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Are all Xa Inhibitors the Same?

Alexander G. G. Turpie, MDProfessor of MedicineMcMaster University

Hamilton, Ontario, Canada

Antithrombotics That Have Antithrombotics That Have Changed Clinical PracticeChanged Clinical Practice

AnticoagulantsAnticoagulants

Low-molecular-weight heparinLow-molecular-weight heparin

Antiplatelet DrugsAntiplatelet Drugs

ThienopyridinesThienopyridines

Glycoprotein IIb/IIIa InhibitorsGlycoprotein IIb/IIIa Inhibitors

Low Molecular Weight HeparinsLow Molecular Weight Heparins

Nadroparin -Nadroparin -FraxiparineFraxiparine

Enoxaparin -Enoxaparin -LovenoxLovenox

OO

NHSONHSO33CaCa

CaOCaO33SOSO

OROR11

Saccharide Saccharide chainchain

OO

OHOHOSOOSO22ONaONa

Saccharide Saccharide chainchain

OO

OO

HH RR2 2

CHORCHOR22

CHCH22OHOH

OHOH

OROR11

HHOO

Saccharide Saccharide chainchain

Dalteparin -Dalteparin -FragminFragmin

RR1 1 = H or SO= H or SO33NaNa

RR2 2 = COONa= COONa

OO

COONaCOONa

Low-Molecular-Weight Heparins Low-Molecular-Weight Heparins

Potential Advantages:Potential Advantages:

Lack of binding to plasma proteins and Lack of binding to plasma proteins and endotheliumendothelium

Good bioavailabilityGood bioavailability

Stable dose responseStable dose response

Long half-lifeLong half-life

Resistance does notResistance does not developdevelop

Low Molecular Weight HeparinLow Molecular Weight Heparin

Venous ThromboembolismVenous Thromboembolism - prophylaxis - prophylaxis - treatment- treatment Ischaemic heart diseaseIschaemic heart disease

– unstable anginaunstable angina– acute MIacute MI– coronary stentingcoronary stenting

Cerebrovascular diseaseCerebrovascular disease– ischaemic strokeischaemic stroke– embolic strokeembolic stroke

Peripheral vascular diseasePeripheral vascular disease– reconstructive surgeryreconstructive surgery

New anticoagulantsNew anticoagulants

TFPI (tifacogin)

FondaparinuxIdraparinux

RivaroxabanApixabanLY517717YM150DU-176bPRT-054021

XimelagatranDabigatran

ORAL PARENTERAL

DX-9065aOtamixaban

Xa

IIa

TF/VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

AT

APC (drotrecogin alfa)sTM (ART-123)

Adapted from Weitz & Bates, J Thromb Haemost 2005

TTP889

Factor Xa inhibitorsFactor Xa inhibitors

FXa may be a better target than thrombinFXa may be a better target than thrombin– Has few functions outside coagulation (compared with Has few functions outside coagulation (compared with

thrombin)thrombin)

– Has a wider therapeutic window than thrombin (separation Has a wider therapeutic window than thrombin (separation of efficacy and bleeding), of efficacy and bleeding), in vitroin vitro

– Thrombin inhibitors are associated with rebound thrombin Thrombin inhibitors are associated with rebound thrombin generation – no evidence with FXa inhibitorsgeneration – no evidence with FXa inhibitors

– Efficacy of heparin-based anticoagulants improves as Efficacy of heparin-based anticoagulants improves as selectivity for FXa increases: selectivity for FXa increases: UFH < LMWH < fondaparinuxUFH < LMWH < fondaparinux

Factor Xa InhibitorsFactor Xa Inhibitors

IndirectIndirect DirectDirect

Herbert JM et alHerbert JM et al. Cardiovasc Drug Rev. Cardiovasc Drug Rev. 1997;15:1. . 1997;15:1. van Boeckel CAA et alvan Boeckel CAA et al. Angew Chem, Int Ed. Angew Chem, Int Ed EngEngll. 1993;32:1671. . 1993;32:1671.

