recent advances in the recent advances in the management

Recent Advances In the Recent Advances In the Management of ITP - PowerPoint PPT Presentation

Recent Advances In the Recent Advances In the Management of ITP Management of ITP Prof Gregory Cheng Prof Gregory Cheng Prof. Gregory Cheng Prof. Gregory Cheng Immune thrombocytopenia (ITP) is a Immune thrombocytopenia (ITP) is a


  1. Recent Advances In the Recent Advances In the Management of ITP Management of ITP Prof Gregory Cheng Prof Gregory Cheng Prof. Gregory Cheng Prof. Gregory Cheng

  2. � Immune thrombocytopenia (ITP) is a � Immune thrombocytopenia (ITP) is a Immune thrombocytopenia (ITP) is a Immune thrombocytopenia (ITP) is a disease characterized by accelerated disease characterized by accelerated destruction of platelets by anti destruction of platelets by anti-platelet destruction of platelets by anti destruction of platelets by anti platelet platelet platelet antibodies antibodies

  3. � Treatment is therefore primarily � Treatment is therefore primarily Treatment is therefore primarily Treatment is therefore primarily directed at reducing destruction of directed at reducing destruction of antibody antibody-coated platelets antibody antibody coated platelets coated platelets coated platelets

  4. Thrombopoietic Factors in ITP: Thrombopoietin Receptor (TPOr)- Thrombopoietin Receptor (TPOr) Targeted Therapy � Platelet production may be decreased in Platelet production may be decreased in a substantial fraction of patients with ITP a substantial fraction of patients with ITP a substantial fraction of patients with ITP a substantial fraction of patients with ITP , , especially those with refractory disease especially those with refractory disease

  5. Impaired platelet production p p p � gpIIb � gpIIb gpIIb IIIa and gpIb gpIIb-IIIa and gpIb IIIa and gpIb-IX) are co IIIa and gpIb IX) are co IX) are co-expressed IX) are co expressed expressed expressed on platelets, megakaryocytes and on platelets, megakaryocytes and megakaryocyte precursors megakaryocyte precursors � Recognized by auto Recognized by auto- g g y y -antibodies and may antibodies and may y lead to impaired megakaryopoiesis, lead to impaired megakaryopoiesis, maturation and platelet release. maturation and platelet release. 1 � ITP ITP – –Plasma containing autoantibodies Plasma containing autoantibodies against gpIb and gpIIb against gpIb and gpIIb IIIa significantly against gpIb and gpIIb against gpIb and gpIIb-IIIa significantly IIIa significantly IIIa significantly suppresed megakaryopoiesis in vitro. suppresed megakaryopoiesis in vitro. 2 1. McMillan R, et al 2000;37:239 ‐ 248 2. Chang M, et al 2003;102:887 ‐ 95

  6. � Thrombopoietin (TPO) levels are � Thrombopoietin (TPO) levels are Thrombopoietin (TPO) levels are Thrombopoietin (TPO) levels are inappropriately low (near normal) in inappropriately low (near normal) in thrombocytopenic ITP patients thrombocytopenic ITP patients thrombocytopenic ITP patients thrombocytopenic ITP patients

  7. TPO levels are TPO levels are inappropriately low inappropriately low in in ITP ITP ITP ITP Kosugi et al. Br J Haematol1996;93:704–706

  8. � Stimulation of platelet production may � Stimulation of platelet production may Stimulation of platelet production may Stimulation of platelet production may be especially useful in patients not be especially useful in patients not responsive to currently available responsive to currently available responsive to currently available responsive to currently available treatment. treatment.

  9. � Eltrombopag is an oral, Eltrombopag is an oral, p g p g , , non non- -peptide, small peptide, small molecule thrombopoietin molecule thrombopoietin receptor agonist receptor agonist receptor agonist receptor agonist � Does not cause activation Does not cause activation and aggregation and aggregation � Less immunogenic than Less immunogenic than thrombopietin and other thrombopietin and other peptidyl agents peptidyl agents tid l tid l t t

  10. Thrombopoietin Receptor (TPOr) Thrombopoietin Receptor (TPOr) � TPOr = cMpl � TPOr TPOr = cMpl TPOr cMpl cMpl –a member of the type I a member of the type I hematopoietic growth factor receptor hematopoietic growth factor receptor hematopoietic growth factor receptor hematopoietic growth factor receptor family family –A homodimer with a transmembrane –A homodimer with a transmembrane A homodimer with a transmembrane A homodimer with a transmembrane domain and an intracellular domain domain and an intracellular domain

  11. � Selectively activates TPOr � Selectively activates TPOr Selectively activates TPOr and the Selectively activates TPOr and the and the and the JAK/STAT signaling pathway JAK/STAT signaling pathway –Oral bioavailability is 89% in monkey Oral bioavailability is 89% in monkey Oral bioavailability is 89% in monkey Oral bioavailability is 89% in monkey / human / human

