9/7/2010. Blood Thinning Therapies: DVT, Anti-coagulation, Follow-on Biologics and Renal Adjustments. Objectives. Venous Thromboembolism

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1 Blood Thinning Therapies: DVT, Anti-coagulation, Follow-on Biologics and Renal Adjustments Lori A. Frank, Pharm.D. Sr. Regional Medical Liaison Cardiovascular/Thrombosis U.S. Medical Affairs sanofi-aventis 1 Objectives Identify patients at risk for venous thromboembolism Describe common signs, symptoms and complications Review the American College of Chest Physicians Guidelines for the management of DVT Discuss management of LMWHs in patients with renal impairment Provide an of overview of new oral anticoagulants and FDA approval of the first generic LMWH 2 Venous Thromboembolism Thrombus in deep vein of leg DVT PE Perfusion defect Anatomy clips from SmartDraw 3 1

2 VTE: The Magnitude of the Problem Total VTE per year???? Undiagnosed VTE???/yr 33% Community Diagnosed 1 67% Hospital Diagnosed 1 Diagnosed VTE 1 N= 900,000/yr VTE = venous thromboembolism; PTS = postthrombotic syndrome; CTPH = chronic thromboembolic pulmonary hypertension. 1. Heit J. Blood. 2005;106(11):abstract Pengo V et al. N Engl J Med. 2004;350: Prandoni P et al. Ann Intern Med. 1996;125: VTE: The Magnitude of the Problem Total VTE per year???? Undiagnosed VTE???/yr 33% Community Diagnosed 1 67% Hospital Diagnosed 1 Diagnosed VTE 1 N= 900,000/yr Non-fatal DVT 1 N= 376,000/yr Non-fatal PE 1 N= 237,000/yr Fatal VTE 1 N= 296,000/yr VTE = venous thromboembolism; PTS = postthrombotic syndrome; CTPH = chronic thromboembolic pulmonary hypertension. 1. Heit J. Blood. 2005;106(11):abstract Pengo V et al. N Engl J Med. 2004;350: Prandoni P et al. Ann Intern Med. 1996;125: VTE: The Magnitude of the Problem Total VTE per year???? Undiagnosed VTE???/yr 33% Community Diagnosed 1 67% Hospital Diagnosed 1 Diagnosed VTE 1 N= 900,000/yr PTS/CTPH??? Non-fatal DVT 1 N= 376,000/yr Non-fatal PE 1 N= 237,000/yr Fatal VTE 1 N= 296,000/yr ~30% PTS 3 4% CTPH 2 VTE = venous thromboembolism; PTS = postthrombotic syndrome; CTPH = chronic thromboembolic pulmonary hypertension. 1. Heit J. Blood. 2005;106(11):abstract Pengo V et al. N Engl J Med. 2004;350: Prandoni P et al. Ann Intern Med. 1996;125:

3 Who is at Risk for DVT? 7 8 Advancing age Immobilization Acute Medical Illness Obesity Virchow s Triad Surgery Prior DVT Central Venous access Trauma Venous compression (tumor, hematoma) Hypercoagulable State Protein C, S or AT III deficiency Activated protein C resistance (Leiden) Hyperhomocystenemia Antiphospholipid antibody Prothrombin mutation Cancer Cancer Therapy Estrogen therapy Pregnancy & postpartum period Erythropoiesis stimulating agents Acquired thrombophilias Geerts WH, et al CHEST 2008; 133:381S 453S 9 3

4 DVT Rate vs. Risk Factors in Surgical Patients 100 Incidence of DVT (%) % 24% 38% 50% or more Number of Risk Factors Wheeler, et al. AM J Surg 1985;150: Levels of Thromboembolism Risk Levels of Risk Low risk - Minor surgery in mobile patients - Medical patients who are fully mobile Moderate risk -Most general, open gynecologic or urologic surgery patients - Medical patients, bed rest or sick - Moderate VTE risk plus high bleeding risk High risk - Hip or knee arthroplasty, HFS - Major trauma, SCI - High VTE risk plus high bleeding risk Approximate DVT Risk Without Thromboprophylaxis < 10% 10-40% 40-80% Geerts W, et al. CHEST 2008; 133:381S 453S) 11 Factors Placing Patients at Higher Risk for VTE Risk Factor OR (95% CI) Hospitalized with recent surgery Hospitalized without recent surgery 7.98 Malignancy with chemotherapy 6.53 Malignancy without chemotherapy 4.05 History of DVT/PE 15.6 Trauma 12.0 Pregnancy 11.4 CHF 9.5 CVC or pacemaker placement 9.1 Neurological disease with extremity paresis 6.9 Immobilization (total confinement to bed) 5.6 Cohen, Thromb Haemost 2005; 94:

5 Complications of VTE 13 Signs and Symptoms of DVT Often asymptomatic Dull ache, tightness, pain in leg Edema Palpable cord Vein distention Red/blue discoloration Warmth Homan s sign (calf pain) Fever (usually low-grade) Ileofemoral Deep Vein Thrombosis 15 5

6 Post Thrombotic Syndrome 16 Recurrent DVT Cumulative Incidence Cumulative incidence days 30 days 90 days 180 days Time from index event 1 yr 2 yrs 5 yrs 10 yrs Ageno et al. Seminars In Thrombosis And Hemostasis 2006; 32: Signs & Symptoms of PE Often asymptomatic Dyspnea Rapid respiratory rate Rapid heart rate Chest pain Cough Syncope Hemoptysis

7 Pulmonary Embolism on Autopsy 19 Initial Treatment of DVT 20 Coagulation Cascade in Thrombus Formation Collagen Intrinsic Pathway Extrinsic Pathway Clotting Factors Clotting Factors Common Pathway Vitamin K-dependent Clotting Factor X Activated Form Prothrombin Thrombin Platelets Fibrinogen FIBRIN Tissue Factor Thrombus Vessel Wall Handin RI. Heart Disease. 5th ed

8 Inhibition of Coagulation Factors by Traditionally-Used Anticoagulants Intrinsic XII Extrinsic XI vtissue Factor Injectable UFH AT IX VIII VII Injectable LMWH AT X V II Oral Warfarin UFH = unfractionated heparin AT = antithrombin v Fibrinogen Hirsh J et al. Chest 2008:133;141S-159S. Fibrin Clot 22 Initial Treatment of Acute DVT ACCP Conference on Antithrombotic and Thrombolytic Therapy For patients with objectively confirmed DVT, we recommend short-term treatment with SC LMWH (Grade 1A), IV UFH (Grade 1A), monitored SC UFH (Grade 1A), fixed-dose SC UFH (Grade 1A), or SC fondaparinux (Grade 1A) rather than no such shortterm treatment For patients with a high clinical suspicion of DVT, we recommend treatment with anticoagulants while awaiting the outcome of diagnostic tests (Grade 1C) Kearon C et al. Chest. 2008;133:454S-545S. 23 Initial Treatment of Acute DVT ACCP Conference on Antithrombotic and Thrombolytic Therapy In patients with acute DVT, we recommend initial treatment with LMWH, UFH, or fondaparinux for at least 5 days and until the INR is 2.0 for 24 h (Grade 1C) In patients with acute DVT, we recommend initiation of VKA together with LMWH, UFH, or fondaparinux on the first treatment day rather than delayed initiation of VKA (Grade 1A) Kearon C et al. Chest. 2008;133:454S-545S. 24 8

9 Why Overlap Parenteral Anticoagulants and Warfarin? Elimination Half Lives of Vitamin K-dependent coagulation proteins Coagulation Factors Factor II Factor VII Factor IX Factor X Anticoagulant Proteins Protein C Protein S hours 4-6 hours hours hours 9 hours 60 hours Wittkowsky A. Dis Mon. 2005;51: Why Overlap Parenteral Anticoagulants and Warfarin? Randomized, double-blind study of IV UFH + acenocoumarol or acenocoumarol alone for initial treatment of proximal DVT Study stopped early by monitoring board because of an excess of symptomatic events in the acenocoumarol alone group UFH + Acenocoumarol Acenocoumarol alone Symptomatic events 6.7% 20% P=0.058 Asymptomatic extension of venous thrombosis 8.2% 39.6% P<0.001 Brandjes DP et al. N Engl J Med. 1992;327: In Texas We know prophylaxis 27 9

