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Disclosures for James B. Bussel, MD

Disclosures for James B. Bussel, MD. N/A = Not Applicable (no conflicts listed) Presentation includes discussion of the following off-label use of a drug or medical device: YES. ITP. Clinical Trials in ITP at Cornell. IVIG 1981-- 1983

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Disclosures for James B. Bussel, MD

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  1. Disclosures for James B. Bussel, MD N/A = Not Applicable (no conflicts listed) Presentation includes discussion of the following off-label use of a drug or medical device: YES

  2. ITP

  3. Clinical Trials in ITP at Cornell • IVIG 1981--1983 • Importance of FcR blockade in 1984-86 using a Monoclonal anti-FcRIII • IV anti-D in 1987--1991 • Anti-CD40 Ligand in 1999-2007 • Rituximab in 2000--2004 • Thrombopoietic Agents in ITP 2002-06 • Rigel935788 Syk Inhibitorin2005---2009

  4. ABT-737 induces thrombocytopenia in mice ABT-737 vehicle ABT-737 Mason et al. 2007 Cell 128:1173

  5. The ‘molecular clock’ model of platelet life span 1. Platelet survival requires Bcl-xL 2. Bcl-xL restrains Bak (and Bax) 3. Bcl-xL degrades more quickly than Bak or Bax 4. As Bcl-xL levels decline, a threshold is reached 5. Bak/Bax are unleashed Mason et al. 2007 Cell 128:1173

  6. Effect on the Platelet Count of Plasma : ITP into Normal 1000 800 600 400 200 Disease incidence (thousands) 1 2 3 1 2 3 4 5 6 7 8 9 Hours Days Harrington WJ, et al. J. Lab Clin Med. 1951;38:1-10.

  7. Platelet Production Is Suboptimal in ITP Patients Autoantibodies inhibit Mk growth and promote apoptosis (Chang, McMillan) Autologous 111In-platelet studies show platelet production < normal in 2/3 pts----same results with absolute platelet retics TPO levels normal in 75% of ITP patients (relative TPO deficiency) Damaged or Dysfunctional Mk in marrow (Houwerijl)

  8. Pathophysiology of ITP Macrophage P Thrombo-poietin Peripheral blood P P Bone marrow P Platelet Megakaryocyte

  9. Cines DB, Blanchette VS. N Engl J Med. 2002;346:995-1008.

  10. Human Fcg Receptors: Extracytoplasmic region Cell membrane Fcg Receptor I (CD64) Fcg Receptor IIA (CD32) Fcg Receptor IIIB (CD16b) Fcg Receptor IIB (CD32) Fcg Receptor IIIA (CD16a) Natural Killer Cells Macrophages Eosinophils Mast Cells Neutrophils Macrophages B Cells Mast Cells Neutrophils Macrophages Eosinophils Platelets Neutrophils Macrophages Eosinophils Adapted from: Kazatchkine MD, Kaveri SV. N Engl J Med. 2001;345:747-755.

  11. Interference with FcR-Mediated Platelet Destruction • IVIG NEJM 1982, Blood 1983 • IV anti-D Lancet 1983 • Monoclonal anti-FcRIII NEJM 1986 • Fc piece of IgG Lancet 1993 • Syk inhibitor Blood 2009

  12. Combination Therapy (SM-IgG-anti-D-VCR) in Adults With ITP 100 90 80 (21) 70 (14) 60 Median platelet count (x103/mL) 50 (20) 40 30 (23) 20 10 0 1 2-5 6-10 11-17 Study day

  13. Of Mice and Men: an Open Label Pilot Study for Treatment of ImmuneThrombocytopenic Purpura (ITP) by an Inhibitor of Syk Anna Podolanczuk, Alan H. Lazarus, Andrew R. Crow, Elliot Grossbard, James B. Bussel Blood February 2009

  14. “Wet” Purpura

  15. Acute Platelet Increase • gold standard: IVIG at 1 gm/kg • IV anti-D: as fast as IVIG at 75 mcg/kg • Steroids: IV solumedrol 30/kg, high dose dexamethasone or Prednisone 2-4/kg • Platelet transfusions • Combinations including Steroids, IVIG, IV anti-D and/or vincristine

