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Welcome Ask The Experts March 24-27, 2007 New Orleans, LA. Are all Xa Inhibitors the Same? Alexander G. G. Turpie, MD Professor of Medicine McMaster University Hamilton, Ontario, Canada. Antithrombotics That Have Changed Clinical Practice. Anticoagulants Low-molecular-weight heparin

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Welcome ask the experts march 24 27 2007 new orleans la

Welcome

Ask The Experts

March 24-27, 2007

New Orleans, LA


Welcome ask the experts march 24 27 2007 new orleans la

Are all Xa Inhibitors the Same?Alexander G. G. Turpie, MDProfessor of MedicineMcMaster UniversityHamilton, Ontario, Canada


Antithrombotics that have changed clinical practice

Antithrombotics That Have Changed Clinical Practice

Anticoagulants

  • Low-molecular-weight heparin

    Antiplatelet Drugs

  • Thienopyridines

  • Glycoprotein IIb/IIIa Inhibitors


Low molecular weight heparins

Low Molecular Weight Heparins

Nadroparin -Fraxiparine

Enoxaparin -Lovenox

COONa

O

CaO3SO

O

O

Saccharide chain

Saccharide chain

OH

NHSO3Ca

OSO2ONa

OR1

Dalteparin -Fragmin

H

R2

R1 = H or SO3NaR2 = COONa

CHOR2

Saccharide chain

CH2OH

O

OH

HO

O

OR1


Low molecular weight heparins1

Low-Molecular-Weight Heparins

Potential Advantages:

  • Lack of binding to plasma proteins and endothelium

  • Good bioavailability

  • Stable dose response

  • Long half-life

  • Resistance does notdevelop


Low molecular weight heparin

Low Molecular Weight Heparin

  • Venous Thromboembolism

    - prophylaxis

    - treatment

  • Ischaemic heart disease

    • unstable angina

    • acute MI

    • coronary stenting

  • Cerebrovascular disease

    • ischaemic stroke

    • embolic stroke

  • Peripheral vascular disease

    • reconstructive surgery


New anticoagulants

New anticoagulants

ORAL

PARENTERAL

TF/VIIa

TFPI (tifacogin)

TTP889

X

IX

APC (drotrecogin alfa)

sTM (ART-123)

IXa

VIIIa

RivaroxabanApixabanLY517717YM150

DU-176bPRT-054021

Va

AT

Xa

FondaparinuxIdraparinux

II

DX-9065aOtamixaban

XimelagatranDabigatran

IIa

Fibrinogen

Fibrin

Adapted from Weitz & Bates, J Thromb Haemost 2005


Factor xa inhibitors

Factor Xa inhibitors

FXa may be a better target than thrombin

  • Has few functions outside coagulation (compared with thrombin)

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

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

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


Factor xa inhibitors1

Factor Xa Inhibitors

  • Indirect

  • Direct


Fondaparinux first in new class of synthetic inhibitors of factorxa

Fondaparinux: First in New Classof Synthetic Inhibitors of FactorXa

Total Chemical Synthesis

  • Single chemical entity

  • Highly selective for its target

  • No risk of pathogen contamination

  • Batch-to-batch consistency

Herbert JM et al. Cardiovasc Drug Rev. 1997;15:1.

van Boeckel CAA et al. Angew Chem, Int EdEngl. 1993;32:1671.


Fondaparinux targeted mechanism of action

Fondaparinux:Targeted Mechanism of Action

Intrinsic

pathway

Extrinsic pathway

Antithrombin

Xa

Xa

AT

AT

AT

Fondaparinux

II

IIa

Fibrinogen

Fibrin clot

Turpie AGG et al. NEngl J Med. 2001;344:619.


Overall efficacy fondaparinux vs enoxaparin

Overall EfficacyFondaparinux vs Enoxaparin

Fondaparinux better

Exact 95% CI

Enoxaparin better

Ephesus

N = 1817

[72.9; 37.5]

58.5%

Pentathlon 2000

N = 1584

[52.2; 7.6]

28.1%

Penthifra

N = 1250

61.6%

[73.4; 45.0]

Pentamaks

N = 724

[75.5; 44.8]

63.1%

Overall Odds Reduction

[63.2; 45.8]

55.3%

P = 10 -17

% odds reduction

0

100

-80

-60

-40

-20

20

40

60

80

-100

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 9

0.06

Fondaparinux

0.04

0.05

Enoxaparin

0.03

0.04

HR 1.01

95% CI 0.90, 1.13

Cumulative hazard

0.03

Cumulative hazard

0.02

0.02

0.01

0.01

0.00

0

1

2

3

4

5

6

7

8

9

0.00

Days

0

1

2

3

4

5

6

7

8

9

Days

OASIS-5 – efficacy and safety at day 9

Death, MI, refractory ischaemia

Major bleeding

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

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

Enoxaparin

HR 0.52

95% CI 0.44, 0.61

p<0.001

Fondaparinux

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


Oasis 5 mortality at 6 months

Enoxaparin

0.06

Fondaparinux

0.04

Cumulative hazard

0.02

0.0

0

20

40

60

80

100

120

140

160

180

Days

OASIS-5 – mortality at 6 months

HR 0.89

95% CI 0.80, 1.00p=0.05

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


Oasis 6 death at study end 3 6 months

0.12

UFH/placebo

0.10

Fondaparinux

0.08

0.06

Cumulative hazard

HR 0.88

95% CI 0.79, 0.99p=0.029

0.04

0.02

0.0

0

18

36

54

72

90

108

126

144

162

180

Days

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

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


Direct factorxa inhibitors

Direct FactorXa Inhibitors


Oral factor xa inhibitors clinical development

Oral Factor Xa inhibitors Clinical development

Rivaroxaban (Bayer) Phase IIb

Phase III

Apixaban (BMS) Phase III

YM150 (Astellas) Phase IIb

DU-176b (Daiichi) Phase IIb

LY517717 (Lilly) Phase IIb

813893 (GSK) Phase I/II

PRT054021(Portola) Phase II


Direct factor xa inhibition

Direct Factor Xa inhibition

XIIa

Tissue factor

×

XIa

VIIa

IXa

Xa

Rivaroxaban

Apixaban

DU-176b

YM150

LY517717

PRT-054021

Factor II(prothrombin)