10 Initial Treatment of DVT Inpatient or Outpatient? American College of Chest Physicians 1 : In patients with acute DVT, we recommend initial treatment with LMWH SC once or twice daily, as an outpatient if possible (Grade 1C),... rather than treatment with IV UFH American College of Physicians/American Academy of Family Physicians 2 : Outpatient treatment of DVT... with LMWH is safe and cost effective for carefully selected patients and should be considered if the required support services are in place American Society of Health-System Pharmacists 3 : The American Society of Health-System Pharmacists believes that the use of low-molecular-weight-heparin (LMWH) therapy for the treatment of acute deep-vein thrombosis (DVT) in appropriate adult outpatients is as safe and effective as traditional inpatient therapy with unfractionated heparin (UFH) 1. Kearon C et al. Chest 2008;133:454S-545S. 2. Snow v et al. Ann Intern Med 2007;146: American Society of Health System Pharmacists. Am J Health-Syst Pharm 2004;61: VTE Treatment FDA-approved Indications FDA Indications Dalteparin Enoxaparin Fondaparinux Treatment of acute DVT ± PE Outpat. TX of acute DVT Treatment of acute PE Fragmin PI April Lovenox PI May Arixtra PI October LMWHs in Renal Impairment 30 10

11 Renal Insufficiency and LMWHs Background Renal failure patients are inherently at increased risk for bleeding LMWH eliminated renally Most LMWH clinical trials exclude patients with severe renal insufficiency 31 College of American Pathologists Consensus Recommendations Anti-factor Xa monitoring may be of value in: Renal insufficiency (Level 3) Markedly obese (Level 3) Very small patient < 40kg * Prolonged duration therapeutic doses of LMWH (Level 3) Pregnant patient (Level 3) Pediatric patient (Level 2) Laposata M, et al. Arch Pathol Lab Med. 1998;122: * Duplaga BA, et al. Pharmacotherapy 2001;21: College of American Pathologists Consensus Recommendations Recommended monitoring issues Calibration with LMWH to establish standard curve (Level 2) Sample drawn 4 hours after SQ dose (Level 3) Target Anti-factor Xa Treatment doses Twice daily doses: IU/ml (Level 3) Once daily doses: IU/ml (Level 3) Laposata M, et al. Arch Pathol Lab Med. 1998;122:

12 Limitations of Anti-Xa Monitoring Lack of rigorously defined therapeutic range Relationship between anti-xa levels and clinical outcomes is unclear Normal therapeutic range Twice-daily dosing: conservative therapeutic range is IU/mL, less conservatively IU/mL Once-daily dosing: Target range less clear, but IU/mL is reasonable Assays are highly variable (Chromogenic assay recommended) Limited availability Lack of recommendations for dose adjustment Anti Xa level does not measure the other effects of LMWH on hemostasis (i.e. TFPI, von Willebrand factor, etc.). Hirsh J, et al. CHEST 2004;126:188S-203S Laposata M, et al. Arch Pathol Lab Med. 1998;122: Renal Impairment Package Insert Dosing Considerations Dalteparin Caution in patients with kidney insufficiency. Anti Factor Xa monitoring recommended for CrCl < 30 ml/min when using for extended treatment of acute VTE in cancer patient. Enoxaparin FDA-approved dose adjustment based on PK data Fondaparinux Contraindicated <30 CrCl Use with caution with CrCl ml/min Lovenox PI 5/07 Fragmin PI 4/07 Arixtra PI 4/ Enoxaparin Dosage Regimens Severe Renal Impairment* Indication Prophylaxis Abdominal surgery Hip or knee replacement surgery Medical patients during acute illness Ischemic complications of UA/NSTEMI Dosage 30 mg SC qd 30 mg SC qd 30 mg SC qd 1 mg/kg SC qd Indication Treatment Inpatient DVT with/without PE Outpatient DVT without PE 1 mg/kg SC qd 1 mg/kg SC qd *CrCl <30 ml/min; when concurrently administered with aspirin; when administered in conjunction with warfarin sodium. UA, unstable angina; NSTEMI, non ST-elevation myocardial infarction; CrCl, creatinine clearance. LOVENOX (enoxaparin sodium injection) Prescribing Information. Sanofi-aventis, Bridgewater, NJ