  16. High Dose Dexamethasone at Diagnosis in Patients with ITP • Potentially useful in adults near diagnosis of ITP • Unclear how many cycles are optimal or if they can be “individualized” • Study at ASH on addition of rituximab to one cycle of dexamethasone------promising but ? overkill

  17. Diagnosis of ITP Failure to respond to 1st line therapies: glucocorticoids, IVIG, IV Anti-D Other alternative diagnoses to consider Inherited thrombocytopenias e.g. MYH9-RD MDS CLL PNH TTP Immuno-logical disorders: SLE Evans Syndrome ALPS CVID Infections: Hepatitis C HIV H pylori CMV Drugs: Heparin Quinidine Valproic acid Oestrogen Investigations for alternative/exacerbating causes of thrombocytopenia Therapeutic options for persistent thrombocytopenia requiring treatment Conventional therapies Emerging therapies Splenectomy / accessory splenectomy Danazol Multi-agent therapya Immunosuppressive therapy (azathioprine, mycophenalate mofetil, vinca alkaloids, cyclosporin A, dapsone) Repeated IVIG or IV anti-D infusions Rituximab Chronic low-dose corticosteriods Cytotoxic chemotherapy (cyclophosphamide) TPO-receptor agonists

  18. Diagnosis of ITP Prednisone Splenectomy ???

  19. Diagnosis of ITP Pred/Dex + IVIG or Anti-D Rituximab Splenectomy ???

  20. Diagnosis of ITP Pred/Dex + IVIG or Anti-D Rituximab Splenectomy Thrombopoietic Agents

  21. Thrombopoietin and Thrombopoietic Agents

  22. Status of Thrombopoietic Agonists in Active ITP Clinical Trial AMG531 ----pivotal studies completed---filed with FDA 2007 ---ODAC 3/12/08 vote: 11-0-----licensed in US August 25th 2008--approved by EMEA for splenectomized patients only Eltrombopag ----pivotal studies completed----filed with FDA 2007---ODAC 5/30/08 vote: 16-0-----licensed in US November 19th 2008--at EMEA AKR501----initial study in ITP completed LGB4665 -----initial study in ITP completed ODAC = Oncology Drug Advisory Committee

  23. AMG531 Romiplostim NPlate ? Other in Europe Eltrombopag Promacta Revolade in Europe The TPO-R Agonists Have Multiple Names

  24. TPO Agonist TPO Agonist Fc Fc Carrier Domain Carrier Domain Peptides Peptides AMG 531 • Unique platform “peptibody” • Made in E. coli • Molecular weight = 60,000 D • 4 Mpl binding sites • No sequence homology with TPO • Cleared endothelial FcRn • Recycled • Cleared RES Bussel JB et al. N Engl J Med. 2006;355:1672.

  25. Eltrombopag: Oral Platelet Growth Factor • Small molecule, non-peptide thrombopoietin receptor (TPO-R) agonist • Does not compete with TPO for binding to TPO-R • Low immunogenic potential • Active only in humans, chimps • Stimulates megakaryocyte proliferation and differentiation • Orally bioavailable • Increases platelet counts in normal volunteers Eltrombopag MW 442 Thrombopoietin MW 64,000

  26. Potential and Real Adverse Consequences of Thrombopoietic Growth Factors Thrombocytosis Thrombosis Stimulation of tumor growth Stimulation of leukemia cell growth-A Interactions with other cytokines Cataracts-E Abnormal LFTs-E Autoantibody formation-A Stem cell depletion Reduction in threshold for platelet activation Rebound worsening of thrombocytopenia Increased bone marrow reticulin Headache

  27. Figure 3. Peak Individual Platelet Counts in Phase 1. The baseline platelet count and the peak platelet count after dose 1 and dose 2 are shown. There were four patients in each dose cohort. Three patients did not receive a second dose. The shaded area shows the targeted platelet range. Platelet counts associated with the use of rescue medication have been excluded.

