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An overview of the differences of different JAK inhibitors

An overview of the differences of different JAK inhibitors. Alessandro M. Vannucchi University of Florence, Italy. JAK2 S ignaling A bnormalities in MPN. JAKs are I nvolved in Multiple C ytokine S ignaling. Vannucchi AM, N Engl J Med. 2010; 363:1180-2.

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An overview of the differences of different JAK inhibitors

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  1. An overview of the differences of different JAK inhibitors Alessandro M. Vannucchi University of Florence, Italy

  2. JAK2 SignalingAbnormalities in MPN

  3. JAKs are Involved in Multiple CytokineSignaling Vannucchi AM, N Engl J Med. 2010; 363:1180-2.

  4. DysregulatedCytokineExpression in MF Patients Verstovsek S et al. NEJM 2010; 363:1117-27

  5. AbnormallyIncreased IL-8 and IL2R Plasma Levels Are PrognosticallyDetrimental Int-1 (n=27) All (n=127) Int-2 (n=70) Treatment naive (n=90) Tefferi A et al. JCO 2011;29:1356-1363

  6. A portfolio of JAK2 inhibitors Reddy M et al. ExpOpinTher targets 2012; 16:313-24

  7. A portfolio of JAK2 inhibitors Reddy M et al. ExpOpinTher targets 2012; 16:313-24

  8. All JAK2 Inhibitors are Type I and are notMutationSpecific

  9. Efficacy of JAK2 Inhibitors: Summary *, >35% by MRI (ruxolitinib) or >50% by palpation (SAR & CYT)

  10. CYT387: Transfusion Independence Response • Of the transfusion dependent patients who did not achieve a full transfusion independence response, 23% achieved at least a 50% reduction in transfusion requirement in any 3-month period • 3 additional subjects achieved 12 week transfusion independence response during the Extension Study 1 Includes 100mg QD (n=3), 200mg QD (n=3), and 400mg QD (n=6) doses 2 Not statistically significant vs. 300mg QD 3 Data based on responders * Ongoing as of November 2012 Pardanani A et al, ASH 2012

  11. CYT387: Effects on Anemia Percentage of Patients Receiving RBC Transfusions in Prior 4 Weeks Pardanani A et al, ASH 2012

  12. Vannucchi AM et al, ASH 2012

  13. Effect of TG101348/SAR302503 therapy on JAK2 V617F allele burden Pardanani A et al. JCO 2011;29:789-796

  14. RuxolitinibInducedInhibition of InflammatoryCytokines Verstovsek S et al. NEJM 2010; 363:1117-27

  15. Inhibition of InflammatoryCytokinesdoesnot Mediate Efficacy of SAR203505 Pardanani A et al, JCO 2011; 29:789-96

  16. CYT387: cytokinechanges ……….. Ourdata suggests a cytokine-mediated effect; a majority of patients had treatment-related decrease in circulating IL-1β and IL-1RA levels, which were the only two cytokines associated with transfusion-independence response. Similarly, spleen response was correlated with treatment-associated decreases in a number of cytokines. Overall, these data implicate down-regulation of circulating inflammatory cytokines, further confirmed by gene expression analysis, as the major mechanism for CYT387’s clinical activity in MF. Pardanani A et al, Leukemia 2013

  17. Toxicity of JAK2 Inhibitors: Summary Courtesy, R. Mesa 2013 Verstovsek S, NEJM 2012; Talpaz M, ASH 2012; Komrojki B, ASH 2012; Pardanani A, Leukemia 2013

  18. Conclusions • A portfolio of different JAK2/(1) inhibitorsisavailable in addition to ruxolitinib • Thereis no cleardifference in efficacyagainstsplenomegaly and symptoms • Different JAK2 inhibitorsmayhavedifferentactivityagainstinflammatorycytokines • CYT387 mayhaveuniqueeffects on anemia • ModestactivityagainstJAK2V617F allele burden • Overlappinghematologictoxicity

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