ASH 2012: New JAK Inhibitors for Myelofibrosis Srdan (Serge) Verstovsek M.D., Ph.D. Professor of Medicine Department of Leukemia University of Texas MD Anderson Cancer Center Houston, Texas, USA 1

Long-Term Outcome of Ruxolitinib Treatment in Patients With Myelofibrosis: Durable Reductions in Spleen Volume, Improvements in Quality of Life, and Overall Survival Advantage in COMFORT-I Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, Catalano JV, Deininger MW, Miller CB, Silver RT, Talpaz M, Winton EF, Harvey JH Jr, Arcasoy MO, Hexner EO, Lyons RM, Paquette R, Raza A, Vaddi K, Erickson-Viitanen S, Sun W, Sandor V, Kantarjian HM Abstract 800

COMFORT-I Background Placebo-controlled, randomized, double-blind, phase III study Ruxolitinib starting doses: Baseline platelet count 100-200×109/L: 15 mg BID Baseline platelet count >200×109/L: 20 mg BID Doses individually titrated based on safety and efficacy Ruxolitinib treatment significantly reduced spleen size and improved myelofibrosis (MF_-related symptoms and QoL and was also associated with a survival advantage relative to placebo1 Objective To describe long-term efficacy and safety of ruxolitinib with 1 year of additional follow-up beyond previously published data (median follow-up ~24 months) Data cutoff for current analysis: March 1, 2012. 1. Verstovsek S, et al. N Engl J Med. 2012;366(9):799-807.

Patient Disposition at Current Analysis Patients, n (%) Ruxolitinib (n = 155) Placebo (n = 151) Placebo Ruxolitinib (n=111) Still on treatment 100 (64.5) 73 (65.8) Discontinued 55 (35.5) 40 (26.5) 38 (34.2) Crossed over 111 (73.5) Primary reasons for discontinuation Death 13 (8.4) 10 (6.6) 11 (9.9) Adverse event 11 (7.1) 9 (6.0) 7 (6.3) Consent withdrawn 9 (5.8) 6 (4.0) 9 (8.1) Disease progression 12 (7.7) 12 (7.9) 5 (4.5) Other 10 (6.5) 3 (2.0) Noncompliance with study medication ̶ 1 (0.9) 12/7/12: T_14_1_99_1_1_351DISP01 and T_14_1_99_1_2_351DISP02 Median time to crossover from ASH 2011 COMFORT-I subgroups presentation All patients receiving placebo at the primary analysis crossed over or discontinued within 3 months of the primary analysis Median time to crossover: 41.1 weeks

Spleen Volume Reduction Primary Analysis (Week 24)1 (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 Last Available Measurement† (Median follow-up ~24 months)* 80 Ruxolitinib (n = 154) Crossover (n = 111) 60 40 20 Change From Baseline, % -20 35% Decrease -40 -60 -80 Individual Patients -100 Second figure: F_14_4_99_42_3_351SPV_WATERF03 Mean reduction in spleen volume: Week 24 = 31.6%; Week 96 = 34.9% Majority of ruxolitinib-treated patients maintained a spleen volume reduction Majority of crossover patients experienced spleen volume reduction relative to original baseline (median follow-up on ruxolitinib: ~14 months) Lesser degree of reduction likely because these patients experienced a period of spleen growth on placebo before starting ruxolitinib Note 1: The SV from an unscheduled visit, which was closest to Week 24 (Days 168) and was within the window of 168±28 days, was used if the patient missed the scheduled SV measurement; particularly, this method was implemented for all crossover patients. Note 2: Placebo = data collected during placebo treatment; for crossover patients, post-crossover data were excluded. Note 3: Ruxolitinib After Crossover = post-crossover data using the last value prior to the first ruxolitinib dose as the baseline. Note 4: The n-value is the number of intent-to-treat patients used as the denominator. *Median follow-up for patients originally randomized to ruxolitinib †Change from baseline to last available spleen volume measurement 1. Verstovsek S, et al. N Engl J Med. 2012;366(9):799-807.

