OMF. Th. Sliwa 5th Med, Department for Hematology, Ocology an Palliative Care Hietzing Hospital, Vienna Austria

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1 OMF Th. Sliwa 5th Med, Department for Hematology, Ocology an Palliative Care Hietzing Hospital, Vienna Austria

2 Th. Sliwa 2013

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4 molecular biology Th. Sliwa 2013

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7 Clinical

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19 Ruxolitinib

20 Ruxolitinib (JAKAVI ) Th. Sliwa 2013

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22 Percent Change in Spleen Volume Mean % Change From Baseline Ruxolitinib BAT (excluding crossover) BAT (including crossover) Week Ruxolitinib, n = BAT BAT Excluding patients who crossed over to ruxolitinib n = Including patients who crossed over to ruxolitinib n = BAT patients who crossed over to ruxolitinib had reductions in spleen volume after crossover In COMFORT-II, ruxolitinib provided rapid and durable reductions in splenomegaly that were sustained over 2 years of treatment in the majority of patients

23 Myelofibrosis Symptom Assessment Form (MFSAF) Patients rated the severity of MF symptoms experienced over the previous 24 hours using a scale from 0 (absent) to 10 (worst imaginable): Night sweats Pruritus/itchiness Abdominal discomfort Pain under the ribs on the left side Early satiety Bone or muscle pain Inactivity TSS (total symptom score) includes sum of scores from all symptoms except inactivity Th. Sliwa 2013

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

26 EORTC QLQ-C30 Over Time Global Health Status/QoL Fatigue Mean Change From Baseline BL Weeks BL Weeks Role Functioning Ruxolitinib Placebo Physical Functioning Mean Change From Baseline BL Weeks -10 BL Weeks Arrows indicate improvement. Th. Sliwa 2013

27 Overall Survival: ITT Population 1.0 Survival Probability HR=0.58 (95% CI: 0.36, 0.95); P=0.028 No. of deaths: Ruxolitinib=27; Placebo=41 Median follow up: 102 weeks Age adjusted HR * =0.61 (95% CI: 0.37, 0.99); P=0.040 Ruxolitinib Placebo No. at risk Weeks Ruxolitinib Placebo 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: (median age: ruxolitinib, 66 years; placebo, 70 years; P<0.05). Th. Sliwa 2013

28 Overall Survival Probability ,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0 n = Ruxolitinib Weeks Lost to follow-up (cumulative) No. of Patients Events Censored Ruxolitinib (13.7%) 126 (86.3%) BAT (21.9%) 57 (78.1%) 3.4% 9.6% 11.0% 14.4% 13.7% 24.7% 26.0% 27.4% 14.4% 27.4% BAT Suggests a relative reduction in the risk of death with ruxolitinib compared with BAT HR = 0.51; 95% CI, Log-rank test P =.041 a 28 a P value for log-rank test is provided for descriptive purposes and was not adjusted for multiple comparisons.

29 Conclusions: critical problems in MF 1. Treatment of Anemia: remain an unmet clinical need 2. Treatment of Splenomegaly: JAK2 Inhibitors (Ruxolitinib) is highly effective 3. Treatment of constitutional symptoms: Ruxolitinib is highly effective 4. OS Benefit observed with Ruxolitinib

30 Reductions in JAK2 V617F Allele Burden With Ruxolitinib Treatment in COMFORT-II, a Phase 3 Study Comparing the Safety and Efficacy of Ruxolitinib With Best Available Therapy Alessandro M. Vannucchi, 1 Francesco Passamonti, 2 Haifa Kathrin Al-Ali, 3 Giovanni Barosi, 4 Claire N. Harrison, 5 Mahtab Marker, 6 Andres Sirulnik, 6 Viktoriya Stalbovskaya, 7 Matthew Squires, 7 Timothy Burn, 8 Laurent Knoops, 9 Francisco Cervantes, 10 Tiziano Barbui, 11 Heinz Gisslinger, 12 Jean-Jacques Kiladjian 13 1 University of Florence, Florence, Italy; 2 Ospedale di Circolo e Fondazione Macchi, Varese, Italy; 3 University of Leipzig, Leipzig, Germany; 4 IRCCS Policlinico San Matteo Foundation, Pavia, Italy; 5 Guy s and St Thomas NHS Foundation Trust, London, UK; 6 Novartis Pharmaceuticals Corporation, East Hanover, NJ; 7 Novartis Pharma AG, Basel, Switzerland; 8 Incyte Corporation, Wilmington, DE; 9 Cliniques Universitaires Saint-Luc and de Duve Institute, Université catholique de Louvain, Brussels, Belgium; 10 Hospital Clínic, IDIBAPS, Barcelona, Spain; 11 A.O. Ospedali Riuniti di Bergamo, Bergamo, Italy; 12 Medical University of Vienna, Vienna, Austria; 13 Hôpital Saint-Louis et Université Paris Diderot, Paris, France