13 Long-Term Treatment of DVT 37 Goals of Long Term DVT Treatment 1. To complete treatment of the acute episode of DVT. This goal predominates during the early phase of long term treatment (ie, the first 3 months) 2. To prevent new episodes of DVT not related to the acute event. This becomes the main goal after the first 3 months Kearon C et al. Chest. 2008;133:454S-545S. 38 Duration of Anticoagulant Therapy Anticoagulant therapy for VTE should be continued until: The benefits (reduction of recurrence of VTE) no longer clearly outweigh the risks (bleeding) or The patient prefers to stop treatment, even if continuing treatment is expected to be of net benefit. Kearon C et al. Chest. 2008;133:454S-545S

14 Duration of Therapy DVT Summary Description Duration of Treatment Comment Transient Risk Factor 3 months Risk factors include: surgery, hospitalization, immobilizing cast, travel, pregnancy Unprovoked 3 months Re-evaluated risk:benefit after 3 months Distal Proximal DVT 3 months Long-term therapy > 1 unprovoked DVT Long-term therapy If risk:benefit ratio favorable DVT + Cancer Indefinite therapy until cancer resolved LMWH first 3-6 months; warfarin/lwmh thereafter Note: Upper extremity DVT should use the same criteria as described above. Kearon C et al. Chest. 2008;133:454S-545S. 40 Risk Factors for Major Bleeding During Anticoagulant Therapy Older age, particularly > 75 years Previous GI bleeding Previous noncardioembolic stroke Chronic renal or hepatic disease Concomitant antiplatelet therapy Other serious acute or chronic illness Poor anticoagulant control Suboptimal monitoring of anticoagulant therapy Kearon C et al. Chest. 2008;133:454S-545S. 41 New Oral Anticoagulants on the Horizon 42 14

15 Historical Context No new oral anticoagulants approved since warfarin in 1954 Ximelagatran Oral Direct Thrombin Inhibitor Presented to the FDA in 2007 Significant risk for hepatotoxicity; concern about increased MI risk in TKR patients Fareed Semin Thromb Haemostas Advances in Anticoagulant Therapy in the United States 1940s Heparin available 1998 First available DTI 1993 First available LMWH 2001 First available synthetic factor Xa inhibitor Injectable Agents Oral Agents 1954 Warfarin available 56 Years 2010 First oral DTI and Xa inhibitor? LMWH = low-molecular-weight heparin DTI = direct thrombin inhibitor AC Management Services 44 Inhibition of Coagulation Factors by Traditionally-Used Anticoagulants Intrinsic XII Extrinsic XI vtissue Factor Injectable UFH AT IX VIII VII Injectable LMWH AT X V II Oral Warfarin UFH = unfractionated heparin AT = antithrombin v Fibrinogen Hirsh J et al. Chest 2008:133;141S-159S. Fibrin Clot 45 15

16 Inhibition of Coagulation Factors by New Anticoagulants Intrinsic XII Extrinsic XI vtissue Factor Inhibitors Xa Rivaroxaban Apixaban IX VIII X V VII v II Fibrinogen DTIs Dabigatran Hirsh J et al. Chest 2008:133;141S-159S. Fibrin Clot 46 Rivaroxaban (Xarelto TM ) Bayer/Johnson&Johnson Direct Xa inhibitor First in Class Oral Once daily Synthetic accessed April 6, Regulatory- US US-NDA July submission by J&J to FDA Indication: seeking approval for rivaroxaban use for DVT and PE prevention in patients undergoing hip or knee replacement surgery FDA Ad Comm March 19, 2009 Vote 15:2 in favor of approval FDA Briefing Guide- Rivaroxaban March 2009 Significant FDA concerns: 1. Bleeding increases with drug exposure 2x the dose = 5x increase in bleeding 2. Drug Interactions may increase bleeding 3. Moderate renal or hepatic impairment may increase bleeding 4. Potential Adverse CV events on d/c of rivaroxaban 5. Liver Toxicity 48 16

