Download RIVAROXABAN: chemical structure

®
Xarelto
Rivaroxaban
The first oral direct factor Xa inhibitor
Eric Alsac
Thomas Bar
Marie Crétal
1
2
Deep Vein Thrombosis
•
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
350.000 to
600.000
Americans
each year
suffer from
DVT
. Coagulation
. Damage to the vein walls
3
en.wikipedia.org/wiki/Deep_vein_thrombosis
Consequences
• Phlebitis
•
•
•
• Pulmonary Embolism
www.nhlbi.nih.gov/health/dci/Diseases/Dvt/DVT_SignsAndSymptoms.html
Swelling of the leg
Pain or tenderness on the leg
Red or discoloured skin on the leg
4
Pulmonary embolism
650.000
cases occur
each year in
the United
States
 Sudden shortness of
breath
 Chest pain that often
mimics a heart attack
 Tachycardia
 Cough that produces
bloody sputum
emedicine.medscape.com/article/300901-overview
5
Complications
• Pulmonary hypertension
 Dyspnea
 Dizziness, fainting
 High pressure in the right
ventricle
•
Heart damages
 Muscles of the right ventricle
damages
 Atrial fibrillation
www.mayoclinic.com/health/pulmonary-embolism
6
Atrial fibrillation
2.2 Millions
Americans
suffer from
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
7
Space for a new
medicine
8
Ideal Anticoagulant
Characteristic
Consequence
 High oral bioavailability
Oral administration
 Efficiency
• Rapid onset
• Predictable pharmacokinetics
and Predictable response
No need for overlap with parenteral anticoagulant
No need for anticoagulation monitoring
 Safety
•
•
•
•
•
Large therapeutic index
No food-drug interactions
Rapid offset of action
Availability of antidote
2 ways of elimination
No need for anticoagulation monitoring
No need for anticoagulation monitoring
Simplified management in bleeding event
Rapid reversal in hemorrhagic event
Safer for patient with renal impairment
 selectivity
• No off-target effect
 Reasonable cost
No need for monitoring
Improve acess
9
Pharmacology
10
Coagulation cascade and
targets
XaProthrombinase
complex
X
A
R
E
L
T
O
®
11
12
Rivaroxaban : Discovery
IC50 = 120 nM
Product from HTS
R=H
4 R = Cl
3
IC50 = 20 µM
IC50 = 90 nM
Optimisation
IC50 = 8 nM
Reevaluation of the HTS hits
IC50 = 0.7 nM
Ki = 0.4 nM
BAY 59-7939
13
J. Med. Chem., 2005, 48 (19), 5900-5908 • DOI: 10.1021/jm050101d
Rivaroxaban: chemical structure
Cl
5 -Chlorothiophène-2-carboxamide
S
Essential for potent Xa
inhibition
O
N H
S-configuration
Specific interaction
with FXa
4-aminomorpholine-3-one
Essential for
a higher potency
H
O
oxazolidinone
N
O
N
O
O
J. Med. Chem., 2005, 48 (19), 5900-5908 • DOI: 10.1021/jm050101d
Cental template for the binding
14
Rivaroxaban : structure-activity
relationship
Tyrosine 228
S1 Pocket
Glycine 219
Acide Aspartique
189
Tryptophane 215
S4 Pocket
Hydrophobic Interactions
Tyrosine 99
Phénylalanine 174
Hydrogen Bonds
X- Ray Crystallography
Prodrugs or not prodrugs…
Rivaroxaban does not need
any liver conversion….
UNLIKE
Ximelagatran
Withdrawn on 14 February 2006
17
EMEA/60465/2006 0.13, CURRENT
Prodrugs or not prodrugs…
Ximelagatran
Melagatran
Dehydroxylation
H2N
H2N
NH
N OH
Liver conversion
HN
O
HN
O
O
N
O
O
H
NH
O
N
O
H
NH
OH
CH3
Dealkylation
.
