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Thrombopoietic Agents for Optimizing Thrombopoiesis

Thrombopoietic Agents for Optimizing Thrombopoiesis. Ilene Weitz, MD Associate Professor of Medicine Jane Anne Nohl Division of Hematology University of Southern California-Keck School of Medicine. Thrombocytopenia: An approach to the differential diagnosis. Platelets <150 x 10 9 /L.

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Thrombopoietic Agents for Optimizing Thrombopoiesis

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  1. Thrombopoietic Agents for Optimizing Thrombopoiesis Ilene Weitz, MD Associate Professor of Medicine Jane Anne Nohl Division of Hematology University of Southern California-Keck School of Medicine

  2. Thrombocytopenia:An approach to the differential diagnosis Platelets <150 x 109/L Medical History Physical examination Are there other cytopenias? Review Blood Smear Differential diagnosis Pseudo- thrombocytopenia Sequestration Splenomegaly Increased destruction Decreased production

  3. Steady State Kinetics: At stable platelet counts: Platelet Destruction = Platelet Production (i.e. turnover) = X

  4. 100 80 60 % platelet - 51Cr injected 40 20 0 0 2 4 6 8 10 12 Days Normal subjects (n=15) Autologous platelet recoveries 65 ± 4% and autologous platelet survivals 9.9 ± 0.6 days. Harker & Finch. J Clin Invest. 1969;48:963-974.

  5. ThrombocytopeniaCauses of increased destruction • Thrombotic thrombocytopenic purpura • atypical Hemolytic uremic Syndrome • Disseminated Intravascular clotting • Drug-induced • Heparin Induced Thrombocytopenia-HIT • Vasculitis • Uncontrolled malignant hypertension • Type IIB von Willebrand’s disease • Immune thrombocytopenic purpura • Rare other: dysfunctional heart valves, dissecting aneurysm, cavernous hemangioma

  6. ThrombocytopeniaCauses of decreased production • Myelodysplasia • Aplastic anemia • Leukemia • Malignancy in the bone marrow • Chemotherapy drugs • Pernicious anemia • Congenital thrombocytopenia: MYH-9 disease In nearly all these circumstances there are abnormalities of other cellular elements of the bone marrow.

  7. Adjunct Treatments reducing thrombocytopenic bleeding • Keep Hemoglobin > 101 • Epsilon amino caproic acid2 • Topical agents 1. El-shahawy, MA, Francis, R, Akmal, M, Massry, SG, Clinical Nephrology 1994; 41(5): 308-13 2. Slichter , SJ, Harker, LA, Clinics in haematology 1978 (0308-2261), 7 (3), p. 523

  8. Thrombopoietin Physiology Kuter DJ et al. Proc Natl Acad Sci USA. 1994;91(23):11104-11108.

  9. Platelet Survival and Production in ITPA Disorder of Decreased Production 1. Harker LA et al. J Clin Invest. 1969;48(6):963-974.2. Ballem PJ et al. J Clin Invest. 1987;80(1):33-40.

  10. Thrombopoietin: Mechanism of Action ThrombopoietinReceptor TPO Active Receptor Inactive Receptor Cell Membrane SHC GRB2 RAS/RAF SOS P P P JAK STAT P Cytoplasm MAPKK p42/44 Signal Transduction Increased Platelet Production

  11. Suppression of Megakaryocyte Production by ITP Plasma 100 75 % Megakaryocytes 50 25 0 ITP-1 ITP-2 ITP-3 ITP-4 ITP-5 ITP-6 ITP-7 ITP-8 ITP-9 ITP-10 ITP-11 ITP-12 McMillan R et al. Blood. 2004;103:1364-1369.

  12. Platelets and Reticulated Platelets in ITP Patients Treated With Thrombopoietin Platelets Reticulated Platelets PEG-rHuMGDF (0.5 µg/kg/d) 1000 10 800 8 600 6 Platelets (x109/L) % Reticulated Platelets 400 4 200 2 0 0 -90 -60 -30 0 7 14 21 28 35 42 49 Days After PEG-rHuMGDF Treatment Nomura S, et al. Blood.2002;100(2):728-730.