Total Chemical SynthesisTotal Chemical Synthesis Single chemical entitySingle chemical entity Highly selective for its target Highly selective for its target No risk of pathogen contamination No risk of pathogen contamination Batch-to-batch consistencyBatch-to-batch consistency

Fondaparinux:Fondaparinux: First in New Class First in New Classof Synthetic Inhibitors of FactorXaof Synthetic Inhibitors of FactorXa

IIaIIaIIII

FibrinogenFibrinogen Fibrin clotFibrin clot

Extrinsic Extrinsic pathwaypathway

IntrinsicIntrinsicpathwaypathway

ATAT XaXaATAT ATAT

Fondaparinux Fondaparinux

XaXa

AntithrombinAntithrombin

FondaparinuxFondaparinux::Targeted MechanismTargeted Mechanism of Action of Action

Turpie AGG Turpie AGG et al. et al. NN EnEngl J Medgl J Med. 2001;344. 2001;344:619.:619.

EphesusN = 1817

Pentathlon 2000N = 1584

PenthifraN = 1250

PentamaksN = 724

Overall Odds Reduction

% odds reduction

Fondaparinux better Enoxaparin better

-100 -80 -60 -40 -20 200 40 60 80 100

58.5%

28.1%

61.6%

63.1%

55.3%

[72.9; 37.5]

[52.2; 7.6]

[73.4; 45.0]

[75.5; 44.8]

[63.2; 45.8]

Exact 95% CI

P = 10 -17

Overall EfficacyOverall EfficacyFondaparinux vs EnoxaparinFondaparinux vs Enoxaparin

Overall odds reduction for proximal DVT = 57.4% [CI: 72.3 - 35.6]; p = 10 x -6

Turpie AGG, et al. Arch Intern Med. 2002;162:1833-1840.

OASIS-5 – efficacy and safety at day 9OASIS-5 – efficacy and safety at day 9

Primary efficacy endpoint: 5.8% (fondaparinux) vs 5.7% Primary efficacy endpoint: 5.8% (fondaparinux) vs 5.7% (enoxaparin)(enoxaparin)

Major bleeding: 2.2% (fondaparinux) vs 4.1% (enoxaparin)Major bleeding: 2.2% (fondaparinux) vs 4.1% (enoxaparin)

0 1 2 3 4 5 6 7 8 90.00

0.01

0.02

0.03

0.04

Days

Cu

mu

lati

ve h

azar

d

Death, MI, refractory ischaemia Major bleeding

Enoxaparin

Fondaparinux

HR 0.5295% CI 0.44, 0.61

p<0.001

OASIS-5 Trial Group NEJM 2006. Available at www.nejm.org

0 1 2 3 4 5 6 7 8 90.00

0.01

0.02

0.03

0.04

0.05

0.06

Days

Cu

mu

lati

ve h

azar

d

Enoxaparin

Fondaparinux

HR 1.0195% CI 0.90, 1.13

Days

Cu

mu

lati

ve h

azar

d0.

00.

020.

040.

06

0 20 40 60 80 100 120 140 160 180

Enoxaparin

Fondaparinux

OASIS-5 – mortality at 6 monthsOASIS-5 – mortality at 6 months

HR 0.8995% CI 0.80, 1.00

p=0.05

OASIS-5 Trial Group NEJM 2006. Available at www.nejm.org

OASIS-6 OASIS-6 –– death at study end (3–6 months) death at study end (3–6 months)

Days

Cu

mu

lati

ve h

azar

d

0.0

0.02

0.04

0.06

0.08

0.10

0.12

0 18 36 54 72 90 108 126 144 162 180

UFH/placebo

Fondaparinux

HR 0.8895% CI 0.79, 0.99

p=0.029

OASIS-6 Trial Group JAMA 2006. Available at www.jama.com

Direct FactorXa InhibitorsDirect FactorXa Inhibitors

Oral Factor Xa inhibitors Oral Factor Xa inhibitors Clinical developmentClinical development

Rivaroxaban (Bayer)Rivaroxaban (Bayer) Phase IIb Phase IIb Phase III Phase III

Apixaban (BMS)Apixaban (BMS) Phase III Phase III

YM150 (Astellas)YM150 (Astellas) Phase IIb Phase IIb

DU-176b (Daiichi)DU-176b (Daiichi) Phase IIb Phase IIb

LY517717 (Lilly)LY517717 (Lilly) Phase IIb Phase IIb

813893 (GSK)813893 (GSK) Phase I/II Phase I/II

PRT054021(Portola) Phase IIPRT054021(Portola) Phase II

VIIa

Xa

IXa

XIa

XIIa

Direct Factor Xa inhibitionDirect Factor Xa inhibition

Tissue factor

Fibrinogen Fibrin clot

Factor II(prothrombin)

