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JAK inhibitors update from ASH

JAK inhibitors update from ASH. Claire Harrison Guy’s and St Thomas’ Hospitals London. Ruxolitinib demonstrated >100-fold selectivity against a broad panel of kinases. INCB18424 - Ruxolitinib – a JAK 1 and 2 inhibitor. Structure and activity in biochemical and cellular assays.

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JAK inhibitors update from ASH

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  1. JAK inhibitors update from ASH Claire Harrison Guy’s and St Thomas’ Hospitals London

  2. Ruxolitinib demonstrated >100-fold selectivity against a broad panel of kinases INCB18424 - Ruxolitinib – a JAK 1 and 2 inhibitor Structure and activity in biochemical and cellular assays Quintás-Cardama et al. Blood 2010;115:3109–17.

  3. COMFORT: Phase 3 trials with ruxolitinib (INCB018424) COntrolled MyeloFibrosis study with ORal JAK inhibitor Therapy Verstovsek S N Engl J Med. 2012;366:799-807; Harrison C et al. N Engl J Med. 2012;366:787-798

  4. COMFORT-I Primary Endpoint: % of Patients With ≥35% Decrease in Spleen Volume at Week 24 • Patients who discontinued prior to week 24 or crossed over prior to week 24 were counted as non-responders 5

  5. 40 20 0 -20 -40 -60 -80 COMFORT-I and COMFORT-IIComparison of Spleen Volume Reductions COMFORT-I At Week 24a COMFORT-II At Week 48a P < .0001 P < .0001 Change From Baseline, % Change From Baseline, % 35% decrease Ruxolitinib Ruxolitinib aPrimary endpoint; bKey secondary endpoint.

  6. Ruxolitinib BAT JAK2V617F positive (n = 75) JAK2V617F positive (n = 24) JAK2V617F negative (n = 22) JAK2V617F negative (n = 8) Unknown mutation status (n = 1) Unknown mutation status (n = 2) Percent Change From Baseline in Spleen Volume by JAK2V617F Mutation Status At Week 48a Change From Baseline, % Primary endpoint • At week 48, the vast majority of patients receiving ruxolitinib experienced spleen volume reductions, including JAK2V617F-positive (88% [66/75]) and JAK2V617F-negative (91% [20/22]) patients 12 Harrison CN,. Blood (ASH) 2011:Abstract 279. a For patients with spleen volume assessments by MRI/CT at both baseline and week 48.

  7. Total Symptom Score: Modified MFSAF v2.0 • Questions 1 to 6 comprise Total Symptom Score • Question 7 queries inactivity, an impact of MF • Administered daily 8 Mesa RA, et al. Leukemia Res. 2009;33:1199-1203.

  8. Ruxolitinib Placebo Worsening Mean % Change From Baseline n=100 n=86 n=96 n=90 n=77 n=89 n=97 n=124 n=109 n=122 n=103 n=98 n=108 n=119 Improvement Abdominaldiscomfort Pain underleft ribs Earlysatiety Nightsweats Itching Bone/musclepain Inactivity Mean % Change in Individual Symptoms • For all individual symptoms above, comparisons between ruxolitinib- and placebo-treated groups were highly statistically significant (P < 0.01) 9

  9. Anemia and Thrombocytopenia • The majority of patients (63% ruxolitinib; 67% BAT) had grade 1/2 anemia at baseline • In both arms, all patients who entered the study had grade 0-1 thrombocytopenia at baseline • Discontinuations: 1 patient in each arm due to thrombocytopenia and 1 patient due to anemia on the ruxolitinib arm

  10. Diarrhea BAT (n = 73) All grades Grades 3/4 Pain in extremity Headache Pruritus Nonhematologic Adverse Events Regardless of Study Drug Relationship (≥ 10% in Any Group) COMFORT-II Ruxolitinib (n = 146) All grades Grades 3/4 Nausea

  11. No serious adverse effects on dose interruption……. 12

  12. 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 Srdan Verstovsek1, Ruben A. Mesa2, Jason Gotlib3, Richard S. Levy, Vikas Gupta5, John F. DiPersio6, John V. Catalano7, Michael W.N. Deininger8*, Carole B. Miller9, Richard T. Silver10, Moshe Talpaz11, Elliott F. Winton12, Jimmie H. Harvey Jr.13, Murat O. Arcasoy14, Elizabeth O. Hexner15, Roger M. Lyons16, Ronald Paquette17, Azra Raza18, Kris Vaddi4, Susan Erickson-Viitanen4, William Sun4, Victor Sandor4 and Hagop M. Kantarjian11University of Texas MD Anderson Cancer Center, Houston, TX; 2Mayo Clinic, Scottsdale, AZ; 3Stanford Cancer Institute, Stanford, CA; 4Incyte Corporation, Wilmington, DE; 5Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada; 6Washington University School of Medicine, St. Louis, MO; 7Frankston Hospital and Department of Clinical Haematology, Monash University, Frankston, Australia; 8Oregon Health & Science University, Portland, OR; 9Saint Agnes Cancer Institute, Baltimore, MD; 10Weill Cornell Medical Center, New York, NY; 11University of Michigan, Comprehensive Cancer Center, Ann Arbor, MI;12Emory University School of Medicine, Atlanta, GA; 13Birmingham Hematology and Oncology, Birmingham, AL; 14Duke University Health System, Durham, NC; 15Abramson Cancer Center at The University of Pennsylvania, Philadelphia, PA; 16Cancer Care Centers of South Texas/US Oncology, San Antonio, TX; 17UCLA Division of Hematology/Oncology, Los Angeles, CA; 18Columbia Presbyterian Medical Center, New York, NY*Currently at Division of Hematology and Hematologic Malignancies and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT

  13. 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.

