Xarelto® Rivaroxaban The first oral direct factor Xa inhibitor Eric Alsac Thomas Bar Marie Crétal

Medical need

350.000 to 600.000 Americans each year suffer from DVT Deep Vein Thrombosis 350.000 to 600.000 Americans each year suffer from DVT Deep venous thrombosis refers to the formation of a thrombus (blood clot) within a deep vein. People who have surgery on the lower extremities are specially vulnerable. 3 major factors: . Stagnant blood flow . Coagulation . Damage to the vein walls 1. This increases the contact time between blood and vein wall irregularities. It also prevents naturally occurring anticoagulants from mixing in the blood. Prolonged bed rest or immobility promotes stasis. 2. Coagulation is encouraged by the presence of tissue debris, collagen or fats in the veins. Orthopaedic surgery often releases these materials into the blood system. During hip replacement surgery, reaming and preparing the bone to receive the prosthesis can also release chemical substances (antigens) that stimulate clot formation into the blood stream. 3. This can occur during surgery as the physician retracts soft tissues as part of the procedure. This can also break intercellular bridges and release substances that promote blood clotting en.wikipedia.org/wiki/Deep_vein_thrombosis

Consequences Swelling of the leg Pain or tenderness on the leg Red or discoloured skin on the leg Phlebitis Pulmonary Embolism www.nhlbi.nih.gov/health/dci/Diseases/Dvt/DVT_SignsAndSymptoms.html www.nhlbi.nih.gov/health/dci/Diseases/Dvt/DVT_SignsAndSymptoms.html

650.000 cases occur each year in the United States Pulmonary embolism Sudden shortness of breath Chest pain that often mimics a heart attack Tachycardia Cough that produces bloody sputum emedicine.medscape.com/article/300901-overview

Complications Dyspnea Pulmonary hypertension Dizziness, fainting High pressure in the right ventricle Muscles of the right ventricle damages Atrial fibrillation www.mayoclinic.com/health/pulmonary-embolism Heart damages www.mayoclinic.com/health/pulmonary-embolism

Atrial fibrillation Speed or rhythm of the heartbeat disorder. 2.2 Millions Americans suffer from atrial fibrillation Atrial fibrillation Speed or rhythm of the heartbeat disorder. Inefficience of the pumping of the upper cardiac chambers. blood stagnancy in the atria a thrombus can appear Cerebrovascular accident ( hemiplegia) en.wikipedia.org/wiki/Atrial_fibrillation

Space for a new medicine

Ideal Anticoagulant Characteristic Consequence High oral bioavailability Efficiency Rapid onset Predictable pharmacokinetics and Predictable response Safety Large therapeutic index No food-drug interactions Rapid offset of action Availability of antidote 2 ways of elimination selectivity No off-target effect Reasonable cost Oral administration No need for overlap with parenteral anticoagulant No need for anticoagulation monitoring Simplified management in bleeding event Rapid reversal in hemorrhagic event Safer for patient with renal impairment No need for monitoring Improve acess

Pharmacology

Coagulation cascade and targets XARELTO® Xa-Prothrombinase complex

Rivaroxaban’s structure

Rivaroxaban : Discovery IC50 = 120 nM IC50 = 8 nM Product from HTS Reevaluation of the HTS hits Downloaded from http://pubs.acs.org on November 25, 2008 3 R = H IC50 = 20 µM 4 R = Cl IC50 = 90 nM IC50 = 0.7 nM Ki = 0.4 nM Optimisation BAY 59-7939 J. Med. Chem., 2005, 48 (19), 5900-5908 • DOI: 10.1021/jm050101d 13

