Ongoing clinical trials with JAK2 inhibitors in MF Jason Gotlib, MD, MS jason.gotlib@stanford.edu Associate Professor of Medicine (Hematology) Stanford Cancer Institute December 7, 2012

JAK Inhibitors in Clinical Use / Trials Agent Trial Name Current Status Ruxolitinib COMFORT-I COMFORT-II FDA Approved SAR302503 (formerly TG101348) JAKARTA Phase III CYT387 Phase II SB1518 CEP-701 LY2784544 Phase I BMS-911543 NS0118

SAR302503 (formerly TG101348)

Phase I Trial with Phase 2 Expansion Cohort Pardanani et. al. JCO 2011;29:789-796

Spleen Responses to SAR302503 Gotlib et al, EHA, 2012

JASON Pre-Trial On treatment JAK2 Inhibitor SAR302503

Symptom Responses to SAR302503 Fatigue Early Satiety Night Sweats Pardanani et. al. JCO 2011;29:789-796

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

SAR302503: JAK2 V617F Allele Burden Gotlib et al, EHA, 2012 ©2011 MFMER | 3133089-9

SAR302503: Spleen and symptom responses defined by baseline platelets Gotlib et al, EHA, 2012 ©2011 MFMER | 3133089-10

SAR302503 Phase III Study Design Multinational, multicenter, double blind, placebo-controlled randomized study RANDOM I Z A T I ON Q 4 weeks SAR302503 500mg Daily oral doses Intermediate-2 or High risk -Primary MF Post-Polycythemia Vera Myelofibrosis Post-Essential Thrombocythemia Myelofibrosis 75 pts End of C6 Q 4 weeks SAR302503 400mg Daily oral doses 75 pts Cross over 1/1 EOT Q 4 weeks Placebo Daily oral doses 75 pts No Stratification factor Randomization 1/1/1 End of C6 or PD 225 pts, Sites ~125, Recruitment: 9 months, 25 countries Safety data monitored by DMC (~Q 6 months) Cross over possible

SB1518 Pacritinib

Baseline spleen size (cm below left costal margin) 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 15 of 34 (44%) patients had response of ≥ 50% Mesa et. al. EHA 2011 (a1022) Oral Sunday

Pacritinib: SB 1518 > 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

Komrokji, ASH 2011 ©2011 MFMER | 3133089-15

CYT387

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

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

CYT387: Transfusion Independence Response Response by Dose 150 mg QD (n=52) 300 mg QD (n=60) 150 mg BID (n=42) Total1 (n=166) Transfusion dependent at baseline (evaluable; n) 25 26 14 68 Median time on study (days) 251 245 141 250 Transfusion independence rate (12 weeks)* 48% 65% 43%2 54% Transfusion independence rate (12 weeks & Hgb≥8g/dL)* 40% 62% 29%2 46% 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 >25% of subjects not receiving transfusions while on study experienced at least a 1 g/dL increase in Hgb for ≥ 8 weeks Pardanani et. al. ASH 2011

CYT387: Duration of Transfusion Response Time to Response Median Min-Max Time to confirmed response (12 wks & Hgb≥8 g/dL) (days) 84 84-293 Duration of transfusion-free period (12 wks & Hgb≥8 g/dL) (days) not yet reached 82-506* Pardanani et. al. ASH 2011

Comparing JAK2 Inhibitors Efficacy Spleen MF Symptoms Anemia JAK2 Burden + + +/- Ruxolitinib + + +/- SAR302503 + + + ? CYT387 + + ? SB1518 LY2784544 NS-018 BMS-911543 Phase I Testing

Comparing JAK2 Inhibitors Safety / Tolerability DRUG Non-Heme Thrombocytopenia Anemia Other Ruxolitinib Bruising/HA/ Diarrhea +++ ++ SAR302503 GI/LFTs/Lipase ++/+++ CYT387 Lipase/HA/Neuropathy - 1st Dose Effect SB1518 GI +/++ -/+

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

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

Koppikar et al, ASH, 2011

Koppikar et al, ASH, 2011

Baffert et al, ASH 2011

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

Acknowledgements Stanford Mayo Clinic (Rochester and Mayo) Marie Nguyen Ayalew Tefferi Andrea Linder Ruben Mesa Hersh Kaur Animesh Pardanani Cheryl Langford Cecelia Perkins MD Anderson Cancer Center Parveen Abidi Srdan Verstovsek Lawrence Okumoto Ben Varasteh IWG-MRT MPN Foundation Funding Charles and Ann Johnson Foundation