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JAKAVI is a potent JAK inhibitor

Dysregulated JAK/STAT pathway is a key driver of PV1-5

  • JAK signalling pathways have been shown in vitro to control the differentiation, growth, development, and survival of haematopoietic cells by activating the transcription factor STAT2
  • JAK signalling is increased in PV, with ~99% of patients exhibiting an activating JAK2 mutation in either JAK2V617F exon 14 or JAK2 exon 123,4
  • Dysregulated JAK signalling leads to proliferation of haematopoietic cells and a chronic inflammatory state caused by overproduction of cytokines1,5

JAKAVI inhibits both JAK1 and JAK26,7

  • JAKAVI has been shown in vitro to bind to the kinase domain of JAK1 and JAK2 and inhibit JAK1 and JAK2 signalling6,7
  • JAKAVI inhibits JAK stimulation of STAT and downstream effects on cellular proliferation6

JAKAVI mechanism of action6

JAKAVI mechanism of action with JAK1 and JAK2 inhibition
JAK=Janus kinase; MOA=mechanism of action; STAT=signal transducer and activator of transcription.

References:

  1. Verstovsek S, Passamonti F, Rambaldi A, et al. A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea. Cancer. 2014;120(4):513-520.
  2. Ghoreschi K, Laurence A, O'Shea JJ. Janus kinases in immune cell signaling. Immunol Rev. 2009;228(1):273-287.
  3. Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, IDH and IKZF1. Leukemia. 2010;24(6):1128-1138.
  4. Hensley B, Geyer H, Mesa R. Polycythemia vera: current pharmacotherapy and future directions. Expert Opin Pharmacother. 2013;14(5):609-617.
  5. Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. 2007;7(9):673-683.
  6. Scossa D, Melko G. JAKAVI (ruxolitinib) Core Data Sheet: Version 1.3. Novartis Pharma AG.July 2014.
  7. Harrison C, Vannucchi AM. Ruxolitinib: a potent and selective Janus kinase 1 and 2 inhibitor in patients with myelofibrosis. An update for clinicians. Ther Adv Hematol. 2012;3(6):341-354.