Spleen Volume Reduction Total Abdominal Symptom Score Reduction in MF-Related Symptoms by Spleen Volume Reduction at Week 241 Total Symptom Score Mean % Change From Baseline ± SEM 70 30 -10 -50 -70 50 10 -30 n = 99 n = 20 P = .0004 n = 46 P<.0001 n = 60 P<.0001 All Placebo Ruxolitinib Spleen Volume Reduction <10% 10 to <35% ≥35% Improvement Worsening Total Abdominal Symptom Score n = 96 n = 20 P = .0304 n = 44 P = .001 n = 59 P<.0001 P value vs all placebo. Total Abdominal Symptom Score: abdominal pain, pain under left ribs, and early satiety. 1. Mesa R, et al. Blood. 2011;118: Abstract 3842.

Durability of Spleen Volume Reduction 1.0 ≥10% reduction (n = 90) 0.8 0.6 Probability ≥35% reduction 0.4 0.2 12/7/12: F_14_4_99_38_5_351DOR_UPDATE5 8 16 24 32 40 48 56 64 72 80 88 96 104 112 No. at risk Weeks From Onset Note 1: The duration was defined only for those patients who had at least one measurement of ≥35% reduction prior to spleen progression. Note 2: Ruxolitinib After Crossover = post-crossover data using the last value prior to the first ruxolitinib dose as the baseline. 90 84 75 72 63 57 52 47 43 41 35 4 4 4 90/155 (58%) had a 35% reduction at any time point during the study 64% maintained a ≥35% reduction for at least 2 years ≥35% reduction: Time from first 35% reduction to <35% reduction and 25% increase from nadir. ≥10% reduction: Time from first 35% reduction to <10% reduction from baseline.

Global Health Status/QoL Mean Change From Baseline EORTC QLQ-C30 Over Time Global Health Status/QoL Mean Change From Baseline BL 12 24 36 48 60 72 84 96 Weeks 20 10 -5 -10 -15 15 5 Fatigue BL 12 24 36 48 60 72 84 96 10 -10 -15 -20 -25 5 -5 Weeks Ruxolitinib Placebo Role Functioning Physical Functioning 15 15 10 12/7/12: F_14_4_99_4_1_EORTC_MPLOT1 F_14_4_99_4_2_EORTC_MPLOT2 F_14_4_99_4_3_EORTC_MPLOT3 F_14_4_99_4_7_EORTC_MPLOT7 10 5 5 Mean Change From Baseline -5 -10 -5 -15 -20 BL 12 24 36 48 60 72 96 84 Weeks -10 BL 12 24 36 48 60 72 96 84 Weeks Arrows indicate improvement.

Overall Survival: ITT Population 1.0 0.8 Ruxolitinib Placebo 0.6 HR = 0.58 (95% CI: 0.36, 0.95); P = .028 Survival Probability No. of deaths: Ruxolitinib = 27; Placebo = 41 0.4 Median follow-up: 102 weeks 0.2 Age-adjusted HR* = 0.61 (95% CI: 0.37, 0.99); P = .040 12/7/12: F_14_4_99_1_25_351OS_UPDATE01F 12 24 36 48 60 72 84 96 108 120 132 Weeks 148 142 133 117 111 102 95 74 32 7 Placebo 154 145 136 125 121 113 96 44 6 Ruxolitinib No. at risk 155 Note: For this unplanned analysis, P-values are descriptive and nominally significant. *Age was the only baseline characteristic that differed significantly between treatment groups as reported in Verstovsek S, et al. N Engl J Med. 2012;366(9):799-807 (median age: ruxolitinib, 66 years; placebo, 70 years; P<.05).

Incidence of New Onset Nonhematologic Adverse Events Regardless of Causality Percent of Patients 0–<6 Months 6–<12 Months 12–<18 Months 18–<24 Months ≥24 Months RUX PBO Fatigue 25.7 31.9 5.8 7.9 8.4 5.4 Diarrhea 23.2 22.9 5.7 3.4 10.3 Ecchymosis 18.1 9.2 5.5 4.3 1.6 Dyspnea 16.8 16.1 4.5 6.4 4.8 4.9 Peripheral edema 16.7 5.3 6.3 5.1 Headache 15.5 5.0 0.9 2.1 1.5 Dizziness 14.2 6.5 3.2 Nausea 12.8 17.0 5.2 3.0 8.0 Constipation 12.0 12.1 4.2 5.9 8.7 Vomiting 10.8 2.5 1.0 4.0 Pain in extremity 11.4 10.7 8.5 Pyrexia 11.3 2.4 3.7 6.7 8.2 Insomnia 2.0 2.8 4.1 Abdominal pain 10.1 40.7 Arthralgia 4.4 Cutoff is >10% at any time point in RUX-treated patients, but this tends to apply to just the 0-6 month interval. 12/7/12: T_14_3_98_8_1_1_AELT01A and T_14_3_98_8_1_2_AELT01B No reports of a specific withdrawal syndrome after discontinuation of ruxolitinib

