Growing evidence for the effectiveness of FXa inhibition

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Growing evidence for the effectiveness of FXa
inhibition
Professor Cedric HERMANS MD, MRCP(UK),
PhD Division of Haematology Cliniques
universitaires Saint-Luc 1200 Brussels
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Conflicts of interests

• Participation in advisory
• boards and consulting activities for anti-Xa and
  anti-IIa anticoagulants
• (Bayer Schering Pharma, Boehringer Ingelheim)

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Coagulation cascade
Thrombin (IIa)
Fibrinogen
Fibrin
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Classic theory of the coagulation cascade
Contact Phase - FXII
Tissue Factor FVIIa
FXI
FIX FVIII
Extrinsic pathway
Intrinsic pathway
FX
Common pathway
FV
Thrombin
FIBRIN CLOT
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Steps in blood coagulation


Steps in coagulation

Inhibition

TFPI
Initiation
TF/
VIIa
X
IX
Amplification
VIII
IXa
Xa
Antithrombin PC/PS
Va
II

Propagation
IIa
Antithrombin

Fibrinogen
Fibrin
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Sites of action of new anticoagulants
FT/VIIa
PARENTERAL
ORAL
X
IX
IXa
VIIIa
DIRECT
INDIRECT
Va
Antithrombin
Rivaroxaban and others
Fondaparinux Idraparinux
Xa
II
DIRECT
Dabigatran and others
IIa
Fibrinogen
Fibrin
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Pentasaccharide (Arixtra - Fondaparinux)
Extrinsic pathway
Intrinsic pathway
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1
2
Xa
Xa
ATIII
ATIII
ATIII
Arixtra
IIa
II
Fibrin clot
Fibrinogen
Pentasaccharide sequence of heparin (present in
UFH and LMWH) binds to AT causing conformational
change at its reactive centre accelerating
1000-fold its interaction with factor Xa.
Olson ST, et al. J. Biol. Chem. 1992
2671252812538.
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Coagulation cascade and targets of new oral
anticoagulants
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Rivaroxaban (XARELTO Bayer Schering) Anti-Xa

• Direct, specific, competitive Factor Xa inhibitor
• Inhibits free and fibrin-bound Factor Xa activity
  and prothrombinase activity
• Inhibits thrombin generation
• No direct effect on platelet aggregation, and
  thus, on primary haemostasis
• Bioavailibility 80100
• Cmax at 24 h

• one-third excreted as unchanged active
  substance in urine
• Of the two-thirds metabolized half eliminated
  renally, half eliminated by faecal route

Roehrig S et al. J Med Chem 20054859008
Perzborn E et al. J Thromb Haemost 2005351421.
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Dabigatran etexilate (Pradaxa Boehringer
Ingelheim) Anti-IIa (Thrombin)

• After oral administration, the prodrug dabigatran
  etexilate is rapidly converted to dabigatran, a
  potent reversible Direct Thrombin Inhibitor (DTI)
• Absolute bioavailability 6.5
• Fast onset of action (Cmax within 2h)
• Not metabolized by CYP450 / Renal excretion 80
• Half life 12-17 hours
• Low potential for drug-drug interactions, no
  drug-food interactions
• Potent antithrombotic effects are achieved by
  specifically blocking the activity of thrombin
  (both free and clot-bound)

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NEW versus OLD anticoagulants
LMWH Vitamin K Antagonist
Pradaxa
Xarelto
Synthetic Per os One or two tablet(s) / day No
monitoring No or little food/drug interaction
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Anti-Xa versus Anti-IIa
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Many targets for new anticoagulants Why target
Factor Xa?
Oral
Parenteral
TF/FactorVIIa
TFPI (tifacogin)
TTP889
X
IX
IXa
APC (drotrecogin alfa) sTM (ART-123)
VIIIa
RivaroxabanApixabanYM150 LY517717 Edoxaban
(DU-176b)Betrixaban (PRT054021)
Va
AT
Factor Xa
FondaparinuxIdrabiotaparinux
DX-9065aOtamixaban
II
XimelagatranDabigatran
Factor IIa
Fibrin
Fibrinogen
Adapted from Weitz Bates. J Thromb Haemost
2005 Gross Weitz. Arterioscler Thromb Vasc
Biol 2008 Carriero Ansell. Expert Opin
Investig Drugs 2008
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Oral, direct FXa inhibitors in development

• Rivaroxaban Bayer and Scios
• LY517717 Lilly
• YM150 Astellas
• DU-176b Daiichi Sankyo
• Apixaban BMS et Pfizer
• 813893 GSK
• PRT-054021 Portola

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Why is FXa an attrative target for new
anticoagulants?