Vasc Health Risk Manag. 2006 March; 2(1): 49–58
18
Pharmacodynamic
data
19
Pharmacodynamic data
 Selectivity
Human Protease Selectivity profile of Rivaroxaban
Inhibition of
Factor Xa
Concentration (nM)
IC50 = 0.7
Ki = 0.4 +/- 0.002
Other Serin Protheases :
thrombin,
Trypsin
plasmin
 FVIIa, FIXa, FXIa
urokinase
activated protein C
IC50 > 20 000
20
Journal of Thrombosis and Haemostasis, 3: 514–521
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
i
IC50=0.7nM
IC50=2.1nM
IC50=75nM
 IC50 =75 nM
21
Drugs of the Future 2006, 31(6): 484-493
Pharmacodynamic data
 Anticoagulant effects concentration-dependent
Rivaroxaban has a concentration-dependent anticoagulant
effect in all tests of the secondary hemostasis
22
Clinical Pharmacology & Therapeutics (2005) 78, 412–421; doi: 10.1016/j.clpt.2005.06.011
Pharmacodynamic data
Anticoagulant effects in human plasma
Relative Change in PT
Relative Change in aPPT
Rivaroxaban prolonged PT, aPTT independently of ATIII
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
Time (h)
PT : prothrombin time
aPPT : (activated) partial thromboplastin time
Clinical Pharmacology & Therapeutics (2005) 78, 412–421; doi: 10.1016/j.clpt.2005.06.011
Summary of
Pharmacodynamic Studies
selective inhibitor
proved pharmacological properties
concentration dependent action
24
25
ABSORPTION :
DISTRIBUTION :
- Plasma protein binding:
high (92-95% SA)
- Volume of distribution:
moderate (50L  0.62L/kg)
- Fabs : 60-80% for the 10mg
dose
- Cmax : 2-4h after tablet intake
- Food does not affect AUC and
Cmax
- low affinity to tissues
METABOLISM & ELIMINATION :
-2/3 of dose undergoes metabolic
METABOLISM & ELIMINATION :
degradation
-Metabolised
by CYP3A4,
-1/3 of the dose
undergoesCYP2J2
direct
and
renalCYP-independent
elimination
mechanisms
Low-clearance drug:
half-life: 7-11h
Half 
eliminated
renally
Half  eliminated
by the fecal route
26
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 1529mL/min
• Inter-individual variability: moderate
27
Inter-individual variations: gender,
weight and renal impairment
« Les nouveaux anticoagulants » N. Rosencher
28
Summary of Pharmacokinetic
studies
High oral bioavailibility
No food and drug interactions
2 ways of elimination
Reversible effect
29
Reproduction toxicity
30
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
31
EMEA: CHMP ASSESSMENT REPORT FOR Xarelto Doc.Ref.: EMEA/543519/2008
32
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
33
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%
34
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
35
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
random
4541
patients
S
u
r
g
e
r
y
Mandatory
bilateral
venography
F
o
l
l
o
w
u
p
Day 36
Day 65
Rivaroxaban 10mg/d
Enoxaparin 40mg/d
Primary efficacy: 1558 patients
Secondary efficacy: 1678 patients
Day 1
: First dose 6-10h after surgery
Eriksson BI, Borris LC, Friedman RJ; N Engl J
Med. 2008;358(26):2765-2775.
: First dose 12h before surgery
36
Record 1
Results of the efficacy study…
P<0,001
Incidence (%)
4
- 70 %
3
2
P<0,001
4
- 88 %
3
2
3,7 %
1
1
2%
1,1 %
0
0,2 %
0
Enoxaparin
Rivaroxaban
Enoxaparin
Rivaroxaban
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.
37
Record 1
2224 received
Enoxaparin
The safety study…
0,5
P=0,18
Incidence (%)
0,4
0,3
+0,2%
0,2
0,3%
0,1
0
0,1%
4433 patients
2209 received
Rivaroxaban
7
6
5
4
3
2
1
0
Enoxaparin Rivaroxaban
5,8%
5,8%
Enoxaparin
Rivaroxaban
40mg/d
10mg/d
129/2224
128/2209
Nonmajor bleeding
40mg/d
10mg/d
2/2224
6/2209
Major bleeding
.
Eriksson BI, Borris LC, Friedman RJ; N Engl J Med. 2008;358(26):2765-2775
38
Record 1
Liver function tests :
1
Enoxaparin 40 mg
once daily
ALT > 3 x ULN
On treatment
Rivaroxaban 10 mg
once daily
51 / 2129
2,7%
43 / 2128
2,0%
During follow-up
6 / 1926
0,3%
3 / 1931
0,2%
ALT > 3 x ULN + Bilirubin > 2 x ULN
ON treatment
1 / 2142
< 0,1%
1 / 2143
< 0,1%
During follow-up
0 / 1925
0,0%
0 / 1943
0,0%
Ximelagatran: ALT ˃ 3 x ULN: 6% (37 patients / 612) vs Placebo: 1% (6 patients / 611)
1:
2:
Eriksson BI, Borris LC, Friedman RJ; N Engl J Med. 2008;358(26):2765-2775.
n engl j med 349;18
2
39
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.