RivaroxabanApixabanDU-176b

YM150LY517717

PRT-054021

×

DirectDirect Factor Xa Inhibitors Factor Xa Inhibitors

FXa in the prothrombinase

complex

FXa

DirectFXa inhibitors

eg Rivaroxaban

• Direct Factor Xa inhibitors can inhibit Factor Xa within the prothrombinase complex

1/chromogenic peptide (µM)

0.000 0.005 0.010 0.015 0.0200

100

200

300

400

500

600

Rivaroxaban 0.9 nM Rivaroxaban 0.7 nMRivaroxaban 0.5 nMRivaroxaban 0.2 nMControl

Rivaroxaban: a direct, competitive Rivaroxaban: a direct, competitive

inhibitor of Factor Xa activityinhibitor of Factor Xa activity

Perzborn et al., J Thromb Haemost 2005

In vitro kinetic analysis

1/O

D/m

inu

te

Rivaroxaban inhibits free Factor Xa, Rivaroxaban inhibits free Factor Xa, prothrombinase-bound FactorXa, and fibrin-bound prothrombinase-bound FactorXa, and fibrin-bound

Factor Xa activityFactor Xa activityIn vitro studies

Rivaroxaban (nM)

0.01 0.1 1 10 100 1000

Inh

ibit

ion

of

Fac

tor

Xa

acti

vity

(%

)

0

20

40

60

80

100

Free Factor Xa1

Prothrombinase activity1

Fibrin-bound Factor Xa2

1Perzborn et al., J Thromb Haemost 2005; 2Depasse et al., ISTH 2005

ApixabanApixaban A highly potent, oral, direct FXa inhibitor (KA highly potent, oral, direct FXa inhibitor (Kii 0.08 nM) 0.08 nM)

– Follow-up to razaxaban (development halted due to Follow-up to razaxaban (development halted due to bleeding concerns)bleeding concerns)

Phase II study for VTE prevention after TKR: completedPhase II study for VTE prevention after TKR: completed

– Double-blind; dose-ranging; three od and three bid Double-blind; dose-ranging; three od and three bid apixaban doses; comparator enoxaparin and warfarin; apixaban doses; comparator enoxaparin and warfarin; target enrolment n=1202target enrolment n=1202

Phase II pilot study for VTE prevention in patients with Phase II pilot study for VTE prevention in patients with advanced metastatic cancer: ongoingadvanced metastatic cancer: ongoing

The Botticelli-DVT study for treatment of acute The Botticelli-DVT study for treatment of acute

symptomatic DVT: ongoing symptomatic DVT: ongoing

– – efficacy and safety of apixaban 5 mg bid, 10 mg bid efficacy and safety of apixaban 5 mg bid, 10 mg bid

and 20 mg od; comparators LMWH or fondaparinux and 20 mg od; comparators LMWH or fondaparinux

followed by VKAfollowed by VKA

Phase II study in patients with recent UA or MI: ongoingPhase II study in patients with recent UA or MI: ongoing

– Placebo-controlled; double-blind; target enrolment Placebo-controlled; double-blind; target enrolment

n=1800n=1800

AF StudyAF Study

ApixabanApixaban

RivaroxabanRivaroxabanHuman Factor Xa/rivaroxaban complexHuman Factor Xa/rivaroxaban complex

Rivaroxaban is an oral, direct Factor Xa inhibitor, with high selectivity for Factor Rivaroxaban is an oral, direct Factor Xa inhibitor, with high selectivity for Factor Xa (KXa (Kii 0.4 0.4±0.02±0.02 nM) nM)

ICIC5050 for Factor VIIa, Factor XIa, thrombin, activated protein C, plasmin, for Factor VIIa, Factor XIa, thrombin, activated protein C, plasmin, urokinase, trypsin: >20,000 nMurokinase, trypsin: >20,000 nM

Roehrig et al., J Med Chem 2005; Perzborn et al., J Thromb Haemost 2005

S4

S1

N NO

NH

O

SCl

O

O

O Rivaroxaban

Rivaroxaban bid (THR/TKR pooled): Rivaroxaban bid (THR/TKR pooled):

*Estimated rates calculated by logistic regression adjusted for study, age, and gender

Efficacy: p=0.39

Safety: p<0.0001

0 10 20 30 40 50 60 Enoxaparin

0

10

20

30

40

DVT, PE, and all-cause mortalityMajor bleeding

Est

imat

ed in

cid

ence

rat

e* (

%)

Rivaroxaban (mg total daily dose)5

Rivaroxaban efficacy and safety after Rivaroxaban efficacy and safety after THR with od dosingTHR with od dosing