  13. 2nd-Generation Thrombopoietic Growth Factors • TPO Peptide mimetics • PEG TPOmp, Romiplostin • TPO Nonpeptide mimetics • Eltrombopag, AKR 501 • TPO Agonist Antibodies

  14. Peptide Receptor Binding Domain FC Carrier Domain • Unique platform peptibody • Expressed in E. coli • Molecular weight = 60,000 D • 4 Mpl binding sites • No sequence homology with TPO • Administered subcu weekly • Cleared endothelial FcRn– Recycled • Cleared RES Romiplostim (AMG 531)

  15. Romilpostin: Mechanism of Action ThrombopoietinReceptor AMG 531 Active Receptor Inactive Receptor Cell Membrane SHC GRB2 RAS/RAF SOS P P P JAK STAT P Cytoplasm MAPKK p42/44 Signal Transduction Increased Platelet Production

  16. Romiplostin: Phase 1 Healthy Subjects Platelet Response was Dose Dependent Aftera Single Subcutaneous Dose 3.2 3.0 Placebo (n=14-16) 2.8 0.3 mcg/kg AMG 531 (n=4) 2.6 1.0 mcg/kg AMG 531 (n=3-4) 2.4 2.0 mcg/kg AMG 531 (n=6-8) 2.2 Fold-Change in Platelet Count 2.0 1.8 1.6 1.4 1.2 1.0 0.8 1 8 15 22 29 36 43 Study Day Wang et al. Clin Pharmacol Ther. 2004;76(6) 628-638.

  17. Studies With Romiplostin in ITP • Phase 1 – Open label study of 24 subjects treated in groups of 4 at 6 dose levels: 0.2, 0.5, 1.0, 3.0, 6.0, 10.0 µg/kg SQ1 • Phase 2 – Double-blind, placebo-controlled trial of 1 or 3 µg/kg AMG 531 (16 subjects) vs placebo (4 subjects)1 • Phase 3 – Double-blind, placebo-controlled trial of variable doses of AMG 531 vs placebo in patients with or without splenectomy2 • Extension Study – Open label safety and efficacy study of long-term weekly treatment of subjects from Phase 1 and Phase 23 • Response: platelets double and ≥50,000 1. Bussel JB et al. N Engl J Med. 2006;355:1672. 2. Kuter et al. Lancet2008;371: 395 3. Bussel et al. Blood

  18. Platelet Response OutcomesRomiplostim Phase 3 Trials in Chronic ITP (24 weeks sc) Placebo Romiplostim DurableResponse Overall Response 100 100 88 79 80 80 61 60 60 Percent Percent 38 40 40 20 20 14 5 0 0 0 0 Splenectomized Nonsplenectomized Splenectomized Nonsplenectomized (P = 0.0013) (P < 0.0001) (P < 0.0001) (P < 0.0001) Kuter DJ, et al. Lancet. 2008;371:395-403.

  19. Mean Platelet Count Levels Between 50 and 250 x 109/L Over 112 Weeks 300 250 200 Mean (SE) Platelet Count x 109/L 150 100 50 0 1 4 8 16 24 32 40 48 56 64 72 80 88 96 104 112 Study Week n = 135 89 65 33 25 22 16 13 12 10 8 Mean (SD) Dose (µg/kg) 6 4 2 0 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.

  20. SERIOUS ADVERSE EVENTS:ALL TRIALS Headaches were more frequent in the treatment arm. No difference in thrombotic events between placebo and romiplostim arm. No correlation with platelet count. There were more frequent major bleeding events (event/100 pt/yr) on the placebo arm. More grade 2 or greater bleeding events in the placebo arm in the extend study (16% vs.34%; P=0.018). No significant increase in thromboembolic events. Increased bone marrow reticulum in 10 patients. Appears reversible upon stopping romiplostim and not associated myelofibrosis. No trichrome positive collagen. Abst 3415: Liebman et al. Long-term safety profile of Romiplostim Abst 3422: Tarantino et al. Evaluation of bleeding and thrombotic events during long-term use of romiplostim Abst 3416: Kuter et al. Evaluation of bone marrow reticulum

  21. AMG 531: Phase II Peak Platelet Counts 900 800 700 600 500 Peak Platelet Count (x10-3/mm3) 400 300 200 100 0 Placebo(n=4) AMG 531, 1 µg/kg(n=8) AMG 531, 3 µg/kg(n=8) Bussel JB, et al. N Engl J Med. 2006;355(16):1672-1681.