Incidence of New Onset Grade 3 or 4 Anemia and Thrombocytopenia Over Time Ruxolitinib Grade 4 Ruxolitinib Grade 3 Placebo Grade 3 Placebo Grade 4 Anemia Thrombocytopenia 12/7/12: T_14_3_98_9_2_LBCTC02 T_14_3_98_9_3_LBCTC03 T_14_3_98_9_5_LBCTC05 T_14_3_98_9_6_LBCTC06 9.9 2.9 0.7 All patients receiving placebo at the primary analysis crossed over or discontinued within 3 months of the primary analysis; therefore, data for patients receiving placebo is shown for 0–<6 months only

Mean Hemoglobin Levels Over Time Mean hemoglobin nadirs after 8–12 weeks of therapy and recovers to a new steady state which remains stable with longer-term therapy 5 Ruxolitinib Placebo -5 Mean Percentage Change From Baseline -10 12/7/12: F_14_4_97_1_6_HGB_MPLOT2 -15 -20 BL 12 24 36 48 60 72 84 96 Weeks Median hemoglobin at baseline: Ruxolitinib, 105 g/L; Placebo, 105 g/L Mean hemoglobin levels dropped to a nadir 8-12 weeks after initiation of therapy, then recovered to a new steady state slightly below baseline values by week 24, and remained stable throughout the remaining 2 years of follow-up

Hemoglobin Levels Over Time by Ruxolitinib Titrated Dose 10 mg BID <10 mg BID ≥20 mg BID 15 mg BID 12/7/12: F_14_4_99_37_2_4_351HGBRETB04 and T_351HGBRETB01 <10 mg BID= <20 mg average total daily dose 10 mg BID= 20-<30 mg average total daily dose 15 mg BID= 30-<40 mg average total daily dose ≥20 mg BID= ≥40 average total daily dose BL Patients titrated to 10 mg BID after nadir hemoglobin showed faster and more complete return of hemoglobin to pretreatment levels Titrated dose is defined as the average dose patients received between Weeks 8 and 56. Hemoglobin levels within 60 days of transfusion are not included.

Efficacy by Titrated Dose n=101 n=24 n=26 n=23 n=39 n=21 Spleen Volume n=103 n=22 n=38 n=20 Total Symptom Score n=35 n=28 n=31 n=17 Week 24 Week 48 12/7/12: F_14_4_99_34_1B_EFFBYADOSE10BID1B, F_14_4_99_34_2B_EFFBYADOSE10BID2B, and F_14_4_99_35_1B_EFFBYADOSE10BID48WK1B DOSE GROUPINGS AVAILABLE WHEN VIEWED IN NOTES PAGE VIEW Week 24   Total daily dose Mean Median N < 10 BID < 20 9.8286 10 25 = 10 BID = 20 20.0000 20 26 15 BID > 20-30 29.3006 30 24 20 BID > 30-40 39.6964 40 >20 BID > 40 50.0000 50 Week 48 10.1416 28 27.3786 39.4470 31 49.1807 17 Titrated dose is defined as the average dose patients received in the last 4 weeks before assessment. Verstovsek S, et al. Blood. 2012;120: Abstract 800.

