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Welcome Ask The Experts March 24-27, 2007 New Orleans, LA

Welcome Ask The Experts March 24-27, 2007 New Orleans, LA. Are all Xa Inhibitors the Same? Alexander G. G. Turpie, MD Professor of Medicine McMaster University Hamilton, Ontario, Canada. Antithrombotics That Have Changed Clinical Practice. Anticoagulants Low-molecular-weight heparin

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Welcome Ask The Experts March 24-27, 2007 New Orleans, LA

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  1. Welcome Ask The Experts March 24-27, 2007 New Orleans, LA

  2. Are all Xa Inhibitors the Same?Alexander G. G. Turpie, MDProfessor of MedicineMcMaster UniversityHamilton, Ontario, Canada

  3. Antithrombotics That Have Changed Clinical Practice Anticoagulants • Low-molecular-weight heparin Antiplatelet Drugs • Thienopyridines • Glycoprotein IIb/IIIa Inhibitors

  4. Low Molecular Weight Heparins Nadroparin -Fraxiparine Enoxaparin -Lovenox COONa O CaO3SO O O Saccharide chain Saccharide chain OH NHSO3Ca OSO2ONa OR1 Dalteparin -Fragmin H R2 R1 = H or SO3NaR2 = COONa CHOR2 Saccharide chain CH2OH O OH HO O OR1

  5. Low-Molecular-Weight Heparins Potential Advantages: • Lack of binding to plasma proteins and endothelium • Good bioavailability • Stable dose response • Long half-life • Resistance does notdevelop

  6. Low Molecular Weight Heparin • Venous Thromboembolism - prophylaxis - treatment • Ischaemic heart disease • unstable angina • acute MI • coronary stenting • Cerebrovascular disease • ischaemic stroke • embolic stroke • Peripheral vascular disease • reconstructive surgery

  7. New anticoagulants ORAL PARENTERAL TF/VIIa TFPI (tifacogin) TTP889 X IX APC (drotrecogin alfa) sTM (ART-123) IXa VIIIa RivaroxabanApixabanLY517717YM150 DU-176bPRT-054021 Va AT Xa FondaparinuxIdraparinux II DX-9065aOtamixaban XimelagatranDabigatran IIa Fibrinogen Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2005

  8. Factor Xa inhibitors FXa may be a better target than thrombin • Has few functions outside coagulation (compared with thrombin) • Has a wider therapeutic window than thrombin (separation of efficacy and bleeding), in vitro • Thrombin inhibitors are associated with rebound thrombin generation – no evidence with FXa inhibitors • Efficacy of heparin-based anticoagulants improves as selectivity for FXa increases: UFH < LMWH < fondaparinux

  9. Factor Xa Inhibitors • Indirect • Direct

  10. Fondaparinux: First in New Classof Synthetic Inhibitors of FactorXa Total Chemical Synthesis • Single chemical entity • Highly selective for its target • No risk of pathogen contamination • Batch-to-batch consistency Herbert JM et al. Cardiovasc Drug Rev. 1997;15:1. van Boeckel CAA et al. Angew Chem, Int EdEngl. 1993;32:1671.

  11. Fondaparinux:Targeted Mechanism of Action Intrinsic pathway Extrinsic pathway Antithrombin Xa Xa AT AT AT Fondaparinux II IIa Fibrinogen Fibrin clot Turpie AGG et al. NEngl J Med. 2001;344:619.

  12. Overall EfficacyFondaparinux vs Enoxaparin Fondaparinux better Exact 95% CI Enoxaparin better Ephesus N = 1817 [72.9; 37.5] 58.5% Pentathlon 2000 N = 1584 [52.2; 7.6] 28.1% Penthifra N = 1250 61.6% [73.4; 45.0] Pentamaks N = 724 [75.5; 44.8] 63.1% Overall Odds Reduction [63.2; 45.8] 55.3% P = 10 -17 % odds reduction 0 100 -80 -60 -40 -20 20 40 60 80 -100 Overall odds reduction for proximal DVT = 57.4% [CI: 72.3 - 35.6]; p = 10 x -6 Turpie AGG, et al. Arch Intern Med. 2002;162:1833-1840.