Rivaroxaban: chemical structure 5 -Chlorothiophène-2-carboxamide Essential for potent Xa inhibition S-configuration Specific interaction with FXa oxazolidinone Cental template for the binding two hydrogen bonds to Gly219: a strong hydrogen bond (2.0 Å) from the carbonyl oxygen of the oxazolidinone core and a weaker one (3.3 Å) from the NH group of the chlorothiophenecarboxamide . Supported by these two hydrogen bonds, the (S)- oxazolidinone core provides the L-shape needed for Fxa binding. It serves as a central template for directing its substituents into the S1 and S4 subsites, a binding mode typical of synthetic direct FXa inhibitors The carbonyl group of the morpholinone does not appear to interact directly with FXa, but rather effects a planarization of the morpholinone ring and brings it into a perpendicular arrangement to the aryl ring. x60-fold higher potency of the morpholinone analogue The key interaction of 5 with FXa in the S1 pocke involves the chlorothiophene moiety: its chlorine substituent interacts with the aromatic ring of Tyr228 located at the bottom of the S1 pocket. 4-aminomorpholine-3-one Essential for a higher potency J. Med. Chem., 2005, 48 (19), 5900-5908 • DOI: 10.1021/jm050101d 14

Rivaroxaban : structure-activity relationship Tyrosine 228 S1 Pocket Acide Aspartique 189 Glycine 219 Tryptophane 215 S4 Pocket Hydrophobic Interactions Tyrosine 99 Hydrogen Bonds Phénylalanine 174 15

X- Ray Crystallography

Prodrugs or not prodrugs… Rivaroxaban does not need any liver conversion…. UNLIKE Ximelagatran Withdrawn on 14 February 2006 EMEA/60465/2006 0.13, CURRENT

Prodrugs or not prodrugs… Ximelagatran Melagatran Dehydroxylation Liver conversion Ximelagatran undergoes rapid enzymatic conversion to melagatran via 2 intermediates, ethyl-melagatran (from the ethyl ester of melagatran formed by reduction of the hydroxyl group) and hydroxyl-melagatran (the hydroxyamidine of melagatran, formed by hydrolysis of the ethyl group) Dealkylation Vasc Health Risk Manag. 2006 March; 2(1): 49–58. 18

Pharmacodynamic data

Pharmacodynamic data Selectivity Inhibition of Human Protease Selectivity profile of Rivaroxaban Inhibition of Concentration (nM) IC50 = 0.7 Ki = 0.4 +/- 0.002 Factor Xa Other Serin Protheases : thrombin, Trypsin plasmin FVIIa, FIXa, FXIa urokinase activated protein C Journal of Thrombosis and Haemostasis, 3: 514–521 In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939—an oral, direct Factor Xa inhibitor IC50 > 20 000 Journal of Thrombosis and Haemostasis, 3: 514–521 20

Pharmacodynamic data Pharmacological actions Competitively inhibits FXa IC50 = 0.7 nM Competitively inhibits prothrombinase activity IC50 = 2.1 nM Inhibition of clot-bound FXa concentration-dependently IC50 =75 nM Drugs of the Future 2006, 31(6): 484-493 Rivaroxaban Inhibition of clot-bound FXa concentration-dependently (almost complete inhibition (85-97%) obtained at concentrations > 500 nM) IC50=0.7nM i IC50=2.1nM IC50=75nM Drugs of the Future 2006, 31(6): 484-493 21

Pharmacodynamic data Anticoagulant effects concentration-dependent Rivaroxaban has a concentration-dependent anticoagulant effect in all tests of the secondary hemostasis Clinical Pharmacology & Therapeutics (2005) 78, 412–421; doi: 10.1016/j.clpt.2005.06.011 Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor Rivaroxaban has a concentration-dependent anticoagulant effect in all tests of the secondary hemostasis except the TT Clinical Pharmacology & Therapeutics (2005) 78, 412–421; doi: 10.1016/j.clpt.2005.06.011 22

Pharmacodynamic data Anticoagulant effects in human plasma Rivaroxaban prolonged PT, aPTT independently of ATIII Relative Change in PT Relative Change in aPPT Source:Clinical Pharmacology & Therapeutics (2005) 78, 412–421; doi: 10.1016/j.clpt.2005.06.011 Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor aPTT activated partial thromboplastin time PT prothrombin time Rivaroxaban had a concentration-dependent anticoagulant effect in all tests except the TT Time (h) Time (h) 1.25 mg BAY 59-7939 5 mg BAY 59-7939 10 mg BAY 59-7939 20 mg BAY 59-7939 40 mg BAY 59-7939 80 mg BAY 59-7939 Placebo PT : prothrombin time aPPT : (activated) partial thromboplastin time Clinical Pharmacology & Therapeutics (2005) 78, 412–421; doi: 10.1016/j.clpt.2005.06.011 23

