Dominick J. Angiolillo, MD, PhD, FACC, FESC Director of Cardiovascular Research Assistant Professor...

Dominick J. Angiolillo, MD, PhD, FACC, FESCDirector of Cardiovascular Research

Assistant Professor of Medicine

Update on Novel Antiplatelet Agents Under Advanced Clinical Development

CRT 2008 Wednesday February 13th, 2008

Presenter Disclosure Information

Name: Dominick J Angiolillo

Within the past 12 months, the presenter or their spouse/partner have had a financial interest/arrangement or affiliation with the organization listed below.

Company Name: Relationship:

Bristol Myers Squibb Consultant/Speaker bureau

Sanofi-Aventis Consultant/Speaker bureau

Eli Lilly Consultant/Speaker bureau

Daiichi Sankyo Consultant/Speaker bureau

Portola Consultant

GSK Educational Grant

Novel ADP P2YNovel ADP P2Y1212 receptor antagonist receptor antagonist

PrasugrelPrasugrel

AZD6140AZD6140

CangrelorCangrelor

Ticlopidine

(1st generation)

N

SCl

Clopidogrel

(2nd generation)

N

SCl

O

O CH3C

Prasugrel (CS-747) (LY640315)

(3rd generation)

N

F

O

S

O

OCH3

The Thienopyridine Family

Active Metabolite FormationActive Metabolite Formation

HOOCHOOC

* HS* HS

NN

OO

FF

NN

SS

OO

CC HH33

CCOO

FF

Active MetaboliteActive MetaboliteActive MetaboliteActive Metabolite

PrasugrelPrasugrel

Sankyo Ann Report 51:1,1999

ClopidogrelClopidogrel

Pro-drugPro-drugPro-drugPro-drug

Hepatic MetabolismHepatic MetabolismCytochrome P450Cytochrome P450

Hepatic MetabolismHepatic MetabolismCytochrome P450Cytochrome P450

Active MetaboliteActive MetaboliteActive MetaboliteActive Metabolite

NN

SS

OO

FFOO

HOOCHOOC

* HS* HS

NN

OO

ClCl

OCH3OCH3

Sem Vasc Med 3:113, 2003

Pre-hepatic Pre-hepatic metabolismmetabolismEsterases in blood Esterases in blood (? Small Intestine)(? Small Intestine)

Pre-hepatic Pre-hepatic metabolismmetabolismEsterases in blood Esterases in blood (? Small Intestine)(? Small Intestine)

OO

85% Inactive 85% Inactive MetabolitesMetabolites

Esterases in bloodEsterases in blood

85% Inactive 85% Inactive MetabolitesMetabolites

Esterases in bloodEsterases in blood

OONN

SS

OO

ClCl

OO CHCH33CHCH33CCCC

NN

SS

OO

ClCl

OO CHCH33CHCH33CCCC

NN

SS

OO

ClCl

OO CHCH33CHCH33CCCC

Healthy volunteer crossover studyHealthy volunteer crossover study IPA (20 IPA (20 M ADP) at 24 hoursM ADP) at 24 hours

Brandt J et al. AHJ 2006Brandt J et al. AHJ 2006

––2020

00

2020

4040

6060

8080

100100In

hib

itio

n o

f p

late

let

agg

reg

atio

n (

%)

Inh

ibit

ion

of

pla

tele

t ag

gre

gat

ion

(%

)

Response to prasugrelResponse to prasugrel60 mg60 mg

Response to clopidogrel Response to clopidogrel 300 mg300 mg

N=64N=64

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

Days

En

dp

oin

t (%

)

12.1

9.9

HR 1.32(1.03-1.68)

P=0.03

Prasugrel

Clopidogrel1.82.4

138 events

35 events

Balance of Balance of Efficacy and SafetyEfficacy and Safety

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 46

NNH = 167

Wiviott et al NEJM 2007

Stent ThrombosisStent Thrombosis(ARC Definite + Probable)(ARC Definite + Probable)

0

1

2

3

0 30 60 90 180 270 360 450

HR 0.48P <0.0001

Prasugrel

Clopidogrel2.4

(142)

NNT= 77

1.1 (68)

