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Ongoing clinical trials with JAK2 inhibitors in MF Jason Gotlib, MD, MS Associate Professor of Medicine (Hematology) Stanford.

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Presentation on theme: "Ongoing clinical trials with JAK2 inhibitors in MF Jason Gotlib, MD, MS Associate Professor of Medicine (Hematology) Stanford."— Presentation transcript:

1 Ongoing clinical trials with JAK2 inhibitors in MF Jason Gotlib, MD, MS Associate Professor of Medicine (Hematology) Stanford Cancer Institute December 7, 2012

2 JAK Inhibitors in Clinical Use / Trials AgentTrial NameCurrent Status RuxolitinibCOMFORT-I COMFORT-II FDA Approved SAR (formerly TG101348) JAKARTAPhase III CYT387Phase II SB1518Phase II CEP-701Phase II LY Phase I BMS Phase I NS0118Phase I

3 SAR (formerly TG101348)

4 Pardanani et. al. JCO 2011;29: Phase I Trial with Phase 2 Expansion Cohort

5 Spleen Responses to SAR Gotlib et al, EHA, 2012

6 Pre-Trial On treatment JAK2 Inhibitor SAR302503

7 Symptom Responses to SAR Pardanani et. al. JCO 2011;29: Early Satiety Fatigue Night Sweats

8 SAR302503: Resolution of leukocytosis/thrombocytosis Gotlib et al, EHA, 2012

9 SAR302503: JAK2 V617F Allele Burden ©2011 MFMER | Gotlib et al, EHA, 2012

10 ©2011 MFMER | Gotlib et al, EHA, 2012 SAR302503: Spleen and symptom responses defined by baseline platelets

11 SAR Phase III Study Design Multinational, multicenter, double blind, placebo-controlled randomized study No Stratification factor Randomization 1/1/1 RA ND O M I Z A T I ON Q 4 weeks SAR mg Daily oral doses Q 4 weeks SAR mg Daily oral doses 75 pts Intermediate-2 or High risk -Primary MF -Post-Polycythemia Vera Myelofibrosis -Post-Essential Thrombocythemia Myelofibrosis Intermediate-2 or High risk -Primary MF -Post-Polycythemia Vera Myelofibrosis -Post-Essential Thrombocythemia Myelofibrosis Cross over 1/1 EOT 75 pts Q 4 weeks SAR mg Daily oral doses Q 4 weeks SAR mg Daily oral doses Q 4 weeks Placebo Daily oral doses Q 4 weeks Placebo Daily oral doses End of C6 or PD End of C6  225 pts, Sites ~125, Recruitment: 9 months, 25 countries  Safety data monitored by DMC (~Q 6 months)  Cross over possible

12 SB1518 Pacritinib

13  15 of 34 (44%) patients had response of ≥ 50% SB1518 Significantly Reduces Splenomegaly in MF patients as Measured by Physical Exam (Phase II N=34) Baseline spleen size (cm below left costal margin) ≥ 16; 11-15; 5-10 Mesa et. al. EHA 2011 (a1022) Oral Sunday

14 > 9 Months Sustained Improvement in MF-related Symptoms 3* Only pts with baseline ≥4 (MFSAF) (N) For paired values * = No change in mean symptom score Komrokji et. al. ASH 2011 Pacritinib: SB 1518

15 ©2011 MFMER | Komrokji, ASH 2011

16 CYT387

17 Constitutional Symptoms Response at Six Months Pardanani et. al. ASH 2011

18 CYT387: Maximal Change in Palpable Spleen Size* (Core Study; n=142) *ongoing ≥ 25% decrease from baseline: 87% ≥ 50% decrease from baseline: 49% ≥ 75% decrease from baseline: 25% 100% decrease from baseline: 16% Pardanani et. al. ASH 2011

19 CYT387: Transfusion Independence Response Response by Dose 150 mg QD (n=52) 300 mg QD (n=60) 150 mg BID (n=42) Total 1 (n=166) Transfusion dependent at baseline (evaluable; n) Median time on study (days) Transfusion independence rate (12 weeks)*48%65%43% 2 54% Transfusion independence rate (12 weeks & Hgb≥8g/dL)*40%62%29% 2 46% >25% of subjects not receiving transfusions while on study experienced at least a 1 g/dL increase in Hgb for ≥ 8 weeks 1 Includes 100 mg QD (n=3), 200 mg QD (n=3), and 400 mg QD (n=6) doses 2 Not statistically significant vs. 300 mg QD * ongoing Pardanani et. al. ASH 2011

20 CYT387: Duration of Transfusion Response Time to ResponseMedianMin-Max Time to confirmed response (12 wks & Hgb≥8 g/dL) (days) Duration of transfusion-free period (12 wks & Hgb≥8 g/dL) (days)not yet reached82-506* Pardanani et. al. ASH 2011

21 Comparing JAK2 Inhibitors Efficacy Spleen MF Symptoms MF Symptoms Anemia JAK2 Burden JAK2 Burden Ruxolitinib SAR CYT387 SB1518 LY NS-018BMS Phase I Testing

22 DRUGNon-HemeThrombocytopeniaAnemiaOther RuxolitinibBruising/HA/ Diarrhea SAR302503GI/LFTs/Lipase+++++/+++ CYT387Lipase/HA/Neuropathy+++-1 st Dose Effect SB1518GI+/++-/+ Comparing JAK2 Inhibitors Safety / Tolerability

23 A B C One Mechanism of Disease Persistence In MF on JAK2 inhibitors JAK2 inhibitor binds to the JAK2 kinase and reduces JAK- STAT pathway activation and cell proliferation Exposure to JAK2 inhibitor results in reactivation of JAK2 by JAK family members JAK1 and TYK2 which heterodimerize with JAK2 Koppikar et al, Nature, 2012 Ligand binding and activation of JAK2 kinase results in STAT dimerization and cellular proliferation

24 JAK 1/2 inhibitor PI3K / AKT/ mTOR inhibitors HDAC inhibitors Hsp90 inhibitors Anti- fibrotics IMiDs HedgeHog Pathway inhibitors FUTURE JAK INHIBITOR COMBINATIONS

25 25 YM Corporate Presentation | Calendar Q4/2011 Koppikar et al, ASH, 2011

26 26 YM Corporate Presentation | Calendar Q4/2011 Koppikar et al, ASH, 2011

27 27 YM Corporate Presentation | Calendar Q4/2011 Baffert et al, ASH 2011

28 Summary  After approval of ruxolitinib, SAR302503, SB1518, and CTY387 represent lead JAK inhibitors in ongoing clinical development  Patient-specific MF symptoms, differences in toxicity profiles, and potential for reversion of anemia will guide selection of agents  Strategies for overcoming disease persistence/ disease ‘creep’ – Combination of JAK inhibitors with novel drugs with different mechanisms of action  Next generation of JAK inhibitors in development

29 Acknowledgements StanfordMayo Clinic (Rochester and Mayo) Marie NguyenAyalew Tefferi Andrea LinderRuben Mesa Hersh KaurAnimesh Pardanani Cheryl Langford Cecelia PerkinsMD Anderson Cancer Center Parveen AbidiSrdan Verstovsek Lawrence Okumoto Ben VarastehIWG-MRT MPN Foundation Funding Charles and Ann Johnson Foundation


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