Summary of Pharmacodynamic Studies selective inhibitor proved pharmacological properties concentration dependent action 02/01/09: predictable PK and PD across a wide range of doses

X A R E L T O Pharmacokinetic data

METABOLISM & ELIMINATION : ABSORPTION : - Fabs : 60-80% for the 10mg dose - Cmax : 2-4h after tablet intake - Food does not affect AUC and Cmax DISTRIBUTION : - Plasma protein binding: high (92-95% SA) - Volume of distribution: moderate (50L  0.62L/kg) - low affinity to tissues METABOLISM & ELIMINATION : 2/3 of dose undergoes metabolic degradation Metabolised by CYP3A4, CYP2J2 and CYP-independent mechanisms METABOLISM & ELIMINATION : 1/3 of the dose undergoes direct renal elimination Low-clearance drug: half-life: 7-11h Half  eliminated renally Half  eliminated by the fecal route EMEA: CHMP ASSESSMENT REPORT FOR Xarelto Doc.Ref.: EMEA/543519/2008

Pharmacokinetic properties Elderly No dose adjustment Hepatic impairment Contraindicated: hepatic disease with coagulopathy and bleeding risk Used with caution: moderate hepatic impairment Renal impairment Not recommended: creatinine clearance<15mL/min Used with caution: creatinine clearance 15-29mL/min Inter-individual variability: moderate

Inter-individual variations: gender, weight and renal impairment « Les nouveaux anticoagulants » N. Rosencher Inter-individual variability: moderate 18 to 33% for AUC 16 to 39% for Cmax « Les nouveaux anticoagulants » N. Rosencher

Summary of Pharmacokinetic studies High oral bioavailibility No food and drug interactions 2 ways of elimination Reversible effect

Reproduction toxicity

Pre-clinical studies: Reproduction toxicity Fertility was unaffected by treatment of male and female animals (rat and rabbit) Target organs in foetus: skeleton (incomplete progressed ossification and malformations), liver and spleen, heart blood vessels  rivaroxaban administration during pregnancy is contraindicated  Xarelto is contraindicated during breast-feeding because it is secreted into milk CHMP ASSESSMENT REPORT FOR Xarelto (EMEA) pages 13-15 EMEA: CHMP ASSESSMENT REPORT FOR Xarelto Doc.Ref.: EMEA/543519/2008

Clinical studies

Rivaroxaban : clinical studies Target: evaluate rivaroxaban in the prevention and treatment of a broad range of acute and chronic blood-clotting disorders A substantial program: 50,000 patients are expected to be enrolled overall into the rivaroxaban clinical development program

Rivaroxaban : clinical studies A FIRST INDICATION TO ENTER THE MARKET RECORD Mid 2008 Venous Blood Clot Prevention in Major Orthopedic Surgery IN UK : 59.205 Hip replacement operations / year incidence of nonfatal DVT: up to 5% 56.652 Knee replacement operations / year incidence of non fatal DVT: up to 14% nice.org.uk Venous Thromboembolism-Rivaroxaban : Final scope

Rivaroxaban : clinical studies RECORD Rivaroxaban compared with Enoxaparin for: Thromboprophylaxis after hip arthroplasty (RECORD 1 and 2) Thromboprophylaxis after knee arthroplasty (RECORD 3 and 4) Randomized, double-blind, parallel-group, multicentre More than 12 500 patients Primary efficacy endpoints: Deep vein thrombosis, non-fatal pulmonary embolism, all-cause mortality Secondary efficacy endpoints: Major venous thromboembolism Primary safety endpoints: Major bleeding Secondary safety endpoints: Cardiovascular events, nonmajor bleeding REgulation of Coagulation in major Orthopedic surgery reducing the Risk of DVT and PE) Eriksson BI, Borris LC, Friedman RJ; N Engl J Med. 2008;358(26):2765-2775.

