How Many Inhibitors for JAK2? Francisco Cervantes Hematology Department, Hospital Clínic, University of Barcelona, Spain Prague, May 2014 1

JAK2 Inhibitors in Myelofibrosis ATP-competitive inhibitors targeting both wild-type and JAK2V617F in vitro Agent Other targets Phase Ruxolitinib JAK1 Approved SAR302503 FLT3, Ret III (filed) SB1518 (pacritinib) FLT3 III CYT387 JAK1, JNK1, TYK2, CDK2 III CEP-701 FLT3, TrkA II AZD1480 JAK1, JAK3 II LY2784544 NA II NS-018 Src I BMS-911543 - I

Ruxolitinib and Spleen Volume Reduction COMFORT-I (week 24) COMFORT-II (week 48) 28.5% P < 0.0001 41.9% P < 0.0001 0.7% Response: >35% reduction of spleen volume by MRI/CT A 35% spleen volume reduction by MRI  52% reduction in spleen length by palpation It occurred at a median of 12 weeks from treatment start Verstovsek S et al., NEJM 2012; 366:799-07 Harrison C et al., NEJM 2012; 366:787-98

Impact on Disease Symptoms and QoL COMFORT-I (week 24) COMFORT-II (week 48) Worsening Improvement Global health status/QoL Role functioning Mean change from baseline 15 10 5 -5 -10 9.1 3.4 9.9 -5.4 Ruxolitinib BAT % of Patients Weeks 24 60 50 40 30 20 10 2 4 6 8 12 14 16 18 22 ruxolitinib placebo Ruxolitinib Placebo % w Response 46 5 p<0.0001, Chi-square test Response: % of patients with >50% reduction in MSAF Total Symptom Score Change in EORTC QLQ-C30 scores at week 48 compared with baseline Verstovsek S et al., NEJM 2012; 366:799-07 Harrison C et al., NEJM 2012; 366:787-98

Overall Survival (ITT Population) COMFORT-I (2 year-follow-up) COMFORT-II (3 year-follow-up) Verstovsek S et al., Haematologica 2013; 98:1865-71 Cervantes F et al., Blood 2013; 122:4047-53

Why more JAK inhibitors? Substantial ruxolitinib drop rate Better control of the anemia Deeper disease modifying effect

Why more JAK inhibitors? Substantial ruxolitinib drop rate Better control of the anemia Deeper disease modifying effect

COMFORT-I: Spleen Volume Reduction Primary Analysis1 (median follow-up ~7 months)* 80 60 40 -80 Change From Baseline (%) Individual Patients -20 20 -40 -60 35% Decrease Ruxolitinib (n=154) Placebo (n=153) -100 Updated Analysis† (median follow-up ~24 months)* 80 60 40 -80 Change From Baseline (%) Individual Patients -20 20 -40 -60 Ruxolitinib (n=154) Crossover (n=111) -100 35% Decrease The majority of ruxolitinib-treated patients maintained a spleen volume reduction The majority of crossover patients experienced spleen volume reduction relative to original baseline (median follow up: 60 weeks) *Median follow up for patients originally randomized to ruxolitinib. †Change from baseline to last available spleen volume measurement. 1. Verstovsek S et al., NEJM 2012; 366:799-07

COMFORT-II: Percent change from baseline in spleen volume % change from baseline at week 48 60 40 20 -20 -40 -60 -80 Primary endpoint Ruxolitinib BAT 80 P < .0001 At week 48 Ruxolitinib BAT ↓ Spleen volume 132 (97%) 35 (56%) ↑ Spleen volume 4 (3%) 28 (44%) Best response at any time on study Harrison C et al., NEJM 2012; 366:787-98

Duration of Spleen Response to Ruxolitinib COMFORT-I (2 year-follow-up) COMFORT-II (3 year-follow-up) Verstovsek S et al., Haematologica 2013; 98:1865-71 Cervantes F et al., Blood 2013; 122:4047-53