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

  15. 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 Overall Survival: ITT Population 1.0 0.8 Ruxolitinib Placebo 0.6 HR=0.58 (95% CI: 0.36, 0.95); P=0.028 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=0.040 0 0 12 24 36 48 60 72 84 96 108 120 132 Weeks 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;366:799-807 (median age: ruxolitinib, 66 years; placebo, 70 years; P<0.05).

  16. BL 12 24 36 48 60 72 84 96 Weeks Mean Platelet Counts Over Time • Platelet counts remain stable with longer-term therapy 10 Ruxolitinib Placebo 0 -10 -20 Mean Percentage Change From Baseline -30 -40 -50 -60 Median platelet count at baseline: Ruxolitinib, 262.0×109/L; Placebo, 238.0×109/L.

  17. 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 Francisco Cervantes,1 Jean-Jacques Kiladjian,2 Dietger Niederwieser,3 Andres Sirulnik,4 Viktoriya Stalbovskaya,5 Mari McQuitty,4 Deborah S. Hunter,6 Richard S. Levy,6 Francesco Passamonti,7 Tiziano Barbui,8 Giovanni Barosi,9 Heinz Gisslinger,10 Alessandro M. Vannucchi,11 Laurent Knoops,12 Claire N. Harrison13 1Hospital Clínic, IDIBAPS, Barcelona, Spain; 2Hôpital Saint-Louis et Université Paris Diderot, Paris, France; 3University of Leipzig, Leipzig, Germany; 4Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 5Novartis Pharma AG, Basel, Switzerland; 6Incyte Corporation, Wilmington, DE, USA; 7Ospedale di Circolo e Fondazione Macchi, Varese, Italy; 8A.O. Ospedali Riuniti di Bergamo, Bergamo, Italy; 9IRCCS Policlinico San Matteo Foundation, Pavia, Italy; 10Medical University of Vienna, Vienna, Austria; 11University of Florence, Florence, Italy; 12Cliniques Universitaires Saint-Luc and de Duve Institute, Université catholique de Louvain, Brussels, Belgium; 13Guy’s and St. Thomas’ NHS Foundation Trust, London, UK

  18. Duration of Spleen Response Loss of response: no longer a ≥ 35% reduction that is also a > 25% increase over nadir. 1.0 0.9 Ruxolitinib 0.8 0.7 0.6 Probability of Maintaining Spleen Response 0.5 0.4 0.3 Ruxolitinib BAT 0.2 No. of Patients Events Censored 70 18 (25.7%) 52 (74.3%) 1 0 1 (100%) 0.1 0.0 0 12 24 36 48 60 72 84 96 Weeks • 58% of patients maintain a response at week 84 • The median duration of spleen response has not yet been reached 19

  19. Ruxolitinib BAT Ruxolitinib No. of Patients Events Censored 146 20 (13.7%) 126 (86.3%) 73 16 (21.9%) 57 (78.1%) BAT Overall Survival 1.0 0.9 0.8 0.7 0.6 Probability 0.5 0.4 0.3 0.2 n = 0.1 146 136 127 116 109 30 0 73 61 51 49 45 11 0 0.0 0 24 48 72 96 120 144 Weeks • Suggests a relative reduction in the risk of death with ruxolitinib compared with BAT (HR = 0.51; 95% CI: 0.26-0.99) 20

  20. Biological effects beyond spleen and symptoms?

  21. Subjects With ≥ 20% Absolute Allele Burden Reduction at Week 48 or Week 72 PET 80 PMF PPV 60 JAK2 V617F Allele Burden (%) 40 20 0 0 6 12 24 48 72 84 96 Time (weeks) • Among patients who achieved a ≥ 20% reduction in allele burden, 39% had PMF, 39% had PPV-MF, and 22% had PET-MF • This distribution was similar to that of the overall study population

  22. N = 16 24 14 15 N = 9 23 8 13 Responders (≥ 35% Spleen Volume Reduction at Week 48) by Absolute Allele Burden Reduction Status % % % Percentage of Responders in Each Allele Burden Reduction Group % % % % % • In the ruxolitinib arm, a higher proportion of patients with a ≥ 20% allele burden reduction achieved a ≥ 35% reduction in spleen volume compared with those with a < 10% reduction at both week 48 and week 72 • There were no responders in the BAT arm

