Anti-thrombotic agentsAnti-thrombotic agents

New and Emerging New and Emerging AnticoagulantsAnticoagulants

Anti – Xa : directAnti – Xa : direct Rivaroxaban (oral)Rivaroxaban (oral) Apixaban (oral)Apixaban (oral) Betrixiban (oral)Betrixiban (oral) Edoxaban (oral)Edoxaban (oral) Otamixaban (parenteral)Otamixaban (parenteral)

Anti – Xa : indirectAnti – Xa : indirect Idraparinux biotinylated Idraparinux biotinylated

(parenteral)(parenteral)

Anti – IIaAnti – IIa Dabigatran (oral)Dabigatran (oral) Odiparcil (oral)Odiparcil (oral) Flovagatran (parenteral)Flovagatran (parenteral) Pegmusirudin (parenteral)Pegmusirudin (parenteral)

Site of Action for New Site of Action for New Anti-thrombotic AgentsAnti-thrombotic Agents

Fibrin Clot

Intrinsic ExtrinsicXII

VIIVIII

IX

XI

Fibrinogen

II

V

Tissue Factor

X Direct Xa Inhibitors

“-xaban”AT

Indirect Xa Inhibitors

“-parinux”

Direct Thrombin Inhibitors

“-gatran”warfarin

Factor Xa vs. Factor IIaFactor Xa vs. Factor IIa

Factor XaFactor Xa One Xa forms many One Xa forms many

IIaIIa Limited role in Limited role in

diversity of action diversity of action outside of coagulation outside of coagulation cascadecascade

Clinical effectivenessClinical effectiveness FondaparinuxFondaparinux

Factor IIaFactor IIa Supports feedback Supports feedback

amplification through amplification through Factor V, Factor VIII, Factor V, Factor VIII, and Factor IXand Factor IX

Has many cellular Has many cellular effectseffects inflammationinflammation

Clinical effectivenessClinical effectiveness ArgatrobanArgatroban HirudinsHirudins

ApixabanApixaban

Oral tabletOral tablet Bioavailability: 50%Bioavailability: 50% Peak Plasma Levels Peak Plasma Levels

= 3 hrs= 3 hrs Half-life ~ 12 hours Half-life ~ 12 hours Metabolized in liver Metabolized in liver

via CYP3A4 and via CYP3A4 and CYP independent CYP independent mechanismsmechanisms

Eliminated via Eliminated via multiple pathwaysmultiple pathways

No laboratory No laboratory monitoring requiredmonitoring required

Manufactured by Manufactured by Bristol-Myers Bristol-Myers Squibb/PfizerSquibb/Pfizer

Plan to submit for Plan to submit for U.S. approval in U.S. approval in 2009-20102009-2010

Apixaban Phase III TrialsApixaban Phase III Trials

KneeKnee KneeKnee HipHipMedically Medically

IllIll

# Patients# Patients 30583058ADVANCE-1

30583058ADVANCE-2ADVANCE-2

40224022ADVANCE-3

65246524ADOPT

Est. Completion Est. Completion DateDate Oct 2008Oct 2008 May 2009May 2009 Feb 2009Feb 2009

March March

20092009

Study ArmsStudy Arms

Apixaban Apixaban 2.5mg BID 2.5mg BID

vs Enox vs Enox 30mg BID30mg BID

ApixabanApixaban

2.5mg BID2.5mg BID

vs vs

Enox Enox

40mg 40mg QDay QDay

Apixaban Apixaban

2.5mg BID 2.5mg BID vs vs

Enox Enox

40mg QDay 40mg QDay

ApixabanApixaban

2.5mg BID x 2.5mg BID x 30 days30 days

vs vs

Enox 40mg Enox 40mg QDay x 6-14 QDay x 6-14

daysdays

0

2

4

6

8

10

12

14

Apixaban 2.5mg BID Enoxaparin 30mg BID

Pri

mar

y E

nd

po

int

(%)

ADVANCE – 1: Results of ADVANCE – 1: Results of Efficacy vs. Enoxaparin 30 mg Efficacy vs. Enoxaparin 30 mg

BIDBID

8.99%N = 1157

8.85%N = 1130

RR: 1.02 (95% CI: 0.78 to 1.32) P=0.06 for non-inferiorityAbsolute Difference: 0.1% (95% CI: -2.22 to 2.44) P<0.001 for non-inferiority

Lassen MR, et al. NEJM 2009;361:594 – 604.

