Ruolo dei nuovi agenti trombopoietici nella terapia dell ITP

Transcription

1 42 CONGRESSO NAZIONALE SIE Società Italiana di Ematologia Milano, MIC Centre, ottobre 2009 Ruolo dei nuovi agenti trombopoietici nella terapia dell ITP Dr. Roberto Stasi Department of Haematology St George's Hospital London

2 Platelet kinetics in ITP Decreased platelet survival Radiolabeled autologous platelets Impaired platelet production Production Platelet count / Platelet survival Normal range Normal range No treatment Prednisone Post-splenectomy No treatment Prednisone Post-splenectomy Heterologous platelets are cleared much faster (minutes-hours) Most patients have inappropriately low or normal rates of platelet production Ballem PJ et al. J Clin Invest. 1987;80:33-40

3 TPO: a major stimulator of megakaryopoiesis

4 c-mpl (TPO-Receptor) Member of the cytokine receptor superfamily Type I TPO-R Gene located on human chromosome 1p34 CRH-1 CRH-2 Expressed in hematopoietic cell lines and in the brain Does not contain intrinsic tyrosine kinase activity JAK2 Histidine 499 JAK2 Ig-like extracellular domains called cytokine receptor homology (CRH) P P Momomers Homodimers when bind to TPO

5 TPO: mechanism of action thrombopoietin thrombopoietin receptor inactive receptor active receptor Cell membrane P SHC GRB2 P SOS RAS/RAF Cytoplasm STAT P P JAK MAPKK p42/44 Signal Transduction Increased platelet production

6 First generation thrombopoietins rhtpo and PEG-rhMGDF Sequence homology with endogenous TPO Improved platelet recovery after non-myeloablative chemotherapy Improved platelet counts in 7/9 ITP patients Nomura et al. Blood. 2002;100:

7 Thrombocytopenia caused by the development of antibodies to PEG-rHuMGDF that cross-reacted with endogenous TPO in healthy volunteers Platelet count TPO antibody titer Li et al Blood 2001;98:

8 Screening strategies for TPO mimetics Peptide libraries Phage display Genetically engineered TPO agonist antibody Nonpeptide organic molecules High-throughput screening (HTS) Naturally derived compounds

9 Second generation thrombopoietic growth factors No sequence homology with endogenous TPO Peptide TPO-R agonists Romiplostim (AMG531) Fab59 Peg-TPOmp Non-peptide TPO-R agonists Eltrombopag (SB497115) AKR-501 LGA-4665, NIP-004,NIP-022, butyzamide TPO agonist antibodies Minibodies [VB22B sc (Fv) 2 ] Domain subclass-converted TPO agonist antibodies (MA01G4G344)

10 Romiplostim (nplate ) No sequence similarity to natural TPO Therefore, does not elicit anti-tpo antibodies FDA- and EMEA-Approved

11 Romiplostim: Mechanism of Action romiplostim thrombopoietin receptor inactive receptor active receptor Cell membrane P SHC GRB2 P SOS RAS/RAF Cytoplasm STAT P P JAK MAPKK p42/44 Signal Transduction Increased platelet production

12 Romiplostim (AMG 531) in healthy volunteers Phase I study Wang et al. Clin Pharmacol Ther 2004;76:628-38

13 Comparison of platelet responses in subjects receiving single IV or SC administration Wang et al. Clin Pharmacol Ther 2004;76:628-38

14 Romiplostim in Chronic ITP: Phase III study Weekly, s.c. romiplostim in slowly escalating doses (1 µg/kg up to 15 µg/kg) for 24 weeks Dose adjusted to achieve a platelet count of 50, ,000 Inclusion criteria: Age 18; ITP with platelet count <30,000 Other treatments were discontinued at least 4 weeks before entry Randomized, double-blind, Phase 3 trial (n = 125) Splenectomy (n = 63) Non-splenectomized (n = 62) Placebo (n = 21) Romiplostim 1 mcg/kg SQ q wk, target Plt x10 9 /L (n = 42) Placebo (n = 21) Romiplostim 1 mcg/kg SQ q wk, target Plt x109/L (n = 41) Kuter DJ et al. Lancet 2008;371:

