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Srdan (Serge) Verstovsek M.D., Ph.D. Professor of Medicine

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.

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Srdan (Serge) Verstovsek M.D., Ph.D. Professor of Medicine

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  1. 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

  2. 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

  3. 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 QoLand 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.

  4. Patient Disposition at Current Analysis • 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

  5. Spleen Volume Reduction Last Available Measurement†(Median follow-up ~24 months)* • 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 80 Ruxolitinib (n = 154) Crossover (n = 111) 60 40 20 0 Change From Baseline, % -20 Primary Analysis (Week 24)1(Median follow-up ~7 months)* 35% Decrease -40 -60 80 Ruxolitinib (n = 154) Placebo (n = 153) -80 60 Individual Patients -100 40 20 Change From Baseline, % 0 -20 35% Decrease -40 -60 *Median follow-up for patients originally randomized to ruxolitinib†Change from baseline to last available spleen volume measurement -80 Individual Patients 1. Verstovsek S, et al. N Engl J Med. 2012;366(9):799-807. -100

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

  7. Durability of Spleen Volume Reduction 1.0 ≥10% reduction (n = 90) 0.8 0.6 Probability ≥35% reduction 0.4 0.2 0 0 8 16 24 32 40 48 72 80 88 104 112 64 96 56 Weeks From Onset No. at risk 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.

  8. EORTC QLQ-C30 Over Time Global Health Status/QoL Fatigue 10 20 5 15 Mean Change From Baseline 10 0 -5 5 BL 12 24 36 48 60 72 84 96 Weeks Weeks Role Functioning Physical Functioning -10 0 Ruxolitinib Placebo 15 15 10 -5 -15 10 5 5 0 Mean Change From Baseline -20 -10 -5 0 BL 12 24 36 48 60 72 84 96 -10 -5 -15 -15 -25 -20 -10 BL 12 24 36 48 60 72 84 96 BL 12 24 36 48 60 72 84 96 Weeks Weeks Arrows indicate improvement.

  9. 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 0 0 12 24 36 48 60 72 84 96 108 120 132 Weeks No. at risk Ruxolitinib 155 154 148 145 136 125 121 113 96 44 6 Placebo 154 148 142 133 117 111 102 95 74 32 7 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).

  10. Incidence of New Onset Nonhematologic Adverse Events Regardless of Causality • No reports of a specific withdrawal syndrome after discontinuation of ruxolitinib

  11. Incidence of New Onset Grade 3 or 4 Anemia and Thrombocytopenia Over Time Ruxolitinib Grade 3 Ruxolitinib Grade 4 Placebo Grade 3 Placebo Grade 4 Anemia Thrombocytopenia 9.9 2.9 0.7 0 • 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

  12. 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 0 -5 Mean Percentage Change From Baseline -10 -15 -20 BL 12 24 36 48 60 72 84 96 Weeks Median hemoglobin at baseline: Ruxolitinib, 105 g/L; Placebo, 105 g/L

  13. Hemoglobin Levels Over Time by Ruxolitinib Titrated Dose <10 mg BID 10 mg BID 15 mg BID ≥20 mg BID 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.

  14. Efficacy by Titrated Dose Total Symptom Score Spleen Volume n=101 n=103 n=21 n=23 n=39 n=24 n=26 Week 24 n=20 n=23 n=38 n=22 n=26 n=35 n=28 n=24 n=20 n=31 n=17 Week 48 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.

  15. 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

  16. Patient Disposition The majority of patients randomized to ruxolitinib remained on treatment after more than 2 years on study

  17. Mean % Change From Baseline in Spleen Volume Over Time Ruxolitinib, n = 146 136 125 111 98 78 64 53 42 31 10 Excluding patients who crossed over to ruxolitinib BAT Including patients who crossed over to ruxolitinib 60 45 40 34 24 20 15 8 3 11 73 n = BAT 60 n = 44 39 34 24 16 6 2 0 0 73 BAT patients who crossed over to ruxolitinib had reductions in spleen volume after crossover

  18. Overall Survival 1.0 n = 146 138 127 117 109 30 0 73 61 51 49 45 12 0 Ruxolitinib BAT No. of Patients Events Censored 146 20 (13.7%) 126 (86.3%) 73 16 (21.9%) 57 (78.1%) Ruxolitinib BAT 3.4% 9.6% 11.0% 14.4% Lost to follow-up (cumulative) 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 aP values are provided for descriptive purposes and were not adjusted for multiple comparisons.

  19. 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

  20. 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.

  21. Reductions in Total Symptom Score and Spleen Length Total Symptom Score Spleen Length n = 41 n = 38 n =35 n = 27 n = 31 n = 39 n = 32 n = 28 n = 28 n = 18 n = 18 n = 24 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.

  22. Change From Qualifying Platelet Count to Nadir and to Week 24 of Individual Patients Qualifying to Nadir Qualifying to Week 24 160 160 140 140 120 120 100 100 Platelet Count (×109/L) Platelet Count. ×109/L 80 80 60 60 40 40 20 20 0 0 Individual Patients Individual Patients

  23. Phase III Study SAR302503 vs. placebo Multinational, multicenter, randomized, double-blind, placebo-controlled Q4 weeks SAR302503 500mg Daily oral doses RANDOMIZ A TION 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)

  24. 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

  25. ARD11936 Study Design RANDOMIZATION • Intermediate-2 or high-risk primary MF (IWG-MRT criteria) • Post-polycythemia vera myelofibrosis according to the 2008 World Health Organization (WHO) criteria 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

  26. 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 – • There was a dose-dependent increase in spleen response with increasing doses of SAR302503. Change in Spleen Volume, % 35% SAR302503 400 mg (n = 10) SAR302503 500 mg (n = 10) SAR302503 300 mg (n = 8)

  27. Symptom Reduction at the End of Cycle 3 by the MPN-SAF in Patients With Symptoms Present at Baselinea aA response was defined as a 2-point improvement in or resolution of the symptom. MPN-SAF: Myeloproliferative Neoplasm Symptom Assessment Form

  28. Most Common Nonhematologic Adverse Eventsa aReported in ≥10% of patients across all dose groups. Safety was assessed in patients who received at least one dose of study drug.

  29. Anemia was the most common hematologic toxicity. Grade 3/4 thrombocytopenia was minimal. LaboratoryAbnormalities aData available for 9 patients in the 300 mg group

  30. THANK YOU sverstov@mdanderson.org

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