Terry B. Gernsheimer, MD Professor of Medicine Division of Hematology University of Washington School of Medicine Seattle, Washington Targeting Growth Factors for the Management of ITP This program is supported by an educational donation from

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clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Days % Platelet - 51 Cr Injected Normal subjects (n = 15) Immediate autologous platelet recovery: 65 ± 4% Mean autologous platelet survival: 9.9 ± 0.6 days Harker LA, et al. J Clin Invest. 1969;48: Reproduced with permission. Platelet Disappearance in Normal Subjects

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Thrombokinetics in Normal Subjects and in ITP Platelets Platelet Survival (days) Turnover (x normal) Normal Subjects ITP Patients Harker, Homologous Branehog, Homologous Stoll, Autologous Ballem, Autologous Harker. Br J Haematol. 1970;19: Branehog et al. Br J Haematol. 1974; 27: Stoll et al. Blood. 1985;65: Ballem et al. J Clin Invest. 1987;80:33-40.

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Thrombopoietin Levels in ITP  In healthy individuals platelet count is high and serum thrombopoietin is low  In ITP patients both the platelet count and serum thrombopoietin levels are low  In contrast, in patients with AMT, platelet counts are low, but serum thrombopoietin levels are high Mukai HY, et al. Thromb Haemost. 1996;76:

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Nomura S, et al. Blood. 2002;100: This research was originally published in Blood. © the American Society of Hematology. Platelets (x 10 9 /L) Reticulated Platelets (%) Days After PEG-rHuMGDF Treatment PEG-rHuMGDF in ITP Indicates days of 0.5 μg/kg PEG-rHuMGDF dosing –Patients 1 and 3 received 7 days of dosing –Patient 2 received only 1 day of dosing because of adverse events –Patient 4 received 6 days of dosing because of adverse events Patient Patient Patient Patient 4

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm PEG-rHuMGDF Antibody Formation Li J, et al. Blood. 2001;98: This research was originally published in Blood. © the American Society of Hematology Study Day Platelet Count (x 10 9 /L) TPO Antibody (µ g/mL)

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Second-Generation Thrombopoietic Growth Factors  TPO peptide mimetics –Romiplostim  TPO nonpeptide mimetics –Eltrombopag –AKR501 –LGA-4665 –S  TPO agonist antibodies

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Thrombopoietin: Mechanism of Action Thrombopoietin Receptor Inactive Receptor Active Receptor Cell Membrane Cytoplasm Signal Transduction Increased Platelet Production RAS/RAF MAPKK p42/44 JAK STAT SHC GRB2 SOS P P P P TPO

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Romiplostim Romiplostim: Mechanism of Action Thrombopoietin Receptor Inactive Receptor Active Receptor Cell Membrane Cytoplasm Signal Transduction Increased Platelet Production RAS/RAF MAPKK p42/44 JAK STAT SHC GRB2 SOS P P P P

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Eltrombopag Eltrombopag: Mechanism of Action Thrombopoietin Receptor Inactive Receptor Active Receptor Cell Membrane Cytoplasm Signal Transduction Increased Platelet Production RAS/RAF MAPKK p42/44 JAK STAT SHC GRB2 SOS P P P P

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Romiplostim  No sequence homology with endogenous TPO  Fusion protein of Fc and TPO mimetic peptides  Stimulates platelet production by same mechanism as TPO  Recycled by FcRn on endothelial cells  Administered subcutaneously weekly

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Romiplostim: Parallel Phase III Trials in Chronic ITP Kuter DJ, et al. Lancet. 2008;371: Romiplostim 1 μg/kg SC wkly starting dose* (splenectomized: n = 42; nonsplenectomized: n = 41) Placebo (splenectomized: n = 21; nonsplenectomized: n = 21) Wk 24 Wk 1 Platelet follow-up through Wk 36 Randomized 2:1 *Individual dose adjustment based on wkly platelet count. Reductions in concurrent ITP therapies allowed when platelet counts > 100 x 10 9 /L. Rescue medications allowed. Splenectomized or nonsplenectomized patients with ITP and platelet count ≤ 30 x 10 9 /L (N = 125; splenectomized n = 63; nonsplenectomized n = 62)