15 Definition of platelet response Durable Platelets 50,000/µL for at least 6 of the last 8 weeks of treatment Transient Four or more weekly platelet responses (Plt 50,000/µL) at any time during the study Kuter et al. Lancet. 2008;371:

16 Platelet Counts Target platelet count 50, ,000/mcl Kuter et al. Lancet. 2008;371:

17 Overall and complete platelet response OR 79% CR 38% OR 88% CR 61% OR 83% CR 49% CR 5% CR 2% Kuter et al. Lancet. 2008;371:

18 Number of weeks with platelet response during the 24-week study Kuter et al. Lancet. 2008;371:

19 Romiplostim doses Target platelet count 50, ,000/mcl Splenectomised ±SEM Mean weekly dose ~ 3 µg/kg Non-splenectomised Mean weekly dose 2 µg/kg Kuter et al. Lancet. 2008;371:

20 Patients receiving rescue therapies Kuter et al. Lancet. 2008;371:

21 Adverse Events Placebo Romiplostim Severe or lifethreatening bleeding 5/41 (12%) 6/84 (7%) Thrombosis 1 1 popliteal art. thrombosis 1 CVA Death 1 ICH 1 PE 1 ICH after starting aspirin to treat thrombosis Increased bone marrow reticulin 1 (reversible) Kuter et al. Lancet. 2008;371:

22 Romiplostim Long-term Treatment S C R E E N I N G Treatment Period Romiplostim starting dose: 1 µg/kg or last dose on prior study Individual dose adjustment based on platelet count Target platelet count: x10 9 /L Maximum dose 10 µg/kg* Reductions in concurrent ITP therapies allowed when platelet counts > 50 x 10 9 /L Rescue medications allowed * A small number of patients are on doses up to 17 µg/kg. Initial maximal dose 30 µg/kg, later reduced to 15 µg/kg, and then 10 µg/kg. I N TE R I M A N A LY S I S Day - 8 Day 1 Study drug administered SC weekly End of Study Longest continuously reported active treatment study with a TPO mimetic Bussel et al. Blood. 2009;113:

23 Platelet Response Over 156 Weeks A platelet response was observed in 87% of all patients Bussel et al. Blood. 2009;113:

24 Romiplostim dose over 156 Weeks Mean (SD) average weekly dose was 5.9 (± 3.9) µg/kg Bussel et al. Blood. 2009;113:

25 SAEs during long term Tx with romiplsotim Bone marrow reticulin, n = 8 (reversible) marrows were not routinely performed, so the true incidence of this event cannot be determined. Severe bleeding events, n = 12 (9%). Thrombotic events, n = 7 (5%) DVT, AMI, CAD, TIA Deaths, n = 3 AMI, post-splenectomy sepsis, cirrhotic complications

26 TPO non-peptide mimetics: Eltrombopag Small molecule (MW=442) Orally bioavailable Once daily dosing Not immunogenic Does not activate platelets Active in humans and chimps but no other species (speciesspecific) FDA-Approved Kuter DJ. Blood 2007;109:4607

27 Eltrombopag: Mechanism of Action thrombopoietin Receptor eltrombopag inactive receptor active receptor Cell membrane P SHC GRB2 P SOS RAS/RAF Cytoplasm STAT P P JAK MAPKK p42/44 Signal Transduction Increased platelet production

28 Eltrombopag in ITP: Phase III, Double- Blind, Placebo-Controlled Study (RAISE) Primary end point: odds of responding with a platelet count 50,000 to 400,000/µL during the 6-month treatment period Randomized Double-blind Phase 3 Trial (n = 197) Placebo (n = 62) Eltrombopag 50 mg PO once daily x 24 wks (n = 135) Cheng et al. Blood 2008;112: Abstract 400