• LOCATION of FXa in the coagulation cascade
• Arixtra gt LMWH gt UFH (degree of inhibition of
  FXa)
• Inhibition of thrombin deleterious consequences
• Larger therapeutic window with Xa inhibition ?
• Results of clinical trials ?
• BUT no head-to-head comparison (anti-Xa versus
  anti-IIa)

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InitiationAmplificationPropagation
Reason 1 Central role of FXa in the coagulation
cascade
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Targets of new anticoagulants FXa or FIIa
(Thrombin)
Fibrinogen
TF
Thrombus
Thrombin
FVIIa
FXa
FVa
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Inhibition of 1 unit of Xa prevents generation of
1000 units of thrombin
Wessler Yin. Circ 197347671
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X
Initiation phase
II
Xa
Amplification phase
IIa
IX
II
Fibrinogen
XIa
IIa
X
Va
Xa
Fibrin monomer
Crosslinked fibrin
IXa
Activated platelet
VIIIa
XIII
XIIIa
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Reason 2Specificity of FXa inhibtion and
antithrombotic activity

• Higher selectivity for FXa inhibition with
  heparins is associated with a more potent
  anticoagulant effect
• Fondaparinux gt LMWH gt UFH

Fondaparinux anti-Xa LMWH anti-FXa gt
anti-IIa UFH anti-FXa anti-IIa
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Fondaparinux vs enoxaparinin orthopedic surgery
Enoxaparin better
Fondaparinux better
Exact 95 CI
Hip replace n 3,411
59.0 27.6
45.4
Hip fracture n 1,250
73.4 45.0
61.6
Knee replace n 724
75.5 44.8
63.1
Overall odds reduction
p lt 0.001
63.2 45.8
55.3
0
100
-80
-60
-40
-20
20
40
60
80
-100
odds reduction
Turpie AGG. Arch Intern Med 20021621833
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Factor Xa inhibitors Success in clinical trials

• Venous thrombo-embolic disease
• Fondaparinux reduced the risk of VTE compared
  with enoxaparin in patients undergoing hip
  fracture surgery and hip and knee arthroplasty
• Rivaroxaban reduced the risk of VTE compared with
  enoxaparin regimens in patients undergoing
  elective total hip and knee replacement surgery
  (RECORD programme)
• Acute Coronary Syndrome
• Fondaparinux lowered long-term morbidity,
  improved survival and reduced the risk of
  bleeding compared with enoxaparin
• Atrial Fibrillation
• None published ongoing trials ARISTOTLE
  apixaban (vs warfarin), AVERROES (vs ASA),
  ROCKET AF rivaroxaban (vs warfarin)

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Reason 3Inhibition of thrombin could in theory
have detrimental consequences, even outside the
clotting system
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Procoagulant Thrombin formation PAI 1
release
Cell Prolif / Inflammation Cytokine release
Smooth muscle cell proliferation
The limited functions of Factor Xa
From J. Ansell 2007
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Thrombin
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Procoagulant Fibrin formation Platelet
activation Feedback activation TAFI
activation
Anticoagulant Protein C activation
Prostacyclin formation
The many functions of Thrombin
Inflammation P-selection expression Cell
adhesion Chemotaxis
Cellular Proliferation Tissue repair Growth
factor secretion Angiogenesis
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Multiplicity of thrombins functions
Fibrin clot and platelet plug Feedback activation
of coagulation
Protein C activation Prostacyclin formation
Procoagulant
Anticoagulant
Thrombin
Cellular proliferation
Inflammation
EC P-selectin expression Neutrophilmonocyte
adhesion Chemotactic for PMNs Endothelial PAF
formation
Direct mitogen for fibroblasts PDGF and TGFß
from platelets PDGF formation in endothelium
Esmon Thromb Haemost 2008
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Factor Xa an attractive target for inhibition

• The only known functions of Factor Xa are either
  procoagulant or proinflammatory
• Thrombin has both of these activities and
  indirect anticoagulant, anti-inflammatory and
  anti-apoptotic activities

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Thrombin anticoagulant

• Thrombin is essential for the activation of
  protein C.
• Activated protein C inactivates FVa and FVIIIa.
• Inhibition of thrombin impairs the activation of
  protein C and thereby the inhibition of FVa and
  FVIIIa.

Esmon Thromb Haemost 2008
Furugohri et al. Eur J Pharmacol 200551435
Morishima et al. Blood 2006108274a
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Thrombin anticoagulant

• Inhibition of FXa does not interfere with the
  PC/PS anticoagulant pathway.
• Direct inhibition of FXa allows the generation of
  small amount of thrombin and the activation of
  protein C into activated protein C.
• Is the protein C anticoagulant pathway still
  needed when thrombin procoagulant activity is
  inhibited ???