40
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
41
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
42
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
43
44
Mode action anticoagulants
Tissue factor (TF)
VIIa- TF
VII
IX
IXa
Heparin
VIIIa
Warfarin
X
Xa
Va
Thrombin
Prothrombin
Fibrinogen
Fibrin
45
New anticoagulants
TF/VIIa
ORAL
PARENTERAL
X
IX
VIIIa
Rivaroxaban
IXa
AT
Xa
Apixaban
Fondaparinux
Idraparinux
Va
Ximelagatran
Dabigatran
Fibrinogen
II
IIa
Fibrin
New anticoagulants. J Thromb Haemost 2005;3:1843–1853
46
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
47
Xarelto® advantages
 Predictable profil:
Reversible
- Rapid onset and offset of action
- Anticoagulation from the first dose
Dose dependant
- Safe and effective regulation of coagulation
48
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
49
Rivaroxaban vs AVK
AVK
warfarine Coumadine®
Rivaroxaban
Xarelto®
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
50
Circulation 2007;116;131-133
Rivaroxaban vs LMWHs
LMWHs
Enoxaparin Lovenox®
Rivaroxaban
Xarelto®
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
51
Indirect inhibitors of FXa
TF/VIIa
X
IX
VIIIa
Rivaroxaban
IXa
AT
Xa
Fondaparinux
Idraparinux
Va
II
IIa
Fibrinogen
Fibrin
52
Rivaroxaban vs Fondaparinux
Fondaparinux
Arixtra®
Rivaroxaban
Xarelto®
Glaxo Smith Kline
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 2007;116;131-133
53
Rivaroxaban vs Idraparinux
Idraparinux
Sanofi-Synthelabo
Need for injections
Rivaroxaban
Xarelto®
Oral administration
Half-life = 130 hours  once- Half-life: 5-9h
weekly administration but
lack an antidote: risk of
bleeding
Significant excess bleeding
(P<0.0001) halted a trial of
idraparinux for stroke
prevention in patients with
atrial fibrillation
54
The Lancet doi:10.1016/S0140-6736(08)60168-3
Oral direct anticoagulants
TF/VIIa
X
IX
VIIIa
IXa
Rivaroxaban
Xa
Apixaban
Va
Ximelagatran
Dabigatran
Fibrinogen
II
IIa
Fibrin
55
Rivaroxaban vs Dabigatran
Oral direct thrombin inhibitor
Dabigatran
Pradaxa®
Rivaroxaban
Xarelto®
Boehringer Ingelheim
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
56
Rivaroxaban vs Ximelagatran
Oral direct thrombin inhibitor
Ximelagatran
Exanta®
Rivaroxaban
Xarelto®
Astra Zeneca
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
57
Circulation 2007;116;131-133
Rivaroxaban vs Apixaban
Oral direct anti-FXa
Apixaban
Bristol-Myers Squibb
Rivaroxaban
Xarelto®
Twice daily
Once daily
Clinical development more
advanced
Bioavailability: 50%
Bioavailability: 60-80%
Clearance is mainly via
Clearance via 2 pathways
biliary/fecal route  better in (65% renal)
patients with renal
insufficiency
Half-life: 9-14h
Half-life: 5-9h
58
Circulation 2007;116;131-133
59
Anticoagulants’s evolution sales
2006
2014
0.1
0.2
LMWHs
Warfarin
0,5
0,4
2,1
Total = 3,1 B $
U.S sales (B $)
Heparin
2,2
4,5
1,5
Other inj.
Anticoag
Novel oral
Anticoag
0.1
Total = 8,5 B $
U.S sales (B $)
60
JNJ Investor relations site
Rivaroxaban estimated sales
(Millions €)
2009
2010
2011
2012
2013
2014
2015
50
120
250
350
400
420
450
300
1200
2200
3100
4000
80
180
300
550
800
250
350
650
850
30
80
120
3280
4800
6220
RECORD
(VTE prev)
ROCKET
(AF)
EINSTEIN
(VTE treat)
MAGELLAN
(VTE prev
hosp patients)
ATLAS
(ACS 2nd prev)
TOTAL
50
120
630
1980
61
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
62
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
- 67 %
Rivaroxaban: 95 $ per patients
63
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
64
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
65