  22. Eltrombopag • Small molecule (MW=564)1 • Orally bioavailable2 • Once daily dosing • Stimulates megakaryocyte proliferation and differentiation3 • Increases platelet counts3 • Not immunogenic • Does not activate platelets4 • Active in humans, chimps but no other species5 1. USAN Supplement. Pharmacop Forum. 2006;32:216. 2. Erickson-Miller C et al. Blood. 2004;104:Abstract 2912. 3. Luengo JI et al. Blood. 2004;104:Abstract 2910. 4. Erhardt J et al. Blood. 2004;104:Abstract 3888. 5. Erickson-Miller C et al. Blood. 2004;104:Abstract 2909.

  23. Eltrombopag (SB497115): Mechanism ThrombopoietinReceptor Eltrombopag Active Receptor Inactive Receptor Cell Membrane SHC GRB2 RAS/RAF SOS P P P JAK STAT P Cytoplasm MAPKK p42/44 Signal Transduction Increased Platelet Production

  24. Eltrombopag, an Oral Platelet Growth Factor, for Treatment of Chronic ITP: A Randomized, Double-blind, Placebo-controlled Trial • Two Randomized Studies of Eltrombopag in ITP • Phase II: 3 dose cohorts of Eltrombopag (30mg, 50mg or 75mg) or placebo for 6 weeks • Phase III: 2:1 Eltrombopag 50 mg or placebo for 6 weeks: increase to 75 mg after 3 weeks if plts <50k • 117 patients in Phase 2 • 114 patients in Phase 3

  25. EltrombopagITP Phase 2 Study Study design • Randomized, double-blind, placebo-controlled study Patient population • Adults with ITP ≥6 months, having failed at least 1 prior therapy, and platelets <30 x 109/L Endpoints • Patients with platelets >50 x 109/L after 6 weeks • Safety and tolerability Bussel JB et al. N Engl J Med. 2007; 357:2237.

  26. EltrombopagPhase 2 Results in ITP Bussel JB et al. N Engl J Med. 2007; 357:2237.

  27. Overall Response to Eltrombopag % of ITP Patients With Platelet Count ≥50,000/µL After 42 Days Dosing 100 p<0.001* OR=54.76(8.48, 353.46) 90 p<0.001* OR=20.77(4.08,105.7 4 80 70 60 Patients (%) 50 18/21 p=0.098 OR=2.80(0.59, 13.26) 16/24 40 30 20 7/25 10 4/25 0 Placebo Eltrombopag 30mg Eltrombopag 50mg Eltrombopag 75mg OR = Odds ratio treatment relative to placebo * = Indicates significance under closed testing procedure

  28. Eltrombopag in ITP: Phase II Summary Platelet response (p<0.001) with 50 and 75mg • 70% patients (50mg) and 81% (75mg) achieved platelet counts ≥50,000/µL • 37% patients (50mg) and 43% (75mg) achieved platelet counts > 200,000/ul • Trend to reduction in bleeding in 50mg and 75mg arms • Phase III: 50mg starting dose (up to 75mg after 3 weeks if platelets <50K) Bussel JB et al. N Engl J Med. 2007; 357:2237.

  29. Efficacy Data

  30. Median Platelet Counts (25th and 75th Percentiles) Baseline to Week 20 350 300 200 150 250 100 50 0 20 33 107 106 106 99 97 92 90 83 76 67 62 65 60 51 55 48 39 43 42 39 Baseline 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Week Number of subjects: Platelet count (Gi/L) Splenectomized pts respond as well as non-splenectomized pts Bussel JB et al. Blood 2007; 110: 174a abst.