Record 1 Rivaroxaban vs Enoxaparin for thromboprophylaxis after hip arthroplasty Primary efficacy: 1595 patients Secondary efficacy: 1686 patients F o l l ow- up Surger y Mandatory bilateral venography Rivaroxaban 10mg/d random 4541 patients Enoxaparin 40mg/d Eriksson BI, Borris LC, Friedman RJ; N Engl J Med. 2008;358(26):2765-2775. Primary efficacy: 1558 patients Secondary efficacy: 1678 patients Day 1 Day 36 Day 65 : First dose 6-10h after surgery : First dose 12h before surgery Eriksson BI, Borris LC, Friedman RJ; N Engl J Med. 2008;358(26):2765-2775.

Record 1 Results of the efficacy study… P<0,001 P<0,001 Incidence (%) - 70 % - 88 % Eriksson BI, Borris LC, Friedman RJ, et al; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765-2775. 40 mg/d 58/1558 10mg/d 18/1595 40 mg/d 33/1678 10mg/d 4/1686 Primary efficacy: deep-vein thrombosis, nonfatal pulmonary embolism, death Secondary efficacy: Major venous thromboembolism Eriksson BI, Borris LC, Friedman RJ; N Engl J Med. 2008;358(26):2765-2775.

Record 1 The safety study… 2224 received Enoxaparin 4433 patients 2209 received Rivaroxaban P=0,18 Incidence (%) Eriksson BI, Borris LC, Friedman RJ, et al; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765-2775. 40mg/d 2/2224 10mg/d 6/2209 40mg/d 129/2224 10mg/d 128/2209 Major bleeding Nonmajor bleeding Eriksson BI, Borris LC, Friedman RJ; N Engl J Med. 2008;358(26):2765-2775.

Record 1 Liver function tests : 1 Enoxaparin 40 mg once daily Rivaroxaban 10 mg once daily ALT > 3 x ULN On treatment During follow-up 51 / 2129 2,7% 6 / 1926 0,3% 43 / 2128 2,0% 3 / 1931 0,2% ALT > 3 x ULN + Bilirubin > 2 x ULN ON treatment 1 / 2142 < 0,1% 0 / 1925 0,0% 1 / 2143 < 0,1% 0 / 1943 0,0% Ximelagatran: ALT ˃ 3 x ULN: 6% (37 patients / 612) vs Placebo: 1% (6 patients / 611) 2 1: Eriksson BI, Borris LC, Friedman RJ; N Engl J Med. 2008;358(26):2765-2775. 2 : n engl j med 349;18

Approvals Venous Blood Clot Prevention in Major Orthopedic Surgery September 2008 the 16th : Health Agency of Canada approve Rivaroxaban. September 2008 the 30th : EMEA approve Rivaroxaban.

Rivaroxaban : clinical studies OTHERS INDICATIONS TO EXTEND THE MARKET EINSTEIN 2010 Venous Blood Clot Treatment ROCKET AF 2010 Stroke Prevention in patients with Atrial Fibrillation MAGELLAN 2011 Prevention of VTE in hospitalised, medically ill patients ATLAS ACS TIMI 46 2012 Secondary Prevention of Acute Coronary Syndrome

Rivaroxaban : clinical studies ROCKET AF Rivaroxaban compared with vitamin K antagonist for the prevention of stroke and Embolism Trial in Atrial Fibrillation Randomized, double-blind, parallel-group, multicentre 14 000 patients Primary efficacy endpoints: Composite of stroke and non central nervous system systemic embolism Primary safety endpoints: Composite of major and non-major clinically relevant bleeding events Expected regulatory filing date: 2010 non CNS systemic embolism (blood clots outside of the brain)

Rivaroxaban : clinical studies EINSTEIN Evaluating Rivaroxaban in patients with acute symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) Randomised, open label, parallel-group, multicentre Rivaroxaban vs enoxaparin plus vitamin K antagonist 7500 patients Primary efficacy endpoints: recurrent DVT, fatal and non fatal Pulmonary Embolism Primary safety endpoints: Major and non-major clinically relevant bleeding events Expected regulatory filing date: 2010