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Kuter DJ, et al. Lancet. 2008;371: Romiplostim: Platelet Response Outcomes in Chronic ITP Patients,% SplenectomizedNon-Splenectomized Placebo (n = 6) Romiplostim (n = 12) P Value Placebo (n = 10) Romiplostim (n = 11) P Value Durable Response <.0001 Overall response 079< <.0001

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Reduction or Discontinuation of Concurrent ITP Therapy  Will reduction in the use of immunosuppressive drugs lead to fewer infections? Kuter DJ, et al. Lancet. 2008;371: Patients With Dose Modification, % SplenectomizedNon-Splenectomized Placebo (n = 6) Romiplostim (n = 12) Placebo (n = 10) Romiplostim (n = 11) Reduced Discontinued by > 25%

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Long-term Use of Romiplostim: Bleeding Events Tarantino M, et al. ASH Abstract Bleeding Events: Romiplostim Extension Study Patients (%) ≤12 wks (n = 101) > 12 to ≤24 wks (n = 94) > 24 to ≤36 wks (n = 92) > 36 to ≤48 wks (n = 86) Time on Study Events of any severity Grade 2 severity or higher  Clinically significant (≥ Grade 2) bleeding events –Romiplostim 16% vs placebo 34% (p =.018)  Severe (≥ Grade 3) bleeding events –Romiplostim 7% vs placebo 12% (p =.36)

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Eltrombopag: Thrombopoietin Receptor Agonist  Small molecule (MW = 442 Da)  Very low immunogenic potential  Orally bioavailable, administered fasting once daily  Interactions –Plasma concentrations  70% by polyvalent cations (Ca++, antacid) –Inhibits OATP1B1 (organic anion transporting polypeptide); interacts with statins  AUC 70% to 80% higher in East Asian patients FDA. Available at:

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Phase II (Part A) Phase III (Part B) 2:1 Randomization vs SoC + Placebo (n = 38) SoC + 50 mg eltrombopag (n = 76) N = 114 N = 117 SoC + Placebo (n = 29) SoC + 30 mg Eltrombopag (n = 30) SoC + 50 mg Eltrombopag (n = 30) SoC + 75 mg Eltrombopag (n = 28) Randomization stratified on basis of concomitant ITP therapy, splenectomy status, platelet count > or ≤ 15 x 10 9 /L Interim Analysis Bussel J, et al. Haematologica/The Hematology Journal. 2007;92(21):143. Abstract Phase III Eltrombopag Treatment of Chronic ITP

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Eltrombopag: Phase III RAISE Study Platelet Response Cheng G, et al. ASH Abstract 400.  52/65 patients responded to eltrombopag with a platelet count of 50 x 10 9 /L during the study  23/33 patients discontinued or had a sustained reduction of their baseline ITP medication –Did not require any subsequent rescue treatment  15/23 patients maintained the discontinuation or reduction of baseline medications for at least 24 weeks

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Eltrombopag: Key Efficacy Data Bussel J, et al. EHA Abstract Outcome, n/N (%) Patients Receiving Eltrombopag Platelet count increases  To ≥ 50 x 10 9 /L at least once 86/108 (80)  To ≥ 400 x 10 9 /L at least once 20/108 (19) Previous responders with platelet count ≥ 50 x 10 9 /L during EXTEND 45/49 (92) Discontinuation of ≥ 1 concomitant ITP medication 14/40 (35) Durability of response  Platelet count ≥ 50 x 10 9 /L continuously for ≥ 10 wks 43/80 (54)  Platelet count ≥ 50 x 10 9 /L continuously for ≥ 25 wks 15/63 (24)

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Eltrombopag EXTEND Trial: Durable Bleeding Reduction Patients (%) Bussel J, et al. ASH Abstract Baseline Grade 1-4 bleeding Grade 2-4 bleeding Week

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Promacta US FDA ODAC Briefing Document. Available at: Liebman H, et al. ASH Abstract Adverse Events With Romiplostim and Eltrombopag Adverse Event, %RomiplostimEltrombopag Gastrointestinal  Abdominal pain  Diarrhea  Nausea 13-- Musculoskeletal  Arthralgia  Myalgia Ophthalmic: cataracts Neurologic  Headache  Dizziness 17--  Paresthesias 6-- Fatigue

