation: Synta Pharmaceuticals Corp, Lexington, Massachusetts, United States of America. ywada@syntapharma.com
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Wada
authors.forename: Irma
authors.initials: I
authors.lastname: Cardinale
authors.forename: Artemis
authors.initials: A
authors.lastname: Khatcherian
authors.forename: John
authors.initials: J
authors.lastname: Chu
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Kantor
authors.forename: Alice B
authors.initials: AB
authors.lastname: Gottlieb
authors.forename: Noriaki
authors.initials: N
authors.lastname: Tatsuta
authors.forename: Eric
authors.initials: E
authors.lastname: Jacobson
authors.forename: James
authors.initials: J
authors.lastname: Barsoum
authors.forename: James G
authors.initials: JG
authors.lastname: Krueger
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D006835:Hydrazones; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology; D053759:Interleukin-23 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage / Q000627:therapeutic use*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D011565:Psoriasis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D011743:Pyrimidines; D012867:Skin / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D014227:Triazines / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D015703:Antigens, CD; D006835:Hydrazones; D053759:Interleukin-23; D009025:Morpholines; D011743:Pyrimidines; D014227:Triazines; D018664:Interleukin-12; C504227:apilimod