  28. Romiplostim Phase 3 Trials in Chronic ITP RANDOM I ZAT I ON S C R E E N I N G P R E T R E A T M EN T E N D O F TR E A T M E N T P LAT E L E T FOL LOW UP 24-Week Treatment Period Romiplostim or Placebo (2:1) 1 µg/kg starting doseIndividual dose adjustment based on platelet count weeks 2–24 Reductions in concurrent ITP therapiesallowed when platelet counts > 100 x 109/L Rescue Medications Allowed prn Study Week 1 Study Week Day–8 25 26–36 Romiplostim Administered SC weekly First Dose • Identical trials in splenectomized and nonsplenectomized ITP patients • All patients eligible for open-label extension

  29. Romiplostim SPLEN: 38% Durable and 79% Overall Response Placebo 20 Romiplostim 15 10 5 0 Overall Response Number of Weeks Platelet Response DurableResponse 100 100 78.6 80 80 12.3 (1.2) 60 60 Durable Platelet Response (%) Mean (SE) Number of Weeks With Platelet Response Overall Platelet Response (%) 38.1 40 40 20 20 0.2 (0.1) 0.0 0.0 0 0 (P < 0.0001) (P = 0.0013) (P < 0.0001) Platelet response: platelet count ≥ 50 x 109/L Durable platelet response: platelet response for ≥ 6 weeks of final 8 weeks,in the absence of rescue medications during 24 week trial Overall response: either durable or transient platelet response (≥ 4 weekly platelet responses) Error bars represent standard deviation of the mean

  30. Romiplostim NOT SPLEN: Durable and Overall Response 20 15 10 5 0 Durable Response Overall Response Number of Weeks Platelet Response 100 100 87.8 15.2 (1.2) 80 80 61.0 60 60 Durable Platelet Response (%) Mean (SE) Number of Weeks With Platelet Response Overall Platelet Response (%) 40 40 1.3 (0.8) 20 20 14.3 4.8 0 0 (P < 0.0001) (P < 0.0001) (P < 0.0001) Placebo Romiplostim Platelet response: platelet count ≥ 50 x 109/L Durable platelet response: platelet response for ≥ 6 weeks of final 8 weeks; no rescue medications during 24 week treatment Overall response: either durable or transient platelet response (≥ 4 weekly platelet responses) Error bars represent standard deviation of the mean

  31. Long-term Dosing of AMG 531 in Thrombocytopenic Patients With Immune Thrombocytopenic Purpura: 4-Year Update James B Bussel,1 David J Kuter,2 Joost ThM de Wolf,3 Troy H Guthrie, Jr,4 Adrian Newland,5 Jeffrey S Wasser,6 Solomon I Hamburg,7 Lara Bjorkquist,8Matthew Guo,8 Janet L Nichol8 1Weill Cornell Medical Center, New York, NY; 2Massachusetts General Hospital, Boston, MA; 3University Medical, Center, Groningen, Netherlands; 4Baptist Cancer Institute/University of Florida, Jacksonville, FL; 5Barts & the London, Queen Mary School of Medicine, London, United Kingdom; 6DeQuattro Community Cancer Center, Manchester, CT; 7Tower Cancer Research Foundation, Los Angeles, CA; 8Amgen Inc., Thousand Oaks, CA Blood March 2009

  32. Mean Platelet Count and Romiplostim Dose Over 204 Weeks 300 250 Mean (SE) Platelet Count x 109/L 200 150 100 50 0 10 8 Mean (SD) Dose (µg/kg) 6 4 Mean Dose 2 0 1 4 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 160 168 176 184 192 200 Study Week n = 212 183 160 146 136 123 118 112 108 103 99 96 86 70 62 58 48 34 26 21 22 21 17 14 12 6 n is the number of patients with available platelet counts, excluding those who received rescue medications.Platelet counts within 8 weeks after receiving any rescue medications were excluded.