17 Rivaroxaban PK ADME (Absorption, Distribution, Metabolism, Excretion) Absorption absolute bioavailability of the 10-mg tablet is estimated to be % irrespective of food Bioavailability decreases with increasing doses > 15 mg. Decreased bioavailability of 20 mg. tablet when given with food (intake decreases AUC by ~ 40%) Distribution Metabolism Vd at steady-state is approximately 50 L(0.62 L/kg), indicating its low affinity to tissues. High plasma protein binding (>90%) 2/3 of the dose is metabolized by the liver Primarily CYP3A4/3A5/CYP2J2 with some CYP independent hydrolysis Note: Rivaroxaban is also a a moderate Pgp substrate Elimination Rivaroxaban has multiple elimination pathways. Approximately 1/3 of the drug is excreted unchanged by the kidney (mainly by active renal secretion, but also by glomerular filtration). Johnson & Johnson Rivaroxaban Briefing Book to the FDA issued February Rivaroxaban Clinical Trial Program Overview Phase 2 Phase 3 VTE prevention-ortho ODIXa-HIP1 (phase 2a) ODIXa-HIP2 ODIXa-KNEE ODIXa-OD-HIP COMPLETED VTE treatment ODIXa-DVT EINSTEIN DVT COMPLETED RECORD RECORD 1 (after THR) RECORD 2 (after THR) RECORD 3 (after TKR) RECORD 4 (after TKR) COMPLETED EINSTEIN EINSTEIN DVT EINSTEIN PE EINSTEIN EXT Stroke prevention in atrial fibrillation ROCKET AF Secondary prevention of Acute Coronary Syndromes ATLAS (TIMI 46) Dose finding COMPLETED NCT (Japan AF) Efficacy and Safety Study for Rivaroxaban in Patients with ACS (ATLAS ACS TIMI 51) Start Date: November 2008 ONGOING Medical Prophyloxis MAGELLAN ONGOING Clinical Trials.gov 50 Rivaroxaban VTE Treatment INDICATION NAME N DESIGN STATUS DVT Treatment EINSTEIN- DVT Evaluation PHASE 3 N/A Randomized, open-label, non-inferiority study. A variable length of 3, 6 or 12 months against current standard treatment of LMWH followed by dose-adjusted VKA. The main dose of rivaroxaban will be 20mg once daily Eligibility: Confirmed acute symptomatic proximal DVT without symptomatic PE ESC 2010 PE treatment EINSTEIN- PE Evaluation PHASE 3 N/A Randomized, open-label, non-inferiority study. A variable length of treatment is 3, 6, or 12 months against current standard treatment of LMWH followed by dose-adjusted VKA vs rivaroxaban 20mg once daily Eligibility: Confirmed acute symptomatic PE with or without symptomatic DVT Open - Start 01/2007 DVT/PE Treatment Extended Secondary Prophylaxis EINSTEIN- Extension PHASE 3 N/A Randomized, double-blind, placebo-controlled, superiority study for efficacy. The main dose of rivaroxaban will be 20mg once daily. Eligibility Criteria: Patients with confirmed symptomatic PE or DVT who have been treated for 6 or 12 months with VKA or rivaroxaban. Exclusion Criteria: Indication for VKA other than DVT and/or PE -Patients in whom anticoagulant treatment for their index PE or DVT should be continued Completed 51 17

18 Rivaroxaban Dosing PROPOSED INDICATION: Orthopedic Prophylaxis: 10 mg. QD 6-8 h post-surg Hip Replacement Knee Replacement FUTURE INDICATIONS: ACS: 2.5 mg twice daily and 5 mg twice daily going into ph. III Atrial Fibrillation: 20 mg once daily DVT/PE: 15 mg twice daily x 3 weeks then 20 mg once daily Medically Ill : 10 mg once daily x 35 days Eikelboom JW, Weitz JI. Circulation. 2007;116; Warfarin Institute of America. Rivaroxaban (BAY ), Xarelto : A possible replacement for warfarin (Coumadin, Jantoven). Available at: Accessed April 3, Kwong LM. US Musculoskeletal Rev. 2006;2: Available at: Accessed April 3, Bayer Investor Relations Web Site. About RECORD studies [backgrounder] Available at: Accessed April 3, Apixaban Oral, direct, selective factor Xa inhibitor Produces concentration-dependent anticoagulation No formation of reactive intermediates No organ toxicity or LFT abnormalities in chronic toxicology studies Low likelihood of drug interactions or QTc prolongation Good oral bioavailability No food effect Balanced elimination (~25% renal) Half-life ~12 hrs O N N O O NH 2 N N O He et al., ASH, 2006, Lassen, et al ASH, Apixaban MOA/PK/PD Mechanism of Action Pharmacologic class Direct anti-factor Xa (Reversible inhibitor) Product origin Synthetic Administration Oral/BID route/convenience ADME (Absorption, Distribution, Metabolism, Excretion) Bioavailability ~66% Drug/food interactions No food interaction; potential for significant drug-drug interactions is expected to be low Vd Low--primarily distributed in blood; 87% protein-bound Cmax 1-3 hours Metabolism Multiple pathways; prominent pathway is CYP 3A4 dependent Elimination 25% renal; ~55% fecal Half-life 8-15 hours Eriksson BI et al. Clin Pharmacokinet 2009;48:

19 Apixaban Phase II-III Clinical Trials Study Name Phase N Study Design Status/ Study Publication VTE Prophylaxis -- Joint Replacement APROPOS II 1238 TKR: Patients randomly assigned to 1 of 6 doses of apixaban (5, 10, or 20 mg) daily or a bid divided dose, or enoxaparin 30 mg bid, or open-label warfarin titrated to an INR of Apixaban and enoxaparin were started hours post-op; warfarin the evening of the day of surgery. Treatment continued for days. J Thromb Haemost 2007;5: PK Modeling (APROPOS) II 855 Construction of an exposure model using NONMEM software. Total of 4694 concentration data points. ISTH 2007 Abst P-M-663 ADVANCE-1 III 3195 TKR: MC, randomized, double-blind, active-controlled, parallel-group, efficacy/safety study. Apixaban 2.5 mg bid versus enoxaparin 30 mg BID. Both treatments started hr post-op for days. ADVANCE-2 III 3057 TKR: MC, randomized, double-blind, active-controlled parallel-group efficacy/safety study. Apixaban 2.5 mg bid started hr post-op versus enoxaparin 40 mg daily started 12±3 hr pre-op for days. ADVANCE-3 III 5406 THR: MC, randomized, double-blind, active-controlled parallel-group efficacy/safety study. Apixaban 2.5 mg bid versus enoxaparin 40 mg daily for 5 weeks. N Engl J Med 2009;361: ISTH 2009 Abst LB-MO-005 Completed Sept 2009 Derived from Trial Trove on October 8, Shantsila E & Lip GYH. Curr Opin Investig Drugs 2008;9: accessed October 8, Apixaban Phase II-III Clinical Trials Study Name Phase N Study Design Status/ Study Publication VTE Treatment Botticelli DVT II 520 Veiled randomized, parallel group dose ranging study versus conventional treatment. Apixaban 5 mg bid, 10 mg bid, or 20 mg daily was blinded; LMWH/VKA was open-label. Treatment duration days. AMPLIFY III 2900 Randomized, double-blind efficacy study. Apixaban 10 mg bid x 7 days then 5 mg bid x 6 months versus enoxaparin bid/warfarin. Eligibility: Clinical diagnosis of DVT or PE. AMPLIFY-EXT III 2430 Randomized, double-blind efficacy study. Apixaban 2.5 or 5 mg bid versus placebo x 12 months. Eligibility: Clinical diagnosis of DVT or PE and completed standard treatment. J Thromb Haemost 2008;6: Est. completion July 2011 Est. completion May 2011 Atrial Fibrillation Phase II Japanese study IIb 222 Randomized, partially-blind safety study. Apixaban 2.5 or 5 mg bid versus warfarin x 12 weeks. Eligibility: NVAF with 1 stroke risk factor. Completed Sept 2009 AVERROES III 5600 Randomized, double-blind, efficacy study. Apixaban 2.5 or 5 mg bid versus aspirin mg daily x 36 months. Eligibility: AF with 1 risk factors for stroke who failed or are unsuitable for VKA. ARISTOTLE III 18,183 Randomized, double-blind, efficacy study. Apixaban 5 mg bid versus warfarin (INR 2-3) up to 39 months. Eligibility: NVAF with 1 risk factors for stroke. Presented ESC 2010 Est. completion Apr 2011 Derived from Trial accessed October 8, 2009 Shantsila E & Lip acce GYH. Curr Opin Investig Drugs 2008;9: accessed October 8, Apixaban Phase II-III Clinical Trials Study Name Phase N Study Design Status/ Study Publication VTE Prophylaxis -- Cancer/Chemotherapy ADVOCATE II 125 to date VTE Prophylaxis -- Medical Patients Randomized, double-blind, safety study. Apixaban 5, 10, or 20 mg versus placebo x 12 weeks. Eligibility: Patients receiving either first or second line chemotherapy for metastatic cancer. ISTH 2009 Abst PP-WE-489 ADOPT III 6524 Randomized, double-blind, efficacy study. Apixaban 2.5 mg bid x 30 days versus enoxaparin 40 mg daily x 6-14 days. Eligibility: age 40 hospitalized with CHF, acute respiratory failure, infection (without septic shock, acute rheumatic disorder, IBD Est. completion Dec 2010 ACS -- Secondary Prevention Phase II Japanese Study II 170 Randomized, double-blind, placebo control, safety study. Apixaban 2.5 or 5 mg bid versus placebo x 24weeks. Eligibility: Recent ( 7 days) ACS. Clinically stable on optimal treatment. Est. completion Oct 2010 APPRAISE-1 II 1715 Randomized, double-blind, placebo control, dose ranging, study. 4 doses of apixaban or placebo x 26 weeks. Apixaban randomization stratified by clopidogrel use. Eligibility: Recent ( 7 days) ACS. Clinically stable on optimal treatment. APPRAISE-2 III 10,848 Randomized, double-blind study. Apixaban 5 mg twice daily versus placebo until 1 st event. Eligibility: Recent ACS. Clinically stable on standard treatment. Circ 2009;119: Est. completion Nov 2011 Derived from Trial Trove on October 8, Shantsila E & Lip GYH. Curr Opin Investig Drugs 2008;9: accessed October 8,