31 COMFORT-II Study Design Randomized, open-label, multicenter phase 3 study 1 Patients with PMF, PPV-MF, or PET-MF with 2 IPSS risk factors 2 N = 219 Randomize 2:1 Ruxolitinib 15 or 20 mg oral bid n = 146 Best available therapy (BAT) n = 73 Ruxolitinib crossover and extension phase A spleen response was defined as a 35% reduction in spleen volume from baseline at week 48 as measured by MRI/CT (primary endpoint) Allele burden was measured from blood samples using allele-specific RT-qPCR as described in Levine, et al (exploratory endpoint) 1. Harrison C, et al. N Engl J Med. 2012;366(9): Cervantes F, et al. Blood. 2009:113(13): Levine RL, et al. Blood. 2006:107(10):

32 Conclusions 22% of patients receiving ruxolitinib achieved a 20% reduction in JAK2 V617F allele burden at week 48 compared with no patients who received BAT Attainment of a 20% reduction in allele burden was associated with an increased chance of achieving a 35% reduction from baseline in spleen volume These data suggest that there is a subset of patients with MF who show a significant reduction in allele burden with ruxolitinib treatment

33 Case Report: female 76 a, post PV-MF (PV since 1990), JAK 2 V617E positiv, Hydoxyurea with transfusion depemdency due to HU. 1/2013 Start Ruxolitinib 20mg 1-0-1

34 Suggested algorithm for approach to selection of first-line therapy (drug therapy vs HCT) by American Society of Hematology Gupta V et al. Blood 2012;120: Th. Sliwa 2013

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36 thank you for your attention Th. Sliwa 2013

37 TSS After Therapy Interruption Number of patients: Days Around Dose Change Return of the symptoms within 7 days Note: Median % change in TSS shown is over the 14 days before and after first ruxolitinib dose interruption. TSS, total symptom score.

38 Nonhematologic Adverse Events ( 10%) Week 0-48 After Week 48 BAT (n = 73) Ruxolitinib (n = 146) Ruxolitinib (n = 115) % All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Diarrhea Peripheral edema Asthenia Nasopharyngitis Dyspnea Nausea Cough Weight increased Pyrexia Fatigue Arthralgia Pain in extremity Headache Abdominal pain Bronchitis Back pain Urinary tract infection Muscle spasms AEs regardless of study drug relationship occurring > 28 days after discontinuation of study medication are not summarized. Summaries are based on randomized and extension phase for patients randomized to ruxolitinib and on randomized phase only for patients randomized to BAT.

39 Aids to decision making in selection of initial therapy (drug therapy vs HCT) in patients with MF. Gupta V et al. Blood 2012;120: by American Society of Hematology Th. Sliwa 2013

40 Platelet Counts Over Time No new decreases in platelet counts were observed with longer exposure to ruxolitinib Randomized Phase (n = 146) Ruxolitinib Randomized + Extension Phases (n = 146) Randomized Phase (n = 73) BAT After Crossover to Ruxolitinib (n = 45) n % n % n % n % Grade Grade Grade Grade n = number of patients who had a lower grade at baseline. Missing baseline values were excluded. Patients are counted only for the worst grade observed postbaseline. Laboratory assessments performed more than 28 days after the discontinuation of study treatment are not summarized. 40

41 Hemoglobin Levels Over Time Mean Hemoglobin (g/l) Ruxolitinib BAT Week Ruxolitinib n = BAT n = Mean hemoglobin levels in the ruxolitinib arm reached a nadir at week 12, then increased to levels similar to those in the BAT arm from week 24 onward 41 Note: Only scheduled visits are included; ruxolitinib randomized arm includes both the randomized and extension phases.