0 5 10 20 40 Enoxaparin300

10

20

40

30

0

10

20

30

Inci

denc

e –

effic

acy

(%) Incidence – safety (%

)

Total daily dose (mg) of rivaroxaban

DVT, PE, and all-cause mortalityMajor, post-operative bleeding

Eriksson et al. ASH 2005

Total rivaroxaban daily doses of 5–20 mg had similar efficacy and safety to enoxaparin when given twice daily

Rivaroxaban 10 mg once daily appears to be the optimum dose

RECORD – RECORD – REREgulation of gulation of CCoagulation in major oagulation in major OOrthopaedic surgery reducing the rthopaedic surgery reducing the RRisk of isk of DDVT and VT and PEPE

Rivaroxaban 10 mg od will be compared with Rivaroxaban 10 mg od will be compared with enoxaparin in over 10,000 patients worldwideenoxaparin in over 10,000 patients worldwide– RECORD 1: THR, 5 weeks therapyRECORD 1: THR, 5 weeks therapy– RECORD 2: THR, 5 weeks vs 10–14 days enoxaparinRECORD 2: THR, 5 weeks vs 10–14 days enoxaparin– RECORD 3: TKR, 10–14 days therapyRECORD 3: TKR, 10–14 days therapy– RECORD 4: TKR, 10–14 days therapyRECORD 4: TKR, 10–14 days therapy

ODIXa-DVT – dose–response ODIXa-DVT – dose–response relationship for efficacyrelationship for efficacy

≥4-point improvement in thrombus burden by CCUS without recurrent VTEDose–response relationship: p=0.67Per-protocol population (n=528)

Primary efficacy outcome

Th

rom

bu

s re

gre

ssio

n w

ith

ou

t re

curr

ent

VT

E (

%)

80

70

60

50

40

30

20

10

06040200

Rivaroxaban total daily dose (mg)

Enox+VKA

bid rivaroxaban dosesod rivaroxaban dose

EINSTEIN-DVT – dose–response EINSTEIN-DVT – dose–response relationship for efficacyrelationship for efficacyR

ate

of

det

erio

rati

on

(%

)

Rivaroxaban total daily dose (mg) LMWH/heparin +VKA

10 30 40

20

18

16

14

1210

8

6

4

2

0

20

Recurrent DVT or PE (fatal or non-fatal) and deterioration in CUS or PLS

Dose–response relationship: p=0.86Per-protocol population (n=449)

Rivaroxaban-Clinical StudiesRivaroxaban-Clinical Studies

- VTE Treatnent

- Atrial Fibrillation

ACS treatment

Factor Xa inhibitors in developmentFactor Xa inhibitors in development

IndicationIndication VTE prevention*VTE prevention* VTE treatmentVTE treatment Stroke Stroke prevention in prevention in

patients with AFpatients with AF

Other?Other?

IdraparinuxIdraparinux –– Phase III results Phase III results expected soonexpected soon

Phase III haltedPhase III halted ––

Rivaroxaban Rivaroxaban Phase IIIPhase III Phase IIIPhase III Phase IIIPhase III ––

LY517717LY517717 Phase IIb Phase IIb completedcompleted

–– –– ––

YM150YM150 Phase IIa Phase IIa completedcompleted

–– PlannedPlanned ––

DU-176bDU-176b Phase IIa Phase IIa completedcompleted

–– PlannedPlanned ACS plannedACS planned

ApixabanApixaban Phase IIb Phase IIb completed; planned completed; planned in cancer patientsin cancer patients

Phase II Phase II underwayunderway

–– Post-ACS plannedPost-ACS planned

PRT-054021PRT-054021 Phase II plannedPhase II planned PlannedPlanned PlannedPlanned Secondary Secondary prevention of stroke prevention of stroke

and MI plannedand MI planned

*Prevention of VTE after major orthopaedic surgery, unless indicated

New anticoagulantsNew anticoagulants

TFPI (tifacogin)

FondaparinuxIdraparinux

RivaroxabanApixabanLY517717YM150DU-176bPRT-054021

XimelagatranDabigatran

ORAL PARENTERAL

DX-9065aOtamixaban

Xa

IIa

TF/VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

AT

APC (drotrecogin alfa)sTM (ART-123)

Adapted from Weitz & Bates, J Thromb Haemost 2005

TTP889

Antithrombotic TherapyAntithrombotic Therapy

2007200720072007

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AnswerAnswer

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