Fibrinogen

Fibrin clot


Direct factor xa inhibitors

FXa

Direct Factor Xa Inhibitors

DirectFXa inhibitors

eg Rivaroxaban

FXa in the

prothrombinase

complex

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


Rivaroxaban a direct competitive inhibitor of factor xa activity

Rivaroxaban: a direct, competitive inhibitor of Factor Xa activity

In vitro kinetic analysis

600

Rivaroxaban 0.9 nM

500

Rivaroxaban 0.7 nM

Rivaroxaban 0.5 nM

Rivaroxaban 0.2 nM

400

Control

1/OD/minute

300

200

100

0

0.000

0.005

0.010

0.015

0.020

1/chromogenic peptide (µM)

Perzborn et al., J Thromb Haemost 2005


Welcome ask the experts march 24 27 2007 new orleans la

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

In vitro studies

100

80

60

Inhibition of Factor Xa activity (%)

40

Free Factor Xa1

20

Prothrombinase activity1

Fibrin-bound Factor Xa2

0

0.01

0.1

1

10

100

1000

Rivaroxaban (nM)

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


Apixaban

Apixaban

  • A highly potent, oral, direct FXa inhibitor (Ki 0.08 nM)

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

  • Phase II study for VTE prevention after TKR: completed

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

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


Apixaban1

Apixaban

  • The Botticelli-DVT study for treatment of acute symptomatic DVT: ongoing

    – efficacy and safety of apixaban 5 mg bid, 10 mg bid and 20 mg od; comparators LMWH or fondaparinux followed by VKA

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

    • Placebo-controlled; double-blind; target enrolment n=1800

  • AF Study


Rivaroxaban human factor xa rivaroxaban complex

Rivaroxaban

S4

S1

RivaroxabanHuman Factor Xa/rivaroxaban complex

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

  • IC50 for Factor VIIa, Factor XIa, thrombin, activated protein C, plasmin, urokinase, trypsin: >20,000 nM

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


Rivaroxaban bid thr tkr pooled

40

DVT, PE, and all-cause mortality

Major bleeding

30

Estimated incidence rate* (%)

20

10

0

20

30

40

50

60

Enoxaparin

0

10

5

Rivaroxaban (mg total daily dose)

Rivaroxaban bid (THR/TKR pooled):

Efficacy: p=0.39

Safety: p<0.0001

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


Rivaroxaban efficacy and safety after thr with od dosing

DVT, PE, and all-cause mortality

40

30

Major, post-operative bleeding

30

20

Incidence – efficacy (%)

Incidence – safety (%)

20

10

10

0

0

0

5

10

20

30

40

Enoxaparin

Total daily dose (mg) of rivaroxaban

Rivaroxaban efficacy and safety after THR with od dosing

  • 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

Eriksson et al. ASH 2005


Welcome ask the experts march 24 27 2007 new orleans la

  • RECORD – REgulation of Coagulation in major Orthopaedic surgery reducing the Risk of DVT and PE

  • Rivaroxaban 10 mg od will be compared with enoxaparin in over 10,000 patients worldwide

    • RECORD 1: THR, 5 weeks therapy

    • RECORD 2: THR, 5 weeks vs 10–14 days enoxaparin

    • RECORD 3: TKR, 10–14 days therapy

    • RECORD 4: TKR, 10–14 days therapy


Odixa dvt dose response relationship for efficacy

80

bid rivaroxaban doses

od rivaroxaban dose

70

60

50

40

30

20

10

0

0

20

40

60

Enox+VKA

Rivaroxaban total daily dose (mg)

ODIXa-DVT – dose–response relationship for efficacy

Primary efficacy outcome

Thrombus regression without recurrent VTE (%)

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


Einstein dvt dose response relationship for efficacy

EINSTEIN-DVT – dose–response relationship for efficacy

20

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

18

16

14

12

10

Rate of deterioration (%)

8

6

4

2

0

10

20

30

40

LMWH/heparin +VKA

Rivaroxaban total daily dose (mg)

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


Rivaroxaban clinical studies

Rivaroxaban-Clinical Studies

- VTE Treatnent

- Atrial Fibrillation

ACS treatment


Factor xa inhibitors in development

Factor Xa inhibitors in development

*Prevention of VTE after major orthopaedic surgery, unless indicated


New anticoagulants1

New anticoagulants

ORAL

PARENTERAL

TF/VIIa

TFPI (tifacogin)

TTP889

X

IX

APC (drotrecogin alfa)

sTM (ART-123)

IXa

VIIIa

RivaroxabanApixabanLY517717YM150

DU-176bPRT-054021

Va

AT

Xa

FondaparinuxIdraparinux

II

DX-9065aOtamixaban

XimelagatranDabigatran

IIa

Fibrinogen

Fibrin

Adapted from Weitz & Bates, J Thromb Haemost 2005


Antithrombotic therapy

Antithrombotic Therapy

2007


Welcome ask the experts march 24 27 2007 new orleans la

Question

&

Answer


Welcome ask the experts march 24 27 2007 new orleans la

Thank You!

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