42 Red Blood Cell Transfusions Percentage of Patients Receiving PRBC Transfusions Ruxolitinib BAT Weeks Ruxolitinib n = BAT n = Transfusion data is from the randomized treatment phase only.

43 Mean Platelet Counts Over Time Platelet counts remain stable with longer-term therapy Mean Percentage Change From Baseline Ruxolitinib Placebo -60 BL Weeks Median platelet count at baseline: Ruxolitinib, /L; Placebo, /L. Th. Sliwa 2013

44 Efficacy, Hematologic Effects, and Dose of Ruxolitinib in Myelofibrosis Patients with Low Starting Platelet Counts ( /L): A Comparison to Patients With Normal or High Starting Platelet Counts Talpaz M, 1 Paquette R, 2 Afrin L, 3 Hamburg S, 4 Jamieson K, 5 Terebelo H, 6 Ortega G, 7 Lyons RM, 8 Tiu R, 9 Winton E, 10 Natrajan K, 11 Odenike O, 12 Peng W, 13 O Neill P, 13 Erickson-Viitanen S, 13 Leopold L, 13 Sandor V, 13 Levy R, 13 Kantarjian H, 14 and Verstovsek S 14 1 University of Michigan, Ann Arbor, MI, USA; 2 UCLA Division of Hematology/Oncology, Los Angeles, CA, USA; 3 Medical University of South Carolina, Charleston, SC, USA; 4 Tower Cancer Research Foundation, Beverly Hills, CA, USA; 5 University of Iowa College of Medicine, Iowa City, IA, USA; 6 Newland Medical Associates, Southfield, MI, USA; 7 Mid-Florida Hematology & Oncology Associates, Orange City, FL, USA; 8 Cancer Care Centers of South Texas/US Oncology, San Antonio, TX, USA; 9 Cleveland Clinic, Cleveland, OH, USA; 10 Emory University School of Medicine, Atlanta, GA, USA; 11 Medical College of Georgia Research Institute, Augusta, GA, USA, 12 University of Chicago, Chicago, IL, USA; 13 Incyte Corporation, Wilmington, DE, USA; 14 University of Texas MD Anderson Cancer Center, Houston, TX, USA 44

45 Background Ruxolitinib, a JAK1/JAK2 inhibitor, has demonstrated clinical benefit in patients with myelofibrosis in the phase III COMFORT studies 1,2 Significant reductions in spleen volume and significant improvements in MFrelated symptoms and quality of life 1,2 Associated with improved survival relative to placebo (COMFORT-I) and best available therapy (COMFORT-II) 1,3,4 Thrombopoietin and erythropoietin signal exclusively through JAK2 Dose-dependent thrombocytopenia and anemia during ruxolitinib therapy are expected Thrombocytopenia and anemia that occurred during the COMFORT studies were manageable and rarely led to treatment discontinuation Starting doses in the COMFORT trials depended on baseline platelet count: /L: starting dose 15 mg BID > /L: starting dose 20 mg BID 1) Verstovsek S, et al. N Engl J Med 2012;366: ; 2) Harrison C, et al. N Engl J Med 2012;366: ; 3) Verstovsek S, et al. ASH 2012 Annual Meeting Abstract 800; 4) Cervantes F, et al. ASH 2012 Annual Meeting Abstract