20 Dabigatran etexilate (Pradaxa or Pradax ) Boehringer Ingelheim Pharma Oral direct thrombin inhibitor Prodrug Completely converted to active form: dabigatran Synthetic Highly selective Reversible binding No effect of food No reversal agent or antidote available Stangier J. Clin Pharmacokinet 2008;47: Pradax Product Monograph -Canada July 31, Dabigatran PK ADME (Absorption, Distribution, Metabolism, Excretion) Absorption Distribution Metabolism High lipophilicity results in poor absorption of dabigatran, therefore converted to dabigatran etexilate T max in healthy volunteers: hrs Absorption has been noted to be slow and delayed on the day of surgery only Vd L after IV administration Protein binding: 35% Not metabolized by CYPs Does not inhibit or induce CYPs activity t ½ : 8-14 hrs Elimination Renal clearance: 80% after IV administration Stangier J. Clin Pharmacokinet 2008; 47: Pradax Product Monograph Canada July 31, Dabigatran Trials completed Study name Dabigatran dose Comparison Study population BISTRO I 1 Dose escalating None THR II BISTRO II 2 Dose escalating Enoxaparin 40mg daily THR or II TKR RE-NOVATE 3 220mg or 150mg daily Enoxaparin 40mg daily THR III RE-MODEL 4 220mg or 150mg daily Enoxaparin 40mg daily TKR III RE-MOBILIZE 5 220mg or 150mg daily Enoxaparin 30mg BID TKR III PETRO 6 50, 150, or 300mg BID * Adjusted dose warfarin A Fib II PETRO EX 7 50, 150, or 300mg BID * None A Fib II Phase RE-LY mg or 150 mg twice daily Adjusted dose warfarin A Fib III RE-COVER 9 150mg twice daily Adjusted dose warfarin VTE III *ASA: 0mg,81mg or 325mg daily 60 20