Rivaroxaban’s place in the market

Mode action anticoagulants Tissue factor (TF) VIIa- TF VII IX IXa Heparin VIIIa Warfarin X Xa Va Thrombin Prothrombin Fibrinogen Fibrin

New anticoagulants ORAL PARENTERAL Rivaroxaban Apixaban TF/VIIa X IX VIIIa AT Rivaroxaban Apixaban Xa Fondaparinux Idraparinux There are many targets for novel anticoagulants in the coagulation pathway: Tissue factor pathway inhibitor (TFPI) bound to Factor Xa inactivates the tissue factor (TF)–Factor VIIa complex, preventing initiation of coagulation Activated protein C (APC) degrades Factors Va and VIIIa, and thrombomodulin (soluble; sTM) converts thrombin (Factor IIa) from a procoagulant to a potent activator of protein C Fondaparinux and idraparinux indirectly inhibit Factor Xa, requiring antithrombin (AT) as a cofactor Direct (AT-independent) inhibitors of Factor Xa include rivaroxaban (BAY 59­7939), LY517717, YM150 and DU-176b (all orally available), and DX-9065a (intravenous) Oral, direct thrombin inhibitors include ximelagatran (now withdrawn) and dabigatran Weitz JI & Bates SM. New anticoagulants. J Thromb Haemost 2005;3:1843–1853 Va Ximelagatran Dabigatran IIa II Fibrinogen Fibrin New anticoagulants. J Thromb Haemost 2005;3:1843–1853

Xarelto® advantages Convenient use: Oral administration Once-daily anticoagulant No dose adjustment for majority of patients No monitoring Use both in and out of hospital in an acute and chronic setting 07/01: Convenient use: Oral administration Convenient use both in and out of hospital in an acute and chronic setting non invasive use Once-daily anticoagulant No dose adjustment for majority of patients No monitoring Saves healthcare costs and patients’ time Predictable profil Reversible, with a rapid onset and offset of action Anticoagulation from the first dose stops quickly after cessation of therapy Dose dependant Safe and effective regulation of coagulation from the first dose and throughout therapy A low risk use -Dose margin between the antithrombotic effect and the risk for increased bleeding -Low risk of food and drug interactions - Pharmacological effects due to interaction with unrelated receptor or enzymes are unlikely - Stops quickly after cessation of therapy -Non invasive use In the in vitro investigations, rivaroxaban competitively inhibited human Fxa -Elimination of rivaroxaban from plasma was rapid with no major circulating metabolites detected in plasma of rat, dog, and man. The main excretion routes in the investigated animal species and in man were renal and faecal/biliary.

Xarelto® advantages Predictable profil: Reversible Rapid onset and offset of action Anticoagulation from the first dose Dose dependant - Safe and effective regulation of coagulation

Xarelto® advantages A low risk use Dose margin between the antithrombotic effect and the risk for increased bleeding is large Low risk of food and drug interactions Stops quickly after cessation of therapy Non invasive use

Rivaroxaban vs AVK AVK Rivaroxaban Xarelto® warfarine Coumadine® Coagulation monitoring ++ No monitoring Difficulty to maintain therapeutic range Simple dosing regimen Food and drug interactions No food interactions Limited drug interactions Half-life: 20-60h Half-life: 5-9h High protein binding (99%) Low protein binding Slow onset Tmax = 2-4h 24/12: t1/2: Br J Clin Pharmacol. 2007 September; 64(3): 263–265. 24/12: AVK sont incontestablement leaders du ttment VTE car seuls VO pr l’instant. Gros pb: variations inter et intra-individuelles, effet anticoagulant n’est pas prévisible, monitoring régulier est nécessaire, interactions avec food et drug (thomson) Tout facteur qui influence le cycle normal de la vitamine K peut modifier cet équilibre (augmentation de l'apport par l'alimentation...). Un grand nombre de médicaments interfère avec le métabolisme et la pharmacodynamique des AVK, entraînant soit une potentialisation (anti inflammatoires), soit une inhibition (inducteurs enzymatiques, anti-épileptiques par exemple) de l'activité des AVK L'INR permet ainsi de définir un niveau d'anticoagulation modéré (INR entre 2 et 3) ou élevé (INR entre 3 et 4.5 Circulation 2007;116;131-133

