Srdan (Serge) Verstovsek M.D., Ph.D. Professor of Medicine Department of Leukemia University of Texas MD Anderson Cancer Center Houston, Texas, USA JAK inhibitors and low blood cell count

JAK inhibitorDiseases and studies CEP701 MF: phase II finished and I/II (new formulation) ongoing ET/PV: phase II completed AZD1480MF: phase I finished, development stopped XL019MF: phase I finished, development stopped NS-018MF: phase I ongoing BMS MF: phase I/II ongoing LY ET/PV/MF: phase I finished; MF: phase II ongoing CYT387 MF: phase I/II QD completed; phase I/II BID completed; phase III planned SB1518MF: phase I/IIx2 completed, phase III ongoing SAR302503/TG MF: phase I/II completed; phase II completed, phase III completed; phase II second line ongoing ET/PV: phase II ongoing; PV: phase III planned INCB018424/Ruxolitinib MF: approved; phase II (low platelets) ongoing ET/PV: phase II completed; PV: phase III completed

JAK2 Inhibitor Side Effects from Phase II Studies GI Anemia Platelets X X X X X X X Neuropathy X

Ruxolitinib vs. Placebo: COMFORT-I Background Placebo-controlled, randomized, double-blind, phase III study Ruxolitinib starting doses: –Baseline platelet count ×10 9 /L: 15 mg BID –Baseline platelet count >200×10 9 /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 placebo 1 Objective To describe long-term efficacy and safety of ruxolitinib with 1 year of additional follow-up beyond previously published data Data cutoff for current analysis: March 1, Verstovsek S, et al. N Engl J Med. 2012;366(9): Verstovsek S, et al. Blood. 2012;120: Abstract 800.

Patient Disposition at Current Analysis Patients, n (%) Ruxolitinib (n = 155) Placebo (n = 151) Placebo  Ruxolitinib (n=111) Still on treatment100 (64.5)073 (65.8) Discontinued55 (35.5)40 (26.5)38 (34.2) Crossed over111 (73.5) Primary reasons for discontinuation Death13 (8.4)10 (6.6)11 (9.9) Adverse event11 (7.1)9 (6.0)7 (6.3) Consent withdrawn9 (5.8)6 (4.0)9 (8.1) Disease progression12 (7.7)12 (7.9)5 (4.5) Other10 (6.5)3 (2.0)5 (4.5) Noncompliance with study medication ̶̶ 1 (0.9) 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 Verstovsek S, et al. Blood. 2012;120: Abstract 800.

Incidence of New Onset Grade 3 or 4 Anemia and Thrombocytopenia Over Time AnemiaThrombocytopenia 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 Ruxolitinib Grade 4Ruxolitinib Grade 3 Placebo Grade 3Placebo Grade Verstovsek S, et al. Blood. 2012;120: Abstract 800.

Mean Daily Dose of Ruxolitinib Over Time Approximately 70% of patients had dose adjustments during the first 12 weeks of therapy Patients achieved a stable dose with longer-term use

Mean Platelet Counts Over Time Platelet counts remain stable with longer-term therapy Mean Percentage Change From Baseline BL Weeks -50 RuxolitinibPlacebo Median platelet count at baseline: Ruxolitinib, 262.0×10 9 /L; Placebo, 238.0×10 9 /L.

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 Mean Percentage Change From Baseline BL Weeks RuxolitinibPlacebo Median hemoglobin at baseline: Ruxolitinib, 105 g/L; Placebo, 105 g/L Verstovsek S, et al. Blood. 2012;120: Abstract 800.

Hemoglobin Levels Over Time in Patients Without Transfusions or Dose Changes Recovery in hemoglobin over time was seen regardless of transfusions and dose modifications Analyses were conducted in patients who completed Week 36. No RBC Transfusions Before Week Mean Percentage Change From Baseline -20 BL42436 Weeks No RBC Transfusions and No Dose Changes Before Week 36 Mean Percentage Change From Baseline BL42436 Weeks

RBC Transfusions Over Time By Week 36, the proportion of ruxolitinib-treated patients receiving RBC transfusions decreased to the level seen with placebo and remained stable thereafter Percentage of Patients BL Weeks From First Ruxolitinib Dose Weighted mean rate of the placebo group = 24.37% RuxolitinibPlacebo Proportion of patients with RBC transfusion in prior month

Hemoglobin Levels Over Time By Ruxolitinib Titrated Dose 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. Patients titrated to 10 mg BID after nadir hemoglobin showed faster and more complete return of hemoglobin to pretreatment levels

Efficacy by Titrated Dose Titrated dose is defined as the average dose patients received in the last 4 weeks before assessment. n=101 n=24n=26 n=23n=39 n=21 Spleen Volume n=103 n=22n=26 n=23n=38 n=20 Total Symptom Score n=35 n=28n=20n=31n=17n=24 Week 24 Week 48 Verstovsek S, et al. Blood. 2012;120: Abstract 800.

Verstovsek S et al. NEJM 2012; 366: Development of Anemia Does not Affect Response to Ruxolitinib Treatment

What happens if the therapy with JAK2 inhibitor is interrupted? Days Around Dose Change Number of patients: Return of the symptoms within 7 days

Serious Adverse Events After Therapy Interruption no report of “withdrawal syndrome” Percent of patients that discontinued ruxolitinib due to side effects was 11% Percent of patient that discontinued placebo due to side effects was 11%

Danazol Erythropoietin Low dose thalidomide Consideration in everyday practice: addition of an “Anemia Drug” to a JAK2 inhibitor

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 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. 15 BID 10 BID 5 BID 15 BID 10 BID 5 BID 10 / BID 5 BID 10 BID 5 BID 10 BID 5 BID 5 / 10 5 BID 10 / 15 5 / 10 Talpaz M, et al. Blood. 2012;120: Abstract 176.

n = 41 n = 39 n = 32 n = 28 n = 18 n = 38 n =35 n = 31 n = 27 n = 24 n = 18 Total Symptom ScoreSpleen Length 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. Weeks TDD, mg Mean Median Reductions in Total Symptom Score and Spleen Length Weeks TDD, mg Mean Median Talpaz M, et al. Blood. 2012;120: Abstract 176.

Change From Qualifying Platelet Count to Nadir and to Week 24 of Individual Patients Qualifying to NadirQualifying to Week 24 Individual Patients Platelet Count. ×10 9 /L Individual Patients Platelet Count (×10 9 /L) Talpaz M, et al. Blood. 2012;120: Abstract 176.

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