Long-Term Efficacy, Safety, and Survival Findings From COMFORT-II, a Phase 3 Study Comparing Ruxolitinib With Best Available Therapy for the Treatment of Myelofibrosis Abstract 801 Cervantes F, Kiladjian J-J, Niederwieser D, Sirulnik A, Stalbovskaya V, McQuitty M, Hunter DS, Levy RS, Passamonti F, Barbui T, Barosi G, Gisslinger H, Vannucchi AM, Knoops L, Harrison CN

Ruxolitinib After Crossover From BAT Patient Disposition n (%) Ruxolitinib (n = 146) BAT (n = 73) Ruxolitinib After Crossover From BAT (n = 45) Still on treatment 81 (55.5) 26 (57.8) Discontinued 65 (44.5) 73 (100.0) 19 (42.2) Crossed over -- 45 (61.6) Primary reasons for discontinuation Adverse event 20 (13.7) 5 (6.8) 5 (11.1) Consent withdrawn 8 (5.5) 9 (12.3) Protocol deviation 2 (1.4) Disease progression 16 (11.0) 4 (5.5) Noncompliance with study medication 3 (2.1) 1 (2.2) Noncompliance with study procedures 1 (1.4) Unsatisfactory therapeutic effect Other 14 (9.6) 2 (4.4) The majority of patients randomized to ruxolitinib remained on treatment after more than 2 years on study

Mean % Change From Baseline in Spleen Volume Over Time 136 125 111 98 78 64 53 Ruxolitinib, 42 31 n = 146 10 BAT Excluding patients who crossed over to ruxolitinib 60 44 39 34 24 16 6 2 73 n = BAT n = 60 45 40 34 24 20 15 8 11 73 3 Including patients who crossed over to ruxolitinib BAT patients who crossed over to ruxolitinib had reductions in spleen volume after crossover

Overall Survival 1.0 No. of Patients Events Censored 146 20 (13.7%) 126 (86.3%) 73 16 (21.9%) 57 (78.1%) Ruxolitinib BAT BAT Ruxolitinib n = 146 138 127 117 109 30 73 61 51 49 45 12 Lost to follow-up (cumulative) 3.4% 9.6% 11.0% 14.4% 14.4% 13.7% 24.7% 26.0% 27.4% 27.4% Suggests a relative reduction in the risk of death with ruxolitinib compared with BAT (HR = 0.51; 95% CI, 0.26-0.99; log-rank test P = .041)a a P values are provided for descriptive purposes and were not adjusted for multiple comparisons.

Efficacy, Hematologic Effects, and Dose of Ruxolitinib in Myelofibrosis Patients with Low Starting Platelet Counts (50–100×109/L) Abstract 176 Talpaz M, Paquette R, Afrin L, Hamburg S, Jamieson K, Terebelo H, Ortega G, Lyons RM, Tiu R, Winton E, Natrajan K, Odenike O, Peng W, O’Neill P, Erickson-Viitanen S, Leopold L, Sandor V, Levy R, Kantarjian H, Verstovsek S

Distribution of Ruxolitinib Dose Over Time In patients who completed 24 weeks of treatment, most have optimized their dose of ruxolitinib to 10 mg BID or higher 10 BID 10 / 15 15 BID 15 BID 10 / 15 10 BID 10 / 15 10 BID 5 / 10 10 BID 5 BID 10 BID 5 / 10 5 / 10 5 / 10 5 BID 5 BID 5 BID 5 BID 5 BID n values represent patients with available dose information at the time of data analysis. Data shown for each time point represent the dose that patients were on during the previous 4 weeks.

Reductions in Total Symptom Score and Spleen Length Weeks 4 8 12 16 20 24 TDD, mg Mean 10.0 13.2 15.1 16.8 18.3 19.1 Median 10 15 Weeks 4 8 12 16 20 24 TDD, mg Mean 10.0 13.2 15.1 16.8 18.3 19.1 Median 10 15 Percent change from baseline is not calculated for patients with a “0” TSS or palpable spleen size of “0 cm” at baseline. Mean and median dose shown for patients with available dosing information. TDD, total daily dose.

Change From Qualifying Platelet Count to Nadir and to Week 24 of Individual Patients Qualifying to Nadir Qualifying to Week 24 Individual Patients 160 140 120 100 80 60 40 20 Platelet Count (×109/L) 160 140 120 100 Platelet Count. ×109/L 80 60 40 20 Individual Patients

Phase III Study SAR302503 vs. placebo Multinational, multicenter, randomized, double-blind, placebo-controlled RANDOMI Z A T I ON Q4 weeks SAR302503 500mg Daily oral doses n=75 - Intermediate-2 or high-risk Primary MF Post-Polycythemia Vera MF Post-Essential Thrombocythemia MF End of C6 Q 4 weeks SAR302503 400mg Daily oral doses n=75 Cross over 1/1 EOT No Stratification factors Randomization 1/1/1 1 cycle = 28 days Q 4 weeks Placebo Daily oral doses n=75 End of C6 or progressive disease 225 patients at ~128 sites Recruitment: 8 months, 25 countries Safety data monitored by DMC (~Q6 months) Cross over possible Enrollment Completed (Sept 2012)

