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SP0169 JAK inhibition in patients with rheumatoid arthritis
  1. J. Kremer
  1. Albany Medical College and The Center for Rheumato, Albany, United States

Abstract

The Janus Kinase (JAK) group of tyrosine kinases are intracellular signaling molecules which become phosphorylated upon activation. There are 3 different JAK enzymes; JAK 1,2 and 3. Each of the JAK targets has somewhat different effects when inhibited. JAK activation is followed by phosphorylation of intracytoplasmic STAT tyrosine kinases which then lead to nuclear transcription of inflammatory mediators.

Molecules in development for treatment of rheumatoid arthritis inhibit various JAK targets including CP-690,550 (JAK 1-3), INCB018424 and INCB028050 (JAK 1 and 2), VX-509 (JAK 3) and GLPG0634 (JAK1). JAK inhibition leads to down regulation of the interferon (IFN) related cytokines, the common γ chain cytokines (IL-2, IL-7, IL-9, IL-15, IL-21) as well as the gp130 family (including IL-6 and related proteins). Recently, CP-690,550 has also been shown to inhibit TNF-induced release of chemokines including IP-10, RANTES and MCP1.

JAK inhibitors are small molecules with short half lives which can be administered orally in BID (CP-690,550; half life of 3 hrs) or QD dosing (INCBO28050; half life of 6 hrs). CP-690,550 has completed several phase III trials including use as: monotherapy; use with background DMARDs; and structure. INCBO18424, INCBO28050 and VX-509 are presently in Phase II.

To date the JAK molecules appear to share certain side effects including transaminase and lipid increases (common) with occasional increases in serum Creatinine along with decreases in both hemoglobin, white blood cells and platelets which can occasionally become clinically significant. Their overall clinical efficacy profile is viewed as robust and generally viewed as being equivalent to approved biologic agents. Specifics of the clinical efficacy and toxicity profile of these agents will be reviewed along with a mechanistic overview.

Disclosure of Interest None Declared

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