29 Platelet counts Eltrombopag was effective regardless of concurrent ITP therapy, splenectomy or baseline platelet count Stasi et al. EHA 2009

30 RAISE: Odds of platelet response OR (99% CI) = 8.2 (3.59,18.73) p< % Responders ( Gi/L) Study Week On-therapy Post therapy Placebo Eltrombopag No differences in response to E-PAG relative to placebo, regardless of splenectomy, concomitant ITP medication or baseline platelet counts ( 15 Gi/L) 1 Based on repeated measures model for binary data adjusted for randomisation stratification variables. GEE used to estimate regression model parameters, exchangeable working correlation structure Cheng et al. Blood 2008;112: Abstract 400

31 Definition of platelet response: Posthoc analysis Durable Platelets 50,000/µL for at least 6 of the last 8 weeks of treatment Transient Four or more weekly platelet responses (Plt 50,000/µL) at any time during the study Stasi et al. EHA 2009

32 Overall and complete platelet response: Posthoc analysis Stasi et al. EHA 2009

33 RAISE: odds of significant bleeding 65% reduction in the odds of Grades 2-4 bleeding OR (95% CI) = 0.35 (0.19,0.64) p<0.001 % of Subjects with Bleeding On-therapy Post therapy Study Week Placebo (G2-G4) Eltrombopag (G2-G4) Cheng et al. Blood 2008;112: Abstract 400

34 Reductions in ITP medications and use of rescue OR = 3.10 (95%CI: ), P=0.016 P = OR: 0.33 (95%CI: 0.16, 0.64), P=0.001 P 25/62 24/135 Primarily reduction in use of corticosteroids

35 Eltrombopag Improved Patient Healthrelated Quality of Life Physical role (P = 0.030) Vitality (P = 0.045) Emotional role (P = 0.023) Mental component summary (P = 0.030)

36 Adverse Events of Special Interest Adverse event, a n (%) Bleeding AEs On-therapy bleeding On-therapy serious bleeding Post-therapy bleeding Placebo n = (31) 4 (7) 6 (10) Eltrombopag n = (19) 1 (<1) b 6 (4) Thromboembolic AEs (on therapy) 0 2 (1) Hepatobiliary AEs (on therapy) 5 (8) 16 (12) Cataracts 5 (8) 5 (4) Malignancies 1 (2) 1 (<1) AEs, adverse events. a Investigator-reported adverse events. b Significantly (P <0.001) reduced in the eltrombopag treatment arm.

37 EXTEND: open-label extension study Chronic ITP patients previously enrolled in Eltrombopag studies Enrolled N=207 Stage 1: Initiate REVOLADE Eltrombopag Dosing Stage 2: Taper Concomitant Medication Stage 3: Stage 4: REVOLADE Eltrombopag Dose Modulation Eltrombopag Maintenance

38 EXTEND: Durable platelet count elevation 80% of patients achieved a platelet count of >50,000/µL at least once and 78% of these patients maintained platelets >50,000/µL for over 50% of their time in the study. 35% of subjects had a response for >10 weeks

39 EXTEND: Eltrombopag decreases bleeding Percentage of Subjects Grade 1-4 Bleeding Grade 2-4 Bleeding Baseline Week 6 Week 12 Week 18 Week 24 Week 30 Week 36 Week 42 Week 48 Week 54 n=207 n=149 n=82 n=53 n=34 n=31 n=25 n=27 n=12 n=9

40 Potential Adverse Consequence of Thrombopoietic Growth Factors Thrombocytosis Thrombosis Stimulation of tumor growth Stimulation of leukemia cell growth Interactions with other cytokines Autoantibody formation Stem cell depletion Reduction in threshold for platelet activation Rebound worsening of thrombocytopenia Increased bone marrow reticulin

41 TPO-R agonists in ITP: Conclusions Proven efficacy in short, medium, and long term for the treatment of ITP plt count, bleeding, improve QOL Efficacious both prior to and after splenectomy Favorable benefit/risk profile in published studies Unknown long term side effects Can replace splenectomy?