  13. 0.06 Fondaparinux 0.04 0.05 Enoxaparin 0.03 0.04 HR 1.01 95% CI 0.90, 1.13 Cumulative hazard 0.03 Cumulative hazard 0.02 0.02 0.01 0.01 0.00 0 1 2 3 4 5 6 7 8 9 0.00 Days 0 1 2 3 4 5 6 7 8 9 Days OASIS-5 – efficacy and safety at day 9 Death, MI, refractory ischaemia Major bleeding • Primary efficacy endpoint: 5.8% (fondaparinux) vs 5.7% (enoxaparin) • Major bleeding: 2.2% (fondaparinux) vs 4.1% (enoxaparin) Enoxaparin HR 0.52 95% CI 0.44, 0.61 p<0.001 Fondaparinux OASIS-5 Trial Group NEJM 2006. Available at www.nejm.org

  14. Enoxaparin 0.06 Fondaparinux 0.04 Cumulative hazard 0.02 0.0 0 20 40 60 80 100 120 140 160 180 Days OASIS-5 – mortality at 6 months HR 0.89 95% CI 0.80, 1.00p=0.05 OASIS-5 Trial Group NEJM 2006. Available at www.nejm.org

  15. 0.12 UFH/placebo 0.10 Fondaparinux 0.08 0.06 Cumulative hazard HR 0.88 95% CI 0.79, 0.99p=0.029 0.04 0.02 0.0 0 18 36 54 72 90 108 126 144 162 180 Days OASIS-6 – death at study end (3–6 months) OASIS-6 Trial Group JAMA 2006. Available at www.jama.com

  16. Direct FactorXa Inhibitors

  17. Oral Factor Xa inhibitors Clinical development Rivaroxaban (Bayer) Phase IIb Phase III Apixaban (BMS) Phase III YM150 (Astellas) Phase IIb DU-176b (Daiichi) Phase IIb LY517717 (Lilly) Phase IIb 813893 (GSK) Phase I/II PRT054021(Portola) Phase II

  18. Direct Factor Xa inhibition XIIa Tissue factor × XIa VIIa IXa Xa Rivaroxaban Apixaban DU-176b YM150 LY517717 PRT-054021 Factor II(prothrombin) Fibrinogen Fibrin clot

  19. FXa Direct Factor Xa Inhibitors DirectFXa inhibitors eg Rivaroxaban FXa in the prothrombinase complex • Direct Factor Xa inhibitors can inhibit Factor Xa within the prothrombinase complex

  20. Rivaroxaban: a direct, competitive inhibitor of Factor Xa activity In vitro kinetic analysis 600 Rivaroxaban 0.9 nM 500 Rivaroxaban 0.7 nM Rivaroxaban 0.5 nM Rivaroxaban 0.2 nM 400 Control 1/OD/minute 300 200 100 0 0.000 0.005 0.010 0.015 0.020 1/chromogenic peptide (µM) Perzborn et al., J Thromb Haemost 2005

  21. Rivaroxaban inhibits free Factor Xa, prothrombinase-bound FactorXa, and fibrin-bound Factor Xa activity In vitro studies 100 80 60 Inhibition of Factor Xa activity (%) 40 Free Factor Xa1 20 Prothrombinase activity1 Fibrin-bound Factor Xa2 0 0.01 0.1 1 10 100 1000 Rivaroxaban (nM) 1Perzborn et al.,J Thromb Haemost 2005; 2Depasse et al., ISTH 2005

  22. Apixaban • A highly potent, oral, direct FXa inhibitor (Ki 0.08 nM) • Follow-up to razaxaban (development halted due to bleeding concerns) • Phase II study for VTE prevention after TKR: completed • Double-blind; dose-ranging; three od and three bid apixaban doses; comparator enoxaparin and warfarin; target enrolment n=1202 • Phase II pilot study for VTE prevention in patients with advanced metastatic cancer: ongoing