Days

En

dp

oin

t (%

)

Any Stent at Index PCIAny Stent at Index PCI N= 12,844 N= 12,844

Diabetic SubgroupDiabetic Subgroup

0

2

4

6

8

10

12

14

16

18

0 30 60 90 180 270 360 450

HR 0.70P<0.001

Days

En

dp

oin

t (%

)

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 21

N=3146N=3146

17.0

12.2

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel 2.6

2.5


Net Clinical BenefitNet Clinical BenefitBleeding Risk SubgroupsBleeding Risk Subgroups

OVERALL

>=60 kg

< 60 kg

< 75

>=75

No

Yes

0.5 1 2

Prior Stroke / TIA

Age

Wgt

Risk (%)

+ 54

-16

-1

-16

+3

-14

-13

Prasugrel Better Clopidogrel BetterHR

Pint = 0.006

Pint = 0.18

Pint = 0.36

Post-hoc analysisPost-hoc analysis


Safety

Significant increase in serious bleeding

(32% increase)

Avoid in pts with prior CVA/TIA

Efficacy

1. A significant reduction in: CV Death/MI/Stroke 19% Stent Thrombosis 52% uTVR 34%

MI 24%

2. An early and sustained benefit

3. Across ACS spectrum

Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD

ConclusionsConclusionsHigher IPA to Support PCIHigher IPA to Support PCI

Net clinical benefit significantly favored PrasugrelNet clinical benefit significantly favored Prasugrel

Optimization of Prasugrel maintenance dosing in a minority of patients may help Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the benefit : risk balanceimprove the benefit : risk balance

PRINCIPLE – TIMI 44 Comparison with Higher Dose Clopidogrel

P<0.0001 for each

IPA (%; 20 M ADP)

Hours 14 Days

IPA (%; 20 M ADP)

P<0.0001

Prasugrel 10 mg

Clopidogrel 150 mg

Wiviott et al Circulation 2007.

N=201

Prasugrel 60 mg

Clopidogrel 600 mg


PrasugrelPrasugrel

AZD6140AZD6140

CangrelorCangrelor

AZD6140 (Ticagrelor)AZD6140 (Ticagrelor) A non-thienopyridine, in the chemical class CPTP

(CycloPentylTriazoloPyrimidine)

First oral reversible ADP P2Y12 receptor antagonist

Direct acting via the P2Y12 receptor - metabolism not required for activity

More potent platelet inhibitor than clopidogrel

A non-thienopyridine, in the chemical class CPTP (CycloPentylTriazoloPyrimidine)

First oral reversible ADP P2Y12 receptor antagonist

Direct acting via the P2Y12 receptor - metabolism not required for activity

More potent platelet inhibitor than clopidogrel

HO

HN

HO OH

O S

F

F

NN

N

NN

DISPERSE: Faster, Greater and More Consistent IPA with AZD6140 vs clopidogrel

Time, hours Time, hours

0

20

40

60

80

100

AZD6140 (100 mg bd)

8 12 8 12

Inh

ibit

ion

, %

24

Clopidogrel

Inh

ibit

ion

, %

Day 1 Day 14 Day 1 Day 14

0

20

40

60

80

100

8 12 8 12 24424242 42

Husted SE et al Eur Heart J 2006; 27: 1038-1047

DISPERSE2 Study Design

DISPERSE2 was a double-blind, randomized study of AZD6140 compared with clopidogrel, both on a background of aspirin (75–100 mg od) 50% of patients in each AZD6140 arm received a loading dose of 270 mg In the clopidogrel arm, thienopyridine treatment-naïve patients received a 300-mg loading dose

Randomization

Visit 1

Day 1

Visit 2 Visit 3 Visit 4 Follow-up

Week 4 Week 8 Week 12 Final Visit+7 days

AZD6140 90 mg bid

AZD6140 180 mg bid

Clopidogrel 75 mg qd

NSTE-ACS patients with onset of chest pain <48 hours

n = 334

n = 329

n = 327

Cannon CP et al. J Am Coll Cardiol 2007

DISPERSE2 Adjudicated Bleeding Rates (%)Week 4 and Overall

0

2

4

6

8

10

Week 4

To

tal B

leed

ing

Ra

te (

%)

0

Overall

To

tal B

leed

ing

Ra

te (

%)12

2

4

6

8

10

12

9.6%

7.7% 8.0%

10.2% 10.2%9.2%

AZD614090 mg bidN = 334

AZD6140180 mg bid

N = 323

Clopidogrel75 mg qdN = 327

AZD614090 mg bidN = 334

AZD6140180 mg bid

N = 323

Clopidogrel75 mg qdN = 327

Minor bleeding* Major bleeding

• Adjudicated total bleeding rates were similar for all groups• No evidence of dose-response for major bleeds

* Minor bleeding without major bleeding Cannon CP et al. J Am Coll Cardiol 2007

DISPERSE-2: Non-bleeding adverse events

0

2

4

6

8

10

12

14

16

18

ClopClopAZD6140AZD6140

90 mg90 mg

AZD6140AZD6140

180 mg180 mg

0

2

4

6

8

10

12

14

16

18

ClopClopAZD6140AZD6140

90 mg90 mg

AZD6140AZD6140

180 mg180 mg

4.4%4.4%5.6%5.6%

9.9%9.9%

6.4%6.4%

10.5%10.5%

15.8%15.8%

Ventricular Pauses >2.5 SecondsDyspnea% %

Discontinuation rates from non-bleeding adverse events were low and similar between groups

Primary endpoint: CVD/MI/stroke

Secondary endpoint: CVD/MI/stroke/revascularization with PCI;CVD/MI/stroke, severe recurrent ischemia

12-month maximum exposure12-month maximum exposure(Min = 6 mo, Max = 12 mo, Mean = 11 mo)(Min = 6 mo, Max = 12 mo, Mean = 11 mo)

(N=18,000)(N=18,000)

ASA + Clopidogrel300 mg ld/75 mg qd

600 mg ld allowed in PCI

ASA + AZD6140180 mg ld/90 mg bid

Moderate- to high-risk ACS patients (UA/NSTEMI/STEMI, PCI,

medically managed, or CABG)

ASA = acetylsalicylic acid; bid = twice daily; CVD = cardiovascular disease; ld = loading dose; MI = myocardial infarction; NSTEMI = non-ST-segment elevation MI; qd = once daily; STEMI = ST-segment elevation MI; UA = unstable angina.

ClinicalTrials.gov Identifier: NCT00391872


PrasugrelPrasugrel

AZD6140AZD6140

CangrelorCangrelor

Cangrelor (AR-C69931MX)Parenteral ADP-P2Y12 receptor antagonist

ATP analogue

Direct and Reversible P2Y12 inhibitor

More potent than clopidogrel ~90% inhibition of platelet aggregation at

1 - 4 mcg/kg/min iv

Plasma half-life of 5-9 min.; 20 min. for return to normal platelet function

O- O- O-

O-O OHO OH

P P PO O

N

HN

NN

N

N

S

S

CF3

O

Cl

Cl-O

% I

nhib

ition

of

Agg

reg

atio

n

Fol

d In

cre

ase

in B

leed

ing

Tim

e

0

20

40

60

80

100

0

1

2

3

4

5

6

7

8

50 100 500 1000 2000

AggregationAggregation

Bleeding timeBleeding time

+ aspirin/heparin/GTN

+ placebo

AR-C69931 (ng.kg-1.min-1) Stepped infusion period Recovery period

7 15 20 45 60 min

Key Phase I resultRapid reversal of dose-dependent effect

Phase II clinical data: Compared with Abciximab in PCI

Double-blind randomized trial performed in US

5.7%5.4%

2.1%

1.0%

Death, MI, revascularization Major bleed (TIMI criteria)

Incidence of events up to 7-days

AR-C69931MX report number SC931-5129 Part 2

Abciximab (N=94)

Cangrelor (N=105)

Greenbaum et al. Am Heart J. 2006;151:689.e1-689.e10 Greenbaum et al. Am Heart J. 2006;151:689.e1-689.e10

CHAMPION-PCIPCI

(with or without stent)

1:1 Double blind, double dummy

Placebocapsules

(to match)

Cangrelorbolus (30µg/kg) &

infusion (4µg