Rivaroxaban vs LMWHs LMWHs Rivaroxaban Xarelto® Enoxaparin Lovenox® Need for injection Oral administration Once or twice-daily dosing Simple dosing regimen in and out of hospital monitoring and dose adjustment no monitoring Need to give pre-operatively according to European label First dose after surgery Short-term use

Indirect inhibitors of FXa TF/VIIa X IX IXa VIIIa AT Xa Fondaparinux Idraparinux Rivaroxaban N’agissent pas directement sur le FXa mais par le biais de l’antithrombine (thomson) Va IIa II Fibrinogen Fibrin

Rivaroxaban vs Fondaparinux Fondaparinux Arixtra® Glaxo Smith Kline Rivaroxaban Xarelto® Need for injections Oral administration Complicated synthesis with more than 50 steps Synthesis in 6 steps Reduced capacity to inhibit FXa when it is incorporated within prothrombinase complex Inactivate free FXa and FXa incorporated within the prothrombinase complex Circulation: « A Replacement for Warfarin: The Search Continues » As direct inhibitors of factor Xa, rivaroxaban and apixaban inactivate free factor Xa and factor Xa incorporated within the prothrombinase complex equally well. In contrast, indirect factor Xa inhibitors such as fondaparinux have reduced capacity to inhibit factor Xa when it is incorporated within the prothrombinase complex. Whether inhibition of plateletbound factor Xa endows direct factor Xa inhibitors with an advantage over indirect inhibitors remains to be established Circulation 2007;116;131-133

Rivaroxaban vs Idraparinux Sanofi-Synthelabo Rivaroxaban Xarelto® Need for injections Oral administration Half-life = 130 hours  once-weekly administration but lack an antidote: risk of bleeding Half-life: 5-9h Significant excess bleeding (P<0.0001) halted a trial of idraparinux for stroke prevention in patients with atrial fibrillation 08/01/09: Idraparinux a donné des résultats égaux à enoxaparin + AVK ds thrombose veineuse profonde ms < pr embolie pulmonaire Réduit apparition trhombose ms augmentation saignements http://www.pharmacorama.com/ezine/20071002092355.php Medical News: Arrhythmias « Idraparinux Causes Excess Bleeding in A-Fib Patients », janvier 2005 http://www.medpagetoday.com/Cardiology/Arrhythmias/8108 http://www.thelancet.com/journals/lancet/article/PIIS0140673608601683/abstract  idraparinux aussi efficace que AVK mais plus de saignements The Lancet doi:10.1016/S0140-6736(08)60168-3

Oral direct anticoagulants TF/VIIa X IX IXa VIIIa Rivaroxaban Apixaban Xa 24/12/08: développement de produits plus stables, plus sûrs, plus faciles d’utilisation (et donc utilisables pendant plus longtemps) (thomson) Va Ximelagatran Dabigatran IIa II Fibrinogen Fibrin

Rivaroxaban vs Dabigatran Oral direct thrombin inhibitor Dabigatran Pradaxa® Boehringer Ingelheim Rivaroxaban Xarelto® Bioavailability: 3,5-5% Bioavailability: 60-80% Renal excretion: 80-100% CI with renal impairment (creatinine clearance< 30 ml/min) Renal excretion: 66% Could be used until creatinine clearance > 15ml/min Clearance: 88.8-135.6 l/h Clearance: 9.8–16.6 l/h Double pro-drug Active drug Twice-daily Once-daily 08/01/09: 1ère prise du dabigatran se ferait entre 1 et 4h après la fin de intervention: plus tôt que notre produit, malade est-il capable d’avaler? Ttment 10j après prothèse genou et 1 mois après prothèse hanche. Combien de temps pr le notre? Boehringer Ingelheim Elimination: xarelto Renal: 66% Faecal and biliary: 28% Elimination: dabigatran Renal: 80% Moins sensible au variations du a la nourriture