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Potential Adverse Consequences of Thrombopoietic Growth Factors  Thrombocytosis  Reduced threshold for platelet activation  Thrombosis  Increased bone marrow reticulin or collagen  Autoantibody formation  Stimulation of leukemia or tumor cell growth  Interactions with other cytokines  Stem cell depletion  Rebound thrombocytopenia –Romiplostim phase III: 4/57 (7%) [1] –Eltrombopag [2] –Phase II A/B 10% vs 6% placebo REPEAT: 30% 1. Romiplostim [package insert]. 2. US FDA ODAC Briefing Document. Available at:

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Patient-Reported Thrombotic Events in ITP Aledort LM, et al. Am J Hem. 2004;76: Adverse EventEvents, n ITP Patients With Event, n (N = 205) At Any TimePostdiagnosis Any 1810 (5%)6 (3%)  Deep vein thrombosis 963  TIA 311  Pulmonary embolism 221  Phlebitis 210  Stroke 111  Myocardial infarction 110

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm *r = duration-adjusted event incidence = event rate per 100 pt-wks = (number of events/pt-wk) x 100 Romiplostim: Thrombotic Events Incidence of Thrombotic/Thromboembolic Adverse Events Phase III StudiesExtension Study Placebo (n = 41) Romiplostim (n = 84) Romiplostim (n = 101) Patient incidence, n (%)1 (2.4)2 (2.4)4 (4) Total number and duration-adjusted event incidence, n (r)*  All1 (0.1)2 (0.09)7 (0.13)  Cerebrovascular accident0 (0)1 (0.05)(0)  Popliteal arterial embolism0 (0)1 (0.05)(0)  Pulmonary embolism1 (0.1)0 (0)(0)  Myocardial infarction(0) 2 (0.04)  Thrombosis(0) 2 (0.04)  Coronary artery occlusion(0) 1 (0.02)  Peripheral septic thrombophlebitis(0) 1 (0.02)  Transient ischemic attack(0) 1 (0.02) Tarantino N, et al. ASH Abstract 3422.

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Eltrombopag: Additional Adverse Events of Interest  Thromboembolic events –2.6% [1]  Hepatobiliary changes –Placebo-controlled studies – Phase II: 10% eltrombopag vs 8% placebo [1] –CTC grade 2-4 (FDA analysis): 8% vs 3% for placebo [2] – Phase III: 13% eltrombopag vs 7% placebo  Cataracts 3% to 5% 1.US FDA ODAC Briefing Document. Available at: b1-02-GSK.pdf. 2. US FDA ODAC Briefing Document. Available at:

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Increased Bone Marrow Reticulin  Animal models [1,2] –Reversible and related to TGF-β  Reversible in 8 AML subjects with rhTPO-related increase [3]  10 reports/271 romiplostim patients [2] –1 with possible collagen fibrosis –Many at high doses (6/10 received ≥ 10 μg/kg) –Many with minimal response to drug –2 with chromosome abnormalities –Decreased in 3 with subsequent bone marrow biopsies  19/117 eltrombopag patients had bone marrow examination [4] –5 reticulin increased, 2 collagen increased 1. Kuter DJ. Blood. 2007;109: Kuter DJ, et al. Blood. 2009;114: Douglas VK, et al. Am J Clin Pathol. 2002;117: US FDA ODAC Briefing Document. Available at:

clinicaloptions.com/oncology Idiopathic Thrombocytopenic Purpura: Shifting the Treatment Paradigm Thrombopoietic Agents in ITP: Conclusions  Up to 87% of patients with chronic ITP respond to short- and long-term (> 156 wks) therapy  The majority of adverse effects are mild to moderate  Serious adverse effects, including thrombosis and marrow fibrosis, are uncommon  Continued observation for long-term consequences of therapy is needed to determine best practice for the use of these agents  Increasing platelet production is an effective and relatively safe approach to the treatment of chronic ITP

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