21 Dabigatran trials completed 1. Eriksson BI et al. Journal of Thrombosis and Haemostasis 2004; 2: Eriksson BI et al. Journal of Thrombosis and Haemostasis 2005; 3: Eriksson BI et al. Lancet 2007; 370: Eriksson BI et al. Journal of Thrombosis and Haemostasis 2007; 5: Ginsberg JS et al. Journal of Arthroplasty 2009; 24: Ezekowitz MD et al. Am J Cardiol 2007;100: The Petro-ex Investigators. Cerebrovascular Diseases 2006; 21(suppl 4): 2. Abstract. 8. Connolly SJ et al. N Engl J Med 2009;361: Schulman S, et al. New Engl J Med 2009; 361: RE-COVER dabigatran vs. warfarin VTE treatment Singledummy period Warfarin placebo Double-dummy period Dabigatran etexilate 150 mg bid Warfarin placebo 30 days follow up Objective confirmation of VTE 72 h Warfarin Initial parenteral therapy Dabigatran etexilate placebo bid Warfarin (INR ) E= enrollment R= randomization E R Until INR 2.0 at two consecutive measurements (parental therapy for at least 5 days) Schulman S, et al. New Engl J Med 2009;361: months End of treatment 62 RECOVER Efficacy Results VTE or related death 3 HR 1.10 (95% CI: ) Percentage AR 0.4 (95% CI: ) P<0.001 For non-inferiority Dabigatran etexilate 150 mg bid Warfarin 30 / / 1265 Schulman S, et al. New Engl J Med 2009;361:

22 RECOVER Safety Major Bleeding 2 HR 0.82 (95% CI: ) p=n.s. 1.9 Percentage Dabigatran etexilate 150 mg bid Warfarin 20 / / 1266 Schulman S, et al. New Engl J Med 2009;361: Follow-On LMWH Biologic Drug Therapy 65 Nomenclature Follow-On Biologic (FOB) products include: Biosimilars: biological compounds comparable to the reference product (nonidentical) Biogenerics: biologic compounds that are therapeutically equivalent, interchangeable and substitutable at the pharmacy/point-of-use level with the innovator product The US FDA uses the term follow-on biologics while the EMEA uses the term biosimilar. 1,2 1. Kalodiki et al. Clinical and Applied Thrombosis Hemostasis 2009; 15 (1) Harenberg J, et al, on behalf of the Subcommittee on Control of Anticoagulation of the SSC of the ISTH. Recommendations on biosimilar low-molecular-weightheparins. J Thromb Haemost 2009; 7:

23 Biological products are different from chemical drugs Protein- or carbohydrate-based products Extracted from living entity Complexed physicochemical structure Manufacturing process defines product Potential immunogenicity epoetin aspirin C. Viskov, CBI meeting, Baltimore, March 10th, 2009 Public Health Services Act 42 U.S.C. 262(i) 67 Framework for drug approval in the United States Food and Drug Administration US Food, Drug, and Cosmetic (FD&C) Act US Public Health Services (PHS) Act Center for Drug Evaluation and Research (CDER) Center for Biologic Evaluation and Research (CBER) 68 Health Care Reform Act Implemented March 23, 2010 Prior to March 2010, there was not a pathway for an abbreviated application of biologic drug therapies The Biologics Price Competition and Innovation Act of 2009 created a framework for the FDA approval of follow-on biologics This new law bears conceptual resemblance to the Hatch-Waxman Act of 1984 which created a path to market entry for small molecule pharmaceuticals but considers the complexity of biologic therapies Patient Protection and Affordable Care Act, Section 7001, Subtitle A 69 23

24 Small Molecular Therapies Is the new legislation applicable to LMWH? As many as 40 small molecule therapies, including LMWHs, were not approved under a Biologic License Agreement (BLA) but rather as a New Drug Application (NDA) Consequently, these molecules are regulated by CDER and not CBER Therefore, the new Biologics Act is not applicable to applications for generic versions of these small molecule therapies, including LMWH Current applications for generic versions of these molecules would be regulated by the Hatch-Waxman Act There is limited grandfathering for biologic products that are in a product class that is the subject of an application which has already been approved under section 505 of the FD&C Action Patient Protection and Affordable Care Act, Section 7001, Subtitle A 70 Framework for drug approval in the United States US Food, Drug, and Cosmetic (FD&C) Act Center for Drug Evaluation and Research (CDER) 505(b)(2) abbreviated pathway 505(j) abbreviated pathway (accelerated new drug application [ANDA]) 71 Requirement for an ANDA submission A generic should be comparable to the branded drug in: Dosage form Strength Route of administration Quality Performance characteristics and intended use A generic drug needs to demonstrate bioequivalence to the branded drug US Department of Health and Human Services. DevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/default.htm. Accessed December 2,

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