Rivaroxaban vs Ximelagatran Oral direct thrombin inhibitor Ximelagatran Exanta® Astra Zeneca Rivaroxaban Xarelto® Elevation in liver enzymes First 3 weeks of treatment: ALAT elevations > 3 times ULN was lower with rivaroxaban than enoxaparin Pro-drug Active drug Bioavailability: 17.4–24.3% Bioavailability: 60-80% Elimination: renal Elimination: renal and fecal Withdrawn Since the 14th February 2006 Br J Clin Pharmacol. 2007 September; 64(3): 263–265. Circulation « A Replacement for Warfarin The Search Continues  » Unexpected hepatotoxicity during recent randomized evaluation of ximelagatran, the first oral direct thrombin inhibitor, has prompted intense scrutiny of the potential hepatic side effects of new oral anticoagulants, including rivaroxaban. During the first 3 weeks of treatment in the ODIXa-DVT trial, the incidence of alanine aminotransferase elevations >3 times the upper limit of normal was significantly lower in patients treated with rivaroxaban than it was in those given enoxaparin/VKA. Circulation 2007;116;131-133

Rivaroxaban vs Apixaban Oral direct anti-FXa Bristol-Myers Squibb Rivaroxaban Xarelto® Twice daily Once daily Clinical development more advanced Bioavailability: 50% Bioavailability: 60-80% Clearance is mainly via biliary/fecal route  better in patients with renal insufficiency Clearance via 2 pathways (65% renal) Half-life: 9-14h Half-life: 5-9h Apixaban bien si utilisé en cas de renal impairment mais comme éliminé par voie biliaire/fécale  risque d’EI au niveau hépatique Circulation « A Replacement for Warfarin: The Search Continues” Hematology: “Properties and status of dabigatran, rivaroxaban, and apixaban » Circulation 2007;116;131-133

Expected sales

Anticoagulants’s evolution sales 0.2 pharmalyst.blogspot.com/2007/06/prospects-for-oral-factor-xa-inhibitors.html 0.1 Total = 3,1 B $ Total = 8,5 B $ U.S sales (B $) U.S sales (B $) JNJ Investor relations site 60

Rivaroxaban estimated sales (Millions €) 2009 2010 2011 2012 2013 2014 2015 RECORD (VTE prev) 50 120 250 350 400 420 450 ROCKET (AF) 300 1200 2200 3100 4000 EINSTEIN (VTE treat) 80 180 550 800 MAGELLAN (VTE prev hosp patients) 650 850 ATLAS (ACS 2nd prev) 30 TOTAL 630 1980 3280 4800 6220 Source: Company, Exane BNP Paribas estimates Company, Exane BNP Paribas estimates

Impact on healthcare costs based on the RECORD 3 study Target: Calculate the impact on healthcare resources in the US The costs of symptomatic VTE was assumed that: Nurses spend three minutes per day administering a subcutaneous Enoxaparin dose and training patients to self-inject for out-patient use. Duration of hospitalization was 5 days. Asymptomatic events had no impact on healthcare costs Kwong L, et al. Blood. 2007;110(11):Abstract #1874. tier1group.com/downloads/media/ASH2007/PPT/16_poster.ppt Kwong L, et al. Blood. 2007;110(11):Abstract #1874

Impact on healthcare costs based on the RECORD 3 study Results: Total cost associated with healthcare resources use in the US: Enoxaparin: 290 $ per patients Rivaroxaban: 95 $ per patients Kwong L, et al. Blood. 2007;110(11):Abstract #1874. tier1group.com/downloads/media/ASH2007/PPT/16_poster.ppt - 67 % Kwong L, et al. Blood. 2007;110(11):Abstract #1874

To conclude Xarelto is considered to be the most important project in Bayer's pharmaceutical pipeline could have a sales potential of more than 50 millions € in 2009 and more than 6 Billions € in 2015 The treatment of chronic indications promises to be far more lucrative Lovenox: 8 $ par jour Rivaroxaban: 9,92 $ par jour

Special thanks We especially want to thank Ms Gras, Mr Tartar, Mr Willand and Mr Marboeuf for their help and the time they gave us