  33. Platelet Response Durability:Consecutive Weeks With Platelet Counts≥ 50 x 109/L 100 90 77% 80 67% 70 60 Proportion of Patients (%) 50 41% 40 30 20 10 0 ≥ 52Consecutive Weeksn = 116 ≥ 25 Consecutive Weeksn = 141 ≥ 10 Consecutive Weeksn = 164 n = number of patients receiving romiplostim for ≥ 5 additional weeks to the number of consecutive weeks counted

  34. TPO Non-peptide Agonists Eltrombopag AKR-501 LGB4665

  35. Studies of Eltrombopag (Promacta) in ITP • 773a----NEJM 11/07 • 773b----Lancet 2/21/09 • RAISE---completed • EXTEND----ongoing • REPEAT----completed • Pediatric Study to start soon

  36. Eltrombopag Increases Platelet Counts and Reduces Bleeding During Treatment of Chronic Idiopathic Thrombocytopenic Purpura (ITP): A Randomized, Double Blind, Placebo-controlled Study James B. Bussel,1 Drew Provan,2 Tahir Shamsi,3 Gregory Cheng,4 Bethan Psaila,1,5 Lidia Kovaleva,6 Abdulgabar Salama,7 Julian M. Jenkins,8 Debasish Roychowdhury,8 Bhabita Mayer,9 Nicole Stone,8 Michael Arning8 LANCET 2/21/09

  37. Phase II Primary Endpoint: Percentage of Patients With Platelet Count Increase to 50,000/µL From a Baseline Count 30,000/µL At Day 43 (LOCF) 100 90 P <0.001* OR = 38.82 (7.62, 197.73) 80 P <0.001* OR = 21.96 (4.72, 102.23) 81% 21/26 70 70% 19/27 Responders (%) 60 50 40 P = 0.07 OR = 3.09 (0.69, 13.75) 30 28% 20 8/29 11% 10 3/27 8/29 19/27 21/26 3/27 0 Eltrombopag Eltrombopag Placebo Eltrombopag 30 mg 50 mg 75 mg *1-sided P value, indicates significance under the closed testing procedure.LOCF, last observation carried forward; OR, odds ratio; treatment/placebo. Logistic regression analysis adjusted for randomization stratification variables. NEJM 11/29/07

  38. Primary Endpoint: Percentage of Patients With Platelets ≥50,000/µL at Day 43 Visit† P <0.001‡OR = 9.61 (3.31, 27.86) Responders (%) Placebo§ Eltrombopag †Last observation carried forward. ‡Indicates significance at 5% (2-sided) level of significance.§1 patient received IVIg on Day 1. Logistic regression analysis adjusted for randomization stratification variables.

  39. Mean (SE) Change from baseline platelet counts at each week of therapyEfficacy Population - LOCF

  40. Oral Eltrombopag for the Long-term Treatment of Patients With Chronic Idiopathic Thrombocytopenic Purpura: Results of a Phase III, Double-blind, Placebo-controlled Study (RAISE) Gregory Cheng,1 Mansoor N. Saleh,2 James B. Bussel,3 Claus Marcher,4 Sandra Vasey,5 Bhabita Mayer,6 Manuel Aivado,5 Michael Arning,5 Nicole L. Stone5 1Chinese University of Hong Kong, Shatin, NT, Hong Kong; 2Georgia Cancer Specialists, Atlanta, GA, United States; 3Weill-Cornell Medical College of Cornell University, New York, NY, United States; 4Odense University Hospital, Odense, Denmark; 5GlaxoSmithKline, Collegeville, PA, United States; 6GlaxoSmithKline, Stockley Park, Middlesex, United Kingdom. Presented at the 50th Annual Meeting of the American Society for Hematology (ASH), December 6-9, 2008, San Francisco, CA. Study supported by GlaxoSmithKline, Collegeville, PA.

  41. Use of TPO-R Agents in ITP: Questions for the Present and the Future • How fast can one increase the count ? • What is the true rate of response and why do certain patients not respond ? • Do the different agents work in the same patients or are responses different ? • ***Do you give these agents indefinitely or may improvement be seen ? • which treatments are especially useful in combination with TPO-R agonists ?

  42. Diagnosis of ITP Pred/Dex + IVIG or Anti-D Rituximab Splenectomy Thrombopoietic Agents ???

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