Esmon Thromb Haemost 2008
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Factor Xa an attractive target for inhibition

• Inhibition of thrombin in the large vessels
  reduces clotting activity and facilitates the
  ability of blood flow to carry thrombin to the
  microcirculation.
• In the microcirculation, thrombin binds to
  thrombomodulin and activates protein C.
• The efficacy of Factor Xa inhibitors should not
  depend on the health of the vasculature unlike
  thrombin inhibitors.

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Thrombin potent platelet agonist

• FIIa is a potent platelet agonist.
• FXa does not activate platelets.
• Thrombin inhibition could increase the risk of
  bleeding.
• Direct FXa inhibitors allow the generation of
  small amounts of thrombin necessary to activate
  platelets and preserve primary haemostasis

Ieko et al. J Thromb Haemost 20042612
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Reason 4 Therapeutic window of anti-Xa inhibiton
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Dose Response Xa vs IIa
Clotting Time vs. Enzyme Concentration
120
100
Thrombin
80
FXa
Clotting Time(s)
60
40
20
0
0
50
100
150
200
250
Enzyme dilution in 14 Human Plasma
C. Esmon
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Choice of Doses
BISTRO II
Safety
Efficacy
Major clinically relevant non-major bleeding ()
Total VTE ()
Dabigatran etexilate total daily dose
Dabigatran etexilate total daily dose
Optimal Efficacy / Safety Balance
Eriksson et al. J Thromb Haemost 2005 3103
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Factor Xa an attractive target for inhibition

• Factor Xa has a shallower doseresponse curve
  than thrombin
• This suggests that maintaining the appropriate
  dose range for Factor Xa inhibitors should be
  easier than for thrombin inhibitors

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Clinical studies
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Pooled Analysis Major VTE and VTE-Related Death
in major orthopaedic surgery
Study Dabigatran 150 mg Dabigatran 220 mg Enoxaparin
RE-NOVATE (THR) 4.3 3.1 3.9
RE-MODEL (TKR) 3.8 2.6 3.5
RE-MOBILIZE (TKR) 3.0 3.4 2.2
Pooled 3.8 3.0 3.3
Absolute risk difference 0.5 -0.2
(Dabigatran Enoxaparin) 95 CI -0.6 to 1.6 -1.3 to 0.9
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Pooled Analysis Bleeding Events
Bleeding event Dabigatran etexilate Dabigatran etexilate Enoxaparin N2716
Bleeding event 150 mg N2737 220 mg N2682 Enoxaparin N2716
Major Bleeding Event 1.1 1.4 1.4
95 CI (0.7 , 1.4) (1.0, 1.9) (1.0, 2.0)
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RECORD3 summary
Rivaroxaban head-to-head comparison with
enoxaparin in patients undergoing total knee
replacement
Total VTE
20
RRR 49
15
Incidence ()
10
Major VTE
SymptomaticVTE
Major bleeding
5
RRR 62
RRR 66
0.5
0.6
2.6
1.0
2.0
18.9
9.6
0.7
0
Total VTE any DVT, non-fatal PE and all-cause
mortality Major VTE proximal DVT, non-fatal PE
and VTE-related death
Rivaroxaban 10 mg once daily
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Comparison of three upcoming novel specific oral
anticoagulants
Drug Class Company Half-life Bioavaila-bility Elimination Dosage(oral)
Apixaban antiXa BMS/Pfizer 8-15 50-85 25 renal75 liver b.i.d.
RivaroxabanantiXa Bayer/JJ 5-13 gt80 33 renal (unchanged)33 renal(inactive metabolites)33 biliary o.d.
DabigatranDTI B-I 14-17 5 80 renal20 biliary o.d./b.i.d.
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Conclusions

• Several reasons suggest that factor Xa might be a
  more appopriate target than IIa.
• The reasons are theoretical and speculative.
• Recent clinical studies in orthopaedic surgery
  indirectly support experimental observations.

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Conclusions

• Clinical trials with oral FIIa and FXa inhibitors
  are ongoing and following parallel paths.
• Which class of drugs will be better ?
• This question will remain unanswered until the
  appropriate head-to-head clinical trials are
  performed.
• At the moment, both classes appear promising.

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Head-to-head comparison between anti-IIa and
anti-Xa inhibitors
Even if we have a study which shows that the
cost-benefit ratio is superior with one compound
versus another one, this will be true a)
only for these two particular drugs b) and only
in one well-defined clinical situation
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Old versus new anticoagulantsAnti-Xa versus
anti-IIa ?
LMWH Vitamin K Antagonist
Pradaxa
Xarelto
Synthetic Per os One or two tablet(s) / day No
monitoring No or little food/drug interaction
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Anti-Xa versus Anti-IIa ????