  12. Eltrombopag Phase I Study: Eltrombopag Phase I Study: Platelet Platelet Platelet-Count Change from Platelet Count Change from Count Change from Count Change from Baseline in Healthy Subjects Baseline in Healthy Subjects � Randomized R Randomized R d d i i d d 160 160 om baseline e placebo controlled placebo controlled 140 phase I trial in 73 phase I trial in 73 phase I trial in 73 phase I trial in 73 120 change fro healthy male healthy male 100 subjects subjects 80 uL(x1000) c � Oral capsules: Oral capsules: 60 once a day, for 10 once a day, for 10 40 d days days Platelets/u 20 � Doses : Doses : 0 5, 10, 20, 30, 50, 5, 10, 20, 30, 50, 5 10 20 30 50 5 10 20 30 50 p placebo 5mg g 10mg g 20mg g 30mg g 50mg g 75mg g 75 mg 75 mg Eltrombopag Dose x 10 days Jenkins, J, et al. 2004; Blood (ASH Abstracts); 104: 2916.

  13. � In two 6 In two 6- -week placebo week placebo- p -controlled controlled 1,2 (N >200), eltrombopag trials 1,2 trials (N >200), eltrombopag 1 2 1 2 significantly increased platelet counts significantly increased platelet counts reduced clinical bleeding in ITP reduced clinical bleeding in ITP reduced clinical bleeding in ITP reduced clinical bleeding in ITP patients and had a favorable safety patients and had a favorable safety profile profile N Engl J Med 2007; 357:2237 - 47 Lancet 2009;373:641 – 8

  14. Response to Eltrombopag: Primary Endpoint (Phase II): % with Plts ≥ 50,000/µL after 42 Days (Baseline ) , /µ y ( Platelets <30,000/µL) 100 100 p<0.001* p<0.001* 90 90 rs rs esponder esponder OR 38 82 OR 38 82 OR=38.82 OR=38.82 p<0.001* p<0.001* 80 80 OR=21.96 OR=21.96 70 70 ge of Re ge of Re 60 60 50 50 p = 0.07 p = 0 07 p = 0 07 p = 0.07 40 40 40 40 Percenta Percenta OR=3.09 OR=3.09 30 30 20 20 20 20 P 10 10 0 Placebo Placebo Placebo Placebo 30mg 30mg 30mg 30mg 50mg 50mg 50mg 50mg 75mg 75mg 75mg 75mg OR = Odds ratio treatment relative to placebo OR = Odds ratio treatment relative to placebo * = Indicates significance under closed testing procedure * = Indicates significance under closed testing procedure N Engl J Med 2007; 357:2237 - 47

  15. Phase II Study: Median Platelet Counts Over Time (25% & 75% Counts Over Time (25% & 75% Quartiles; Observed Analysis) LOCF Analysis 50mg 75mg 5 g

  16. Eltrombopag in Chronic ITP Phase 2 Results: Increased Platelet Results: Increased Platelet Production, Decreased Bleeding Platelet count Bleeding events 200000 18 180000 16 nts nt eding even atelet coun - (%) of on- 160000 14 140000 12 120000 10 erapy blee 100000 100000 Median pla Incidence 8 80000 6 60000 4 the 40000 40000 M I 2 20000 0 0 Placebo 30 mg g 50 mg g 75 mg g Dosage of eltrombopag: once daily for 6 weeks N Engl J Med 2007; 357:2237 - 47

  17. � RAISE is a phase III, placebo RAISE is a phase III, placebo- p p , p , p -controlled, controlled, , double double- -blind trial of eltrombopag blind trial of eltrombopag treatment treatment � To evaluate the efficacy and safety of To evaluate the efficacy and safety of up to 6 months of treatment with up to 6 months of treatment with eltrombopag in patients with chronic ITP eltrombopag in patients with chronic ITP lt lt b b i i ti ti t t ith h ith h i ITP i ITP

  18. � Adult patients with chronic ITP who � Adult patients with chronic ITP who Adult patients with chronic ITP who Adult patients with chronic ITP who had a platelet count <30,000/µL and had a platelet count <30,000/µL and had received ≥ 1 prior ITP therapies had received ≥ 1 prior ITP therapies had received ≥ 1 prior ITP therapies had received ≥ 1 prior ITP therapies were eligible for RAISE were eligible for RAISE � Patients were randomized 2:1 Patients were randomized 2:1 (eltrombopag:placebo) and stratified (eltrombopag:placebo) and stratified (eltrombopag:placebo) and stratified (eltrombopag:placebo) and stratified by splenectomy status, concomitant by splenectomy status, concomitant ITP medication use, and platelet count ITP medication use, and platelet count , , p p ≤ 15,000/µL 15,000/µL

  19. � Eltrombopag (or matching placebo) was � Eltrombopag (or matching placebo) was Eltrombopag (or matching placebo) was Eltrombopag (or matching placebo) was initiated at 50 mg once daily initiated at 50 mg once daily Screening Follow-up period period BL 1 2 3 4 5 6 10 14 18 22 26FU FU FU 1 2 4 Study week BL, baseline; FU, follow-up .

Recommend


More recommend