46 Study Design 24-week, open-label phase II study (Study 258; NCT ) Inclusion criteria Primary, post-polycythemia vera, or post-essential thrombocythemia MF with symptoms Platelet count: /L Intermediate-1, intermediate-2, or high risk MF according to DIPSS 1 Assessments Spleen volume by MRI or CT: Baseline and week 24 Spleen palpation: Each study visit Modified MFSAF v2.0: Daily Patients rated night sweats, itching, abdominal discomfort, pain under ribs on left side, early satiety, bone/muscle pain, and inactivity (0=absent; 10=worst imaginable) Total Symptom Score (TSS) is the average of the daily sum of individual symptom scores over time (baseline: 7 days; Week 24: 28 days) except inactivity EORTC QLQ-C30: Baseline and weeks 4, 12, and 24 PGIC: Every study visit starting at week 4 DIPSS, Dynamic International Prognostic Scoring System; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; MFSAF, Myelofibrosis Symptom Assessment Form; PGIC, Patient Global Impression of Change. 1) Passamonti F, et al. Blood 2010;115:

47 Dosing Schedule All patients begin at 5 mg BID All dose increases are optional 5 mg BID 5 mg AM/ 10 mg PM 10 mg BID 10 mg AM/ 15 mg PM 15 mg BID In addition to adequate platelet count and ANC, further dose increases above 10 mg BID require PGIC score of 3 (minimally improved) to 7 (very much worse) Baseline (Day 7) Weeks on Study Dose reductions required for platelet count /L to < /L Dose interruptions required for platelet count < /L, ANC < /L, or Grade 2 active hemorrhage (regardless of causality) Dosing could be restarted or re-escalated when platelet count was /L ANC, absolute neutrophil count. 47

48 Patient Disposition 41 patients have available data a the time of this interim analysis (median exposure: 22 weeks) 19 patients completed 24 weeks of ruxolitinib therapy 16 patients have not yet completed the week 24 visit and remain on study 6 patients discontinued before week 24 Death (n=1) Consent withdrawn (n=2) Disease progression (n=2) Other (n=1) 48

49 Baseline Characteristics in Study 258 and COMFORT-I Baseline Parameter Study 258 Ruxolitinib (N=41) COMFORT-I Ruxolitinib (n=155) COMFORT-I Placebo (n=154) Median age (range), years 69 (44 91) 66 (43 91) 70 (40 86) MF subtype, % of patients Primary MF Post-polycythemia vera MF Post-essential thrombocythemia MF Previous hydroxyurea use, % of patients Mean platelet count 10 9 /L Mean hemoglobin in patients with no transfusions, g/l Mean Total Symptom Score Median spleen length (range), cm 15 (0 32) 16 (0 32) 16 (5 34) Median spleen volume (range), cm 2235 ( ) 2598 ( ) 2566 ( ) 49

50 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 / BID 15 BID 10 BID 10 / / 15 5 / BID 10 BID 5 BID 5 / BID 5 BID 5 / 10 5 / 10 5 BID 5 BID 5 BID 5 BID n=41 n=36 n=31 n=28 n=25 n=17 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. 50

51 Changes in Total Symptom Score and Spleen Volume in Individual Patients at Week 24 Total Symptom Score* Spleen Volume* Majority of patients experienced TSS improvements and spleen volume reductions 36.4% had 50% improvement in TSS 33.3% had 35% reduction in spleen volume *Patients included in the figure completed the week 24 assessment. For the responder analysis, patients who discontinued before week 24 were considered nonresponders for all study visits that they would have completed up to the date of analysis. 51

52 Conclusions For patients with baseline platelet counts of /L, starting at a dose of 5 mg BID and titrating to 10 mg BID or greater resulted in spleen volume reductions and improvements in symptoms and QoL that were consistent with COMFORT-I Decreases in mean Hgb were of lesser magnitude compared with ruxolitinibtreated patients in COMFORT-I Changes in mean platelet count were similar to patients receiving placebo in COMFORT-I These findings suggest that titration to 10 mg BID may be an effective and well tolerated approach for patients with MF starting with or developing low Hgb or platelet count, while higher doses are beneficial for patients with higher Hgb and platelet count and those with inadequate response to 10 mg BID 52

53 Mean Platelet Counts Over Time Platelet counts remain stable with longer-term therapy Mean Percentage Change From Baseline Ruxolitinib Placebo -60 BL Weeks Median platelet count at baseline: Ruxolitinib, /L; Placebo, /L. Th. Sliwa 2013