A Phase II Randomized Dose-Ranging Study of the JAK2-Selective Inhibitor SAR302503 in Patients With Intermediate-2 or High-Risk Primary Myelofibrosis (MF), Post-Polycythemia Vera MF, or Post-Essential Thrombocythemia MF Abstract 2837 Talpaz M, Jamieson C, Gabrail NY, Lebedinsky C, Neumann F, Gao G, Liu F, Tefferi A, Pardanani A

ARD11936 Study Design Intermediate-2 or high-risk primary MF (IWG-MRT criteria) Post-polycythemia vera myelofibrosis according to the 2008 World Health Organization (WHO) criteria RANDOMIZATION SAR302503 300 mg orally once daily SAR302503 400 mg orally once daily Patients who continued to benefit clinically could remain on study until the occurrence of disease progression or unacceptable toxicity 1 cycle = 28 days SAR302503 500 mg orally once daily Primary endpoint: Secondary endpoints: % change in spleen volume at EOC 3 by central review assessed by MRI % of patients who achieve ≥35% reduction in spleen volume from baseline To measure improvement in baseline MPN-associated symptoms Safety (NCI CTCAE v4.03), PK/PD EOC, end of cycle; MF, myelofibrosis; MPN-SAF, myeloproliferative neoplasm symptom assessment form; MRI, magnetic resonance imaging; PK/PD, pharmacokinetics/pharmacodynamics

Change in Spleen Volume, % Percent Change in Spleen Volume From Baseline in Individual Patients at the End of Cycle 3 30 – 20 – 10 – 0 – -10 – -20 – -30 – -40 – -50 – -60 – -70 – -80 – Change in Spleen Volume, % 35% SAR302503 300 mg (n = 8) SAR302503 400 mg (n = 10) SAR302503 500 mg (n = 10) There was a dose-dependent increase in spleen response with increasing doses of SAR302503.

Symptom Reduction at the End of Cycle 3 by the MPN-SAF in Patients With Symptoms Present at Baselinea SAR302503 300 mg n = 10 400 mg 500 mg n = 11 Proportion of patients with ≥50% reduction in total MPN-SAF score from baseline n (%) [95% CI] 5 (50) [19 - 81] 4 (36) [11 - 69] Symptom Response,a n/N Night sweats 5/5 (100%) 5/6 (83%) 4/4 (100%) Itching 6/7 (86%) 1/3 (33%) 3/4 (75%) Abdominal discomfort 4/7 (57%) 3/7 (43%) 3/6 (50%) Abdominal pain 3/5 (60%) Bone pain 2/3 (67%) 1/4 (25%) Early satiety Inactivity 2/6 (33%) aA response was defined as a 2-point improvement in or resolution of the symptom. MPN-SAF: Myeloproliferative Neoplasm Symptom Assessment Form

Most Common Nonhematologic Adverse Eventsa SAR302503 300 mg n = 10 400 mg 500 mg n = 11 n (%) All grades Grade 3/4 All Grades Fatigue 3 (30) 1 (10) 4 (36) Diarrhea 7 (70) 9 (90) 2 (20) 6 (55) Nausea 6 (60) 5 (50) 8 (73) Vomiting 4 (40) 7 (64) Constipation 1 (9) Pruritis Edema, peripheral Infections 3 (27) Hyperkalemia Paresthesia 2 (18) Dyspnea Cough aReported in ≥10% of patients across all dose groups. Safety was assessed in patients who received at least one dose of study drug.

Laboratory Abnormalities SAR302503 300 mg n = 10 400 mg 500 mg n = 11 n (%) All grades Grade 3/4 All Grades Anemia 9 (100)a 3 (33)a 10 (100) 3 (30) 10 (91) 6 (55) Neutropenia 1 (10) Thrombocytopenia 5 (50) 2 (20) 1 (9) aData available for 9 patients in the 300 mg group Anemia was the most common hematologic toxicity. Grade 3/4 thrombocytopenia was minimal.

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