  23. Apixaban • The Botticelli-DVT study for treatment of acute symptomatic DVT: ongoing – efficacy and safety of apixaban 5 mg bid, 10 mg bid and 20 mg od; comparators LMWH or fondaparinux followed by VKA • Phase II study in patients with recent UA or MI: ongoing • Placebo-controlled; double-blind; target enrolment n=1800 • AF Study

  24. Rivaroxaban S4 S1 RivaroxabanHuman Factor Xa/rivaroxaban complex • Rivaroxaban is an oral, direct Factor Xa inhibitor, with high selectivity for Factor Xa (Ki 0.4±0.02 nM) • IC50 for Factor VIIa, Factor XIa, thrombin, activated protein C, plasmin, urokinase, trypsin: >20,000 nM Roehrig et al., J Med Chem 2005; Perzborn et al., J Thromb Haemost 2005

  25. 40 DVT, PE, and all-cause mortality Major bleeding 30 Estimated incidence rate* (%) 20 10 0 20 30 40 50 60 Enoxaparin 0 10 5 Rivaroxaban (mg total daily dose) Rivaroxaban bid (THR/TKR pooled): Efficacy: p=0.39 Safety: p<0.0001 *Estimated rates calculated by logistic regression adjusted for study, age, and gender

  26. DVT, PE, and all-cause mortality 40 30 Major, post-operative bleeding 30 20 Incidence – efficacy (%) Incidence – safety (%) 20 10 10 0 0 0 5 10 20 30 40 Enoxaparin Total daily dose (mg) of rivaroxaban Rivaroxaban efficacy and safety after THR with od dosing • Total rivaroxaban daily doses of 5–20 mg had similar efficacy and safety to enoxaparin when given twice daily • Rivaroxaban 10 mg once daily appears to be the optimum dose Eriksson et al. ASH 2005

  27. RECORD – REgulation of Coagulation in major Orthopaedic surgery reducing the Risk of DVT and PE • Rivaroxaban 10 mg od will be compared with enoxaparin in over 10,000 patients worldwide • RECORD 1: THR, 5 weeks therapy • RECORD 2: THR, 5 weeks vs 10–14 days enoxaparin • RECORD 3: TKR, 10–14 days therapy • RECORD 4: TKR, 10–14 days therapy

  28. 80 bid rivaroxaban doses od rivaroxaban dose 70 60 50 40 30 20 10 0 0 20 40 60 Enox+VKA Rivaroxaban total daily dose (mg) ODIXa-DVT – dose–response relationship for efficacy Primary efficacy outcome Thrombus regression without recurrent VTE (%) ≥4-point improvement in thrombus burden by CCUS without recurrent VTEDose–response relationship: p=0.67Per-protocol population (n=528)

  29. EINSTEIN-DVT – dose–response relationship for efficacy 20 Recurrent DVT or PE (fatal or non-fatal) and deterioration in CUS or PLS 18 16 14 12 10 Rate of deterioration (%) 8 6 4 2 0 10 20 30 40 LMWH/heparin +VKA Rivaroxaban total daily dose (mg) Dose–response relationship: p=0.86Per-protocol population (n=449)

  30. Rivaroxaban-Clinical Studies - VTE Treatnent - Atrial Fibrillation ACS treatment

  31. Factor Xa inhibitors in development *Prevention of VTE after major orthopaedic surgery, unless indicated

  32. New anticoagulants ORAL PARENTERAL TF/VIIa TFPI (tifacogin) TTP889 X IX APC (drotrecogin alfa) sTM (ART-123) IXa VIIIa RivaroxabanApixabanLY517717YM150 DU-176bPRT-054021 Va AT Xa FondaparinuxIdraparinux II DX-9065aOtamixaban XimelagatranDabigatran IIa Fibrinogen Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2005

  33. Antithrombotic Therapy 2007

  34. Question & Answer

  35. Thank You! Please make sure to hand in your evaluation and pick up a ClinicalTrialResults.org flash drive

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