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

2. Medical need

3. 350.000 to 600.000 Americans each year suffer from DVT
Deep Vein Thrombosis
to 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

4. Consequences Swelling of the leg Pain or tenderness on the leg
Red or discoloured skin on the leg
Phlebitis
Pulmonary Embolism

5. 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/ overview

6. Complications Dyspnea Pulmonary hypertension Dizziness, fainting
High pressure in the right ventricle
Muscles of the right ventricle damages
Atrial fibrillation
Heart damages

7. 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

8. Space for a new medicine

9. 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

10. Pharmacology

11. Coagulation cascade and targets
XARELTO®
Xa-Prothrombinase complex

12. Rivaroxaban’s structure

13. Rivaroxaban : Discovery
IC50 = 120 nM
IC50 = 8 nM
Product from HTS
Reevaluation of the HTS hits
Downloaded from 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
J. Med. Chem., 2005, 48 (19), • DOI: /jm050101d 13

14. 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), • DOI: /jm050101d 14

15. 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

16. X- Ray Crystallography

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Withdrawn on 14 February 2006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

18. 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 March; 2(1): 49–58. 18

19. Pharmacodynamic data

20. Pharmacodynamic data Selectivity Inhibition of
Human Protease Selectivity profile of Rivaroxaban
Inhibition of
Concentration (nM)
IC50 = 0.7
Ki = 0.4 +/
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 —an oral, direct Factor Xa inhibitor
IC50 >
Journal of Thrombosis and Haemostasis, 3: 514–521 20

21. 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):
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): 21

22. 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: /j.clpt
Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY , 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: /j.clpt 22

23. 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: /j.clpt
Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY , 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
5 mg BAY
10 mg BAY
20 mg BAY
40 mg BAY
80 mg BAY
Placebo
PT : prothrombin time
aPPT : (activated) partial thromboplastin time
Clinical Pharmacology & Therapeutics (2005) 78, 412–421; doi: /j.clpt 23

24. 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

25. X A R E L T O
Pharmacokinetic data

26. 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

27. 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

28. 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

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

30. Reproduction toxicity

31. 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

32. Clinical studies

33. 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

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

35. 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 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):

36. Record 1 Rivaroxaban vs Enoxaparin for thromboprophylaxis after hip arthroplasty
Primary efficacy: 1595 patients
Secondary efficacy: 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):
Primary efficacy: 1558 patients
Secondary efficacy: 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):

37. 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):
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):

38. 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):
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):

39. 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 / ,7%
6 / ,3%
43 / ,0%
3 / ,2%
ALT > 3 x ULN + Bilirubin > 2 x ULN
ON treatment
1 / < 0,1%
0 / ,0%
1 / < 0,1%
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):
2 : n engl j med 349;18

40. 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.

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

42. 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
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)

43. 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

44. Rivaroxaban’s place in the market

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

46. 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

47. 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.

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

49. 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

50. 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 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;

51. 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

52. 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

53. 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;

54. 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
Medical News: Arrhythmias « Idraparinux Causes Excess Bleeding in A-Fib Patients », janvier 2005
 idraparinux aussi efficace que AVK mais plus de saignements
The Lancet doi: /S (08)

55. 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

56. Rivaroxaban vs Dabigatran Oral direct thrombin inhibitor
Dabigatran Pradaxa®
Boehringer Ingelheim
Rivaroxaban Xarelto®
Bioavailability: 3,5-5%
Bioavailability: 60-80%
Renal excretion: %
CI with renal impairment (creatinine clearance< 30 ml/min)
Renal excretion: 66%
Could be used until creatinine clearance > 15ml/min
Clearance: 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

57. 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 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;

58. 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;

59. Expected sales

60. 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

61. 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

62. 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

63. Impact on healthcare costs based on the RECORD 3 study
Results: Total cost associated with healthcare resources use in the US:
Enoxaparin: $ 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

64. 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

65. 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