Growing evidence for the effectiveness of FXa inhibition

Professor Cedric HERMANS MD, MRCP(UK), PhD Division of Haematology Cliniques universitaires Saint-Luc 1200 Brussels

Conflicts of interests

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

Coagulation cascade

Fibrinogen

Thrombin (IIa)

Fibrin

Classic theory of the coagulation cascade

Contact Phase - FXII Tissue Factor + FVIIa FXI FIX + FVIII

Intrinsic pathway

FX

Extrinsic pathway

FV Thrombin

Common pathway FIBRIN CLOT

Sites of action of new anticoagulants ORAL

DIRECT

Rivaroxaban and others

DIRECT

Dabigatran and others X Fibrinogen FT/VIIa IX PARENTERAL VIIIa IXa Xa Va

INDIRECT

Antithrombin Fondaparinux Idraparinux II IIa Fibrin

1 ATIII

Pentasaccharide (Arixtra - Fondaparinux)

Intrinsic pathway Extrinsic pathway 2 3 ATIII ATIII Xa Xa Arixtra Platelets IIA II IIa Fibrinogen Fibrin clot

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; 267:12528 –12538.

Coagulation cascade and targets of new oral anticoagulants

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: 80 –100 % • C max at 2 –4 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

2005;48:5900 –8; Perzborn E

et al. J Thromb Haemost

2005;3:514 –21.

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 (C max 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) Intrinsic

XII XI IX

Dabigatran

VIII Xa V IIa I Fibrin Clot VII

Extrinsic Tissue Factor

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

Many targets for new anticoagulants: Why target Factor Xa?

Oral TF/Factor VIIa Parenteral TFPI (tifacogin) TTP889 X IX Rivaroxaban Apixaban YM150 LY517717 Edoxaban (DU-176b) Betrixaban (PRT054021) VIIIa IXa Factor Va Xa II AT APC (drotrecogin alfa) sTM (ART-123) Fondaparinux Idrabiotaparinux DX-9065a Otamixaban Ximelagatran Dabigatran Factor IIa Fibrinogen Fibrin

Adapted from Weitz & Bates.

J Thromb Haemost

2005; Gross & Weitz.

Arterioscler Thromb Vasc Biol

2008; Carriero & Ansell.

Expert Opin Investig Drugs

2008

Why is FXa an attrative target for new anticoagulants?

• LOCATION of FXa in the coagulation cascade • Arixtra > LMWH > 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)

Reason 1 Central role of FXa in the coagulation cascade Initiation Amplification Propagation…

Targets of new anticoagulants : FXa or FIIa (Thrombin)

TF FVIIa FXa FVa

Fibrinogen

Thrombin Thrombus

Inhibition of 1 unit of Xa prevents generation of 1000 units of thrombin

Wessler & Yin. Circ 1973;47:671

Reason 2 Specificity of FXa inhibtion and antithrombotic activity

Higher selectivity for FXa inhibition with heparins is associated with a more potent anticoagulant effect : Fondaparinux > LMWH > UFH Fondaparinux : anti-Xa LMWH : anti-FXa > anti-IIa UFH : anti-FXa = anti-IIa

Fondaparinux vs enoxaparin in orthopedic surgery

Hip replace n = 3,411 Hip fracture n = 1,250 Knee replace n = 724 Fondaparinux better 45.4% 61.6% 63.1% Enoxaparin better Exact 95% CI [59.0; 27.6] [73.4; 45.0] [75.5; 44.8] Overall odds reduction % odds reduction -100 -80 55.3% -60 -40 -20 0 20 p = < 0.001

40 60 80 [63.2; 45.8]

100

Turpie AGG. Arch Intern Med 2002;162:1833

Reason 3 Inhibition of thrombin could in theory have detrimental consequences, even outside the clotting system

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

Procoagulant Fibrin formation Platelet activation Feedback activation TAFI activation Anticoagulant Protein C activation Prostacyclin formation Inflammation P-selection expression Cell adhesion Chemotaxis

The many functions of

Thrombin Cellular Proliferation Tissue repair Growth factor secretion Angiogenesis

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

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

2005;514:35 Morishima et al.

Blood

2006;108:274a

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

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

2004;2:612

Reason 4 Therapeutic window of anti-Xa inhibiton

120 100 80 Clotting Time(s) 60 40 20 0 0 Dose Response: Xa vs IIa Clotting Time vs. Enzyme Concentration Thrombin FXa 50 100 150 200 Enzyme dilution in 1:4 Human Plasma 250

C. Esmon

Choice of Doses

30 20 10 28.5

Efficacy 16.6

13.1

24.0

BISTRO II 0 100 mg 300 mg 450 mg Dabigatran etexilate total daily dose Enoxaparin Safety 10 8 2 0 6 4 2.6

8.3

8.4

4.6

100 mg 300 mg 450 mg Dabigatran etexilate total daily dose Enoxaparin Optimal Efficacy / Safety Balance Eriksson et al. J Thromb Haemost 2005; 3:103

Efficacy and safety results Hip surgery Knee surgery

Total venous thromboembolism and all-cause mortality Major, post-operative bleeding 60 50 40 30 20 10 0 0 5 10 20 30 40 50 Rivaroxaban total daily dose (mg) 60 Enoxaparin 40 mg od 60 50 40 30 20 10 0 0 5 10 20 30 40 50 Rivaroxaban total daily dose (mg) 60 Enoxaparin 30 mg bid  Total daily rivaroxaban doses of 5 –20 mg had similar efficacy and safety to enoxaparin

5

Factor Xa = an attractive target for inhibition

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

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.

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.

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

Old versus new anticoagulants

Anti-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