  23. Phase 3 COMFORT studies • First phase 3 studies in MF • Highly significant reduction of spleen volume and resolution of disabling symptoms • Median duration of response NOT reached • BOTH studies demonstrate survival advantage • Effective regardless of JAK V617F status • Anaemia and thrombocytopenia occur but no increase in grade 4 • No new safety features including no AEs related to discontinuation after 2 year update

  24. Spleen Reduction by Palpation on Ruxolitinib Implies Survival Advantage Patients with a confirmed reduction >50% of spleen size had better survival than those with <25% Verstovsek et al, ASH 2011 abstract 3851

  25. Exploring different strategies for use of JAK inhibitors • Earlier disease? • Other drugs? • Combination strategies?

  26. Courtesy of Ruben Mesa

  27. Trials with Other JAK2 Inhibitors in MF Pardanani et al. JCO 2011; 29:789-96. Pardanani et al. Blood 201; 116:206 (abstract) 28

  28. SAR302503 Phase III Study Design Multinational, multicenter, double blind, placebo-controlled randomized study Q 4 weeks SAR302503 500mg Daily oral doses RANDOMIZ A TION 75 pts - Intermediate-2 or High risk Primary MF • Post-Polycythemia Vera Myelofibrosis • Post-Essential Thrombocythemia Myelofibrosis End of C6 Q 4 weeks SAR302503 400mg Daily oral doses 75 pts Cross over 1/1 EOT No Stratification factor Randomization 1/1/1 Q 4 weeks Placebo Daily oral doses 75 pts End of C6 or PD • 225 pts, Sites ~125, Recruitment: 9 months, 25 countries • Safety data monitored by DMC (Q 6 months) • Cross over possible 03/03/13 30

  29. SAR302503 Phase II Study Design: ARD12181JAKARTA 2 Phase 2, single arm, multicenter, open-label study • Subjects who previously received Ruxolitinib treatment for PMF or Post-PV MF or Post-ET MF or PV or ET for at least 14 days and discontinued the treatment for at least 14 days prior to study entry • Intermediate or High risk Primary MF • Post-Polycythemia Vera Myelofibrosis Post-Essential Thrombocythemia Myelofibrosis according to the 2008 World Health Organization (WHO) criteria Recent amendment changing discontinuation period from 30 days to 14 days 70 pts Dose regimen • SAR302503 once daily, • Starting dose: 400mg/day • Continuously in 28-day cycles • Titration allowed: 200mg, 300mg, 400mg, 500mg or 600mg • Primary endpoint: • % of patients who achieve ≥35% reduction in spleen volume from baseline at C6 EOC by MRI/CT. • Secondary endpoint: • - % of subjects with a ≥50% reduction from baseline to the end of Cycle 6 in the total symptom score using the modified MFSAF • Safety, PK/PD, JAK2V617F allele burden, JAK-STAT and other signaling pathways, OS 32

  30. Country participation 10 Countries – 50 Sites – 70 patients • 26 Subjects Enrolled at 12 sites (6 Countries) • 23 Subjects under treatment  Data cut off: December, 4

  31. Exploring different strategies for use of JAK inhibitors • Earlier disease? • Other drugs? • Combination strategies? Rationale • To reduce unwanted side effects (anaemia, thrombocytopenia) without compromising response • To increase or broaden the benefits seen with JAK inhibitors

  32. Potential combination strategies

  33. Panobinostat & Ruxolitinib Combo in mouse models of JAK2V617F-driven diseaseEffects on bioluminescence Baffert eta al Blood 2011, Abstract 798, ASH 201 Panobinostat & Ruxolitinib Combo in MF patientsPhase Ib design 37

  34. Combination with BMT?? - Splenomegaly is a negative risk factor for survival after Allo-BMT- Significant improvement in performance status rapid onset no major problem with drug withdrawal i.e. patients are fitterFavourable effects upon cytokine storm and potential effects upon GVHD

  35. Current MPN Trials in the UK Academic -open • PT-1 amended • Low risk • Intermediate risk closed expect results next year • MAJIC for HC resistant PV and ET • PEGASYS vs HC for newly diagnosed ET or PV Unfunded but in process • JAKi pre-BMT • SAR302503 + HDAC • Ruxolitinib + azacytadine in sAML

  36. Trials • SAR302503 JAKARTA phase 3 –------ Closed UK highest recruiter In ET/PV phase 2; 8 sites selected just reopening JAKARTA-2 in MF resistant of intolerant to ruxolitinib • Pacritinib SB1518 – PERSIST 1 and 2 Vs placebo in MF no lower limited for platelets count prior ruxolitinib allowed. • ?? CYT 387 phase III

  37. In Myelofibrosis • Phase 1 ruxolitinib MF low platelets • Phase 1 ruxolitinib PLUS panobinostat Phase 1 ruxolitinib PLUS PI3 kinase inhibitor • Phase 1 ruxolitinib PLUS smoothened inhibitor • To come smoothened inhibitor alone

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