  31. 150 300 350 250 100 200 50 0 21 41 37 46 36 30 29 30 28 26 21 21 19 16 11 15 12 10 10 13 7 7 6 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 Week Number of subjects: Median Platelet Counts (25th and 75th Percentiles) – Week 21 to Week 41 Platelet count

  32. Most Common Adverse Events Reported

  33. Serious Adverse Events

  34. HEMOSTATIC ABNORMALITIES ASSOCIATED WITH LIVER DISEASE Defective synthesis of coagulation proteins Thrombocytopenia Accelerated fibrino/fibrinogenolysis Dysfibrinogenemia

  35. INCIDENCE OF THROMBOCYTOPENIA IN LIVER DISEASE • Thrombocytopenia (platelets<150 x109/L)is reported in 15 to 70% of patients with liver disease. • Thrombocytopenia is much more frequent in patients with advanced cirrhosis, acute liver failure and chronic active hepatitis. • Kajiwara et al, Am J Gastroenterol 1995;90:962 • Yanaga et al. Ann Surg 1989; 210: 180 • Stein SF & Harker LA. J Lab Clin Med 1982; 99: 217

  36. INCIDENCE OF THROMBOCYTOPENIA IN LIVER DISEASE • Thrombocytopenia (platelets<150 x109/L)is reported in 15 to 70% of patients with liver disease. • Thrombocytopenia is much more frequent in patients with advanced cirrhosis, acute liver failure and chronic active hepatitis. • Kajiwara et al, Am J Gastroenterol 1995;90:962 • Yanaga et al. Ann Surg 1989; 210: 180 • Stein SF & Harker LA. J Lab Clin Med 1982; 99: 217

  37. MECHANISMS RESPONSIBLE FOR THROMBOCYTOPENIA IN LIVERDISEASE • Portal hypertension with splenic sequestration. • Decreased thrombopoietin production. • Immune complex induced accelerated clearance. • Anti-platelet glycoprotein antibodies.

  38. THROMBOCYTOPENIA WITH CHRONIC HEPATITIS C • Thrombocytopenia (< 150 x 109/L) was observed in 151 of 368 (41%) of patients with chronic HCV infection compared with 10 of 53 (19%) with chronic HBV. • Severe thrombocytopenia with platelet counts of less than 50 x 109/L is reported in 9% of HCV infected patients. • Nagamine et al. J Hepatol 1996; 24: 135

  39. Phase II Study of Eltrombopag in Hepatitis C Thrombocytopenia McHutchison JG et al. N Engl J Med. 2007;357:2227-36.

  40. Patient Response at Week 4Phase II Study of Eltrombopag in Hepatitis C Thrombocytopenia < 0.0001 0.00015 100% 0.0007 80% 95% 79% 75% 60% Percent subjects with platelet count ≥100,000/mm3 at Week 4 40% 20% 20/21 15/19 0% 9/12 0% Placebo 30 mg 50 mg 75 mg Eltrombopag McHutchison JG et al. N Engl J Med. 2007;357:2227-36.

  41. Future Directions • Chronic liver disease prior to procedures: Afdhal, NH et.al, NEJM 2012; 367(8): 716-24 Treatment prior to procedures. Reduction of platelet transfusions but increased risk of portal, portal-mesenteric vein thrombosis Kawaguchi, T J Gastro2012; 47 (12): 1342-51 Safety and efficacy of 3 different doses of Eltrombopag in patients with 38 pts with Child A/B cirrhosis. 1 episode of portal vein thrombosis @ highest dose. • Chemotherapy induced thrombocytopenia Chawla, SP et.al BMC Cancer 2013;13: 121 Phase I dose escalation study if Elthrombopag in soft tissue sarcoma treated with ifosphamide/doxorubincin i

  42. Future directions Thrombopoetin agonists • Aplastic Anemia1 • MDS/ Acute Myelogenous Leukemia2 1. Olmes, MJ, et.al, NEJM 2012; 367(1): 11-9 2. Will, B, etal, Blood 2009; 114(18): 3899-908

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