0

5

10

15

20

25

30

Apixaban 2.5 mg BID Enoxaparin 40 mg Qday

Pri

mar

y E

nd

po

int

(%)

ADVANCE – 2: Primary ADVANCE – 2: Primary Efficacy ResultsEfficacy Results

15.1%n = 975

24.5%n = 997

RR: 0.62; 95% CI: 0.51 – 0.74p<0.0001*

*Composite of adjudicated asymptomatic DVT by venography; objectively confirmed

symptomatic DVT or PE; or death from any cause. One-sided p-value for superiority.

Summary of ADVANCE – 2 Summary of ADVANCE – 2 StudyStudy

Apixaban 2.5mg BID vs. Enoxaparin 40mg QDApixaban 2.5mg BID vs. Enoxaparin 40mg QD Superior for:Superior for:

Primary endpoint of ANY DVT/PE/All-Cause DeathPrimary endpoint of ANY DVT/PE/All-Cause Death Secondary endpoint for Major VTESecondary endpoint for Major VTE

Lower observed bleeding rates Lower observed bleeding rates Major Major Clinically relevant non-major Clinically relevant non-major

Similar overall safety profileSimilar overall safety profile

RivaroxabanRivaroxaban

Brand name XareltoBrand name Xarelto®®, , BayerBayer

Oral tabletOral tablet High oral bioavailability High oral bioavailability

(>80%)(>80%) Onset of action 2-4 Onset of action 2-4

hourshours Half-life 9-12 hoursHalf-life 9-12 hours No observed effects on No observed effects on

agonist-induced platelet agonist-induced platelet aggregationaggregation

Primarily renal Primarily renal eliminationelimination

No laboratory monitoring No laboratory monitoring requiredrequired

No dosage adjustment No dosage adjustment for gender, age, extreme for gender, age, extreme body weightbody weight

Approved by Europe and Approved by Europe and Canadian agencies, and Canadian agencies, and under FDA review under FDA review currently currently

Indirect Factor Xa Indirect Factor Xa InhibitorsInhibitors

Fibrin Clot

XII

VIIVIII

IX

XI

Fibrinogen

II

V

X

TF

Intrinsic

Extrinsic

ATIndirect Xa Inhibitors

“-parinux”

IdraparinuxIdraparinux Once weekly SC injectionOnce weekly SC injection 100% SC bioavailability100% SC bioavailability Half-life ~ 96-130 hoursHalf-life ~ 96-130 hours Renal eliminationRenal elimination No monitoring requiredNo monitoring required Manufactured by Manufactured by Sanofi-AventisSanofi-Aventis Plan to file for U.S. Plan to file for U.S.

approval in 2009approval in 2009

SummarySummary

PropertyProperty RivaroxabanRivaroxaban ApixabanApixaban IdraparinuxIdraparinux DabigatranDabigatran

TargetTarget Factor XaFactor Xa Factor XaFactor Xa Factor Xa Factor Xa (indirect)(indirect)

ThrombinThrombin

ROAROA OralOral OralOral SubcutaneousSubcutaneous OralOral

ProdrugProdrug No No NoNo YesYes YesYes

BioavailabilityBioavailability > 80%> 80% > 50%> 50% 100%100% 6%6%

Time to peak Time to peak 33 33 ______ 22

Half-life Half-life 9 hrs9 hrs 9 – 14 hrs9 – 14 hrs 80 hrs80 hrs 14 – 17 hrs14 – 17 hrs

Frequency of Frequency of AdministrationAdministration

QdayQday BIDBID Q WeekQ Week Qday or BIDQday or BID

Drug Drug InteractionsInteractions

Potent CYP3A4 & Potent CYP3A4 & P-glycoprotein P-glycoprotein

inhibitorsinhibitors

Potent CYP3A4 & Potent CYP3A4 & P-glycoprotein P-glycoprotein

inhibitorsinhibitors

______ P-glycoprotein P-glycoprotein inhibitorsinhibitors

Renal excretion Renal excretion 66%66% 25%25% YesYes 80%80%

Safe in Safe in pregnancypregnancy

NoNo NoNo UnknownUnknown NoNo

AntidoteAntidote NoNo NoNo NoNo NoNoAdapted from: Gross, PL. Arterioscler Thromb Vasc Biol. 2008; 28:380-386.

ConclusionConclusion

Several oral and parenteral Anti Xa and Anti IIa Several oral and parenteral Anti Xa and Anti IIa drugs are under development at this timedrugs are under development at this time

Rivaroxaban and Dabigatran are approved in Rivaroxaban and Dabigatran are approved in the European Union and Canada for the the European Union and Canada for the prophylaxis of DVT and awaiting FDA prophylaxis of DVT and awaiting FDA review/approvalreview/approval

Safety issues are of prime importance in the Safety issues are of prime importance in the development of these drugs and will be development of these drugs and will be strongly scrutinized upon reviewstrongly scrutinized upon review