COMFORT-II Patient Disposition (median FU, 151 wk) Ruxolitinib (n = 146) BAT (n = 73) Ruxolitinib after cross-over from BAT (n = 45) Ongoing 66 (45.2) 22 (48.9) Discontinued 80 (54.8) 28 (38.4) 23 (51.1) Crossed over – 45 (61.6) After qualifying progression event   26 (35.6) After protocol amendment 5 13 (17.8) Othera 6 (8.2) Primary reason for discontinuation Adverse event(s) 24 (16.4) 5 (6.8) 6 (13.3) Consent withdrawn 9 (6.2) 9 (12.3) Protocol deviation 2 (1.4) 5 (11.1) Disease progression 22 (15.1) 4 (5.5) Non-compliance with study medication 3 (2.1) 1 (2.2) Non-compliance with study procedures 1 (1.4) Unsatisfactory therapeutic effect 5 (3.4) Otherb 15 (10.3) 4 (8.9) a 6 patients crossed over from BAT to ruxolitinib prior to the protocol amendment 5 without experiencing qualifying progression events (5 patients discontinued due to the protocol deviation and one patient discontinued due to other reason). b Other reasons for discontinuation included patients who underwent stem cell transplantation. Cervantes F et al., Blood 2013; 122:4047-53 Cervantes F et al., Blood 2013; 122:4047-53

Fedratinib (SAR302503) Phase I Study in MF Main Results (n= 59) Feature Response & toxicity Spleen 45%* Constitutional symptoms 50- 89% Anemia response No JAK2 allelic burden reduction 39-45% Grade 3-4 anemia 35% Grade 3-4 thrombocytopenia 24% Non-hematologic toxicity G-I symptoms * IWG-MRT criteria Pardanani A et al., JCO 2011; 29:789-96

By baseline platelet count (×109/L) Fedratinib in Ruxolitinib Resistance/Intolerance Spleen response at end of cycle 3 (n= 20) By baseline platelet count (×109/L) Proportion of patients with ≥35% reduction in spleen volume at end of Cycle 3 (%) 43 43 40 39 33 6/14 2/6 8/20b 3/7 5/13 RUX resistanta RUX intolerant Overall <100 ≥100 Overall Spleen response (≥35% reduction in spleen volume from baseline) was the primary endpoint for this interim analysis aAs reported by the investigator b7 patients not evaluable: no post-baseline MRI/CT scan (n=5); no baseline MRI/CT scan (n=1); MRI/CT scan outside time window end of cycle 3 assessment (n=1). Harrison C et al., ASH 2013

Change in spleen volume from baseline at EOC3 (%) Fedratinib in Ruxolitinib Resistance/Intolerance Spleen volume changes in individual pts at end of cycle 3 30 20 10 –10 Change in spleen volume from baseline at EOC3 (%) –20 –30 –35% –40 RUX resistanta (n=14) –50 RUX intolerant (n=6) –60 –70 Data are shown for the 20 patients with evaluable spleen volume assessment at the end of Cycle 3 Harrison C et al., ASH 2013

Fedratinib Safety Issues Cases consistent with Wernicke’s encephalopathy have been reported in patients participating in fedratinib trials. Following a thorough risk-benefit analysis, the risk to patient safety was considered to outweigh the benefit that fedratinib would bring to patients. All clinical trials involving fedratinib have been halted, and fedratinib treatment discontinued in patients enrolled in ongoing trials.

Momelotinib (CYT387) Phase I/II Study Spleen Response Number of Subjects (%) Total enrollment 166 (100%) Baseline spleen size > 5 cm at baseline 148 (89%) ≥ 50% reduction in splenomegaly that lasts ≥ 8 weeks for splenomegaly ≥ 10 cm at baseline: A (A/148) 52 (35%) Resolution of splenomegaly that lasts ≥ 8 weeks for splenomegaly > 5 and < 10 cm: B (B/148) 6 (4%) Spleen Response: A + B 58 (39%) Pardanani A et al., ASH 2013

Momelotinib After Failure to Other JAK Inhibitors (n= 27) Pardanani A et al., ASH 2013

Phase 2 Study of Pacritinib in MF Spleen Response Komrojki et al., ASH 2013

Why more JAK inhibitors? Substantial ruxolitinib drop rate Better control of the anemia Deeper disease modifying effect

Clinical Manifestations of Myelofibrosis Anemia Thrombosis Symptomatic splenomegaly Constitutional symptoms Extramedul. hemopoiesis Bone pain Infection Bleeding Pruritus

Ruxolitinib Phase I/II Study in MF. Main Efficacy Results (n= 153) Disease feature Response Spleen shrinkage, overall 80% > 50% 44% Constitutional symptoms 45-90% Leukocytosis response 50% Anemia response 14% Reduction JAK2 allelic burden Scarce Verstovsek S et al., NEJM 2010; 363:1117-1127

Laboratory Data: Hemoglobin Levels Over Time COMFORT-II Laboratory Data: Hemoglobin Levels Over Time 12.0 Baseline 11.0 10.0 10 g/dL 9.0 8.0 n = Ruxolitinib 146 127 121 101 101 96 90 78 71 64 61 59 49 50 22 BAT 73 59 53 37 31 29 19 10 6 1 In the ruxolitinib arm, mean hemoglobin levels decreased over the first 12 weeks of treatment and then recovered to levels similar to those in the BAT arm and remained > 10 g/dL from week 24 onward (> 151 weeks) Note: Only scheduled visits are included; ruxolitinib includes both the randomized and extension phases; BAT includes randomized phase only and not assessments after crossover.

Momelotinib (CYT387) Phase I/II Study Anemia Response Number of Subjects (%) Transfusion dependent at baseline 72 (43%) Achieved transfusion independence on study that lasts ≥ 12 weeks: C (C/72) 49 (68%) Transfusion independent with Hgb < 10 g/dL at baseline 39 (24%) Rise in Hb ≥ 2 g/dL on study that lasts ≥ 12 weeks: D (D/39) 10 (26%) Anemia Response: C + D 59 (53%) Transfusion dependence at baseline is defined as ≥ 2 units of RBC transfusions in the 30 days prior to C1/D1 and/or identified as transfusion dependent in medical history Pardanani A et al., ASH 2013

Momelotinib (CYT387) Phase I/II Study Duration of Anemia Response 1.0  Event  Censored 0.9 Number of events (%): 18 (30.5) Number of censored (%): 41 (69.5) Median (days) (95% CI): 1,042 (514, NE) 0.8 0.7 0.6 Probability 0.5 0.4 0.3 0.2 0.1 200 400 600 800 1000 Duration of anemia response (days) Pardanani A et al., ASH 2013

Phase 2 Study of Pacritinib in MF Evolution of Hb Values Komrojki et al., ASH 2013

Why more JAK inhibitors? Substantial ruxolitinib drop rate Better control of the anemia Deeper disease modifying effect

Survival Prolongation with Ruxolitinib Passamonti F et al., Blood 2014 (Epub ahead of print)

Change in BM Fibrosis Over Time with Ruxolitinib and BAT* 48 mo 60 mo Rux BAT Rux BAT Rux BAT Rux BAT Rux BAT Rux BAT 75% 76% 75% 56% 46% 36% 32% 26% 25% 22% 3% 2% 3% Odds Ratio [95% CI]** for worsening BM fibrosis at 48 mo Odds Ratio [95% CI]** for worsening BM fibrosis at 60 mo Rux 0.12 [0.03 – 0.50] Rux 0.07 [0.01 – 0.34]*** * Compilation of data - not a formal comparison ** Logistic regression method *** Last available grade from 54, 60, or 66 mo Kvasnicka HM, et al., 2013 ASH abs 4055

COMFORT-II: JAK2 V617F Allele Burden Reductions at Week 48 and Week 72 More patients in the ruxolitinib arm had ≥ 10% allele burden reductions compared with BAT at week 48 (42% [29/69] vs 9% [2/22]) and at week 72 (40% [21/53] vs 0%) Vannucchi AM et al., EHA 2013 29

Momelotinib (CYT387) Phase I/II Study in MF Main Results (n= 166)* Feature Response & toxicity Spleen 37% § Constitutional symptoms 75- 90% Anemia 48%* Transfusion-dependent pts. 75% JAK2 allelic burden reduction Scarce Grade 3-4 thrombocytopenia 24% Non-hematologic toxicity Unfrequent * Median follow-up: 16.9 months § IWG-MRT criteria Pardanani A et al., ASH 2012

Efficacy of JAK Inhibitors in Myelofibrosis Spleen MF Sympt. Anemia Survival effect JAK2 + + + ? Ruxolitinib NEJM 2012 ; Blood 2013 + + ? ? SAR302503 JCO 2011 + ? + ? SB1518 EHA 2011 + + + ? ? CYT387 ASH 2012 + + CEP-701 AZD1480 LY2784544 a4807 NS-018 a4106 BMS-911543 a4112 Phase I/II Testing 31

A More Selective JAK Inhibitor for Myelofibrosis? Pros - Higher effect on JAK2 allele burden - Less hematological toxicity - Less potential for long-term immunosuppression Loss of the off-target effects of ruxolitinib (constitutional symptoms, splenomegaly…) - Lack of efficacy in JAK2-negative patients? Cons

Conclusions Despite the success of ruxolitinib in MF, in the mid term more than half of the patients discontinue due to resistance or intolerance. There are indications that a proportion of these patients can respond to other JAK inhibitors. Newer drugs of this class effective for the anemia of MF are necessary. A deeper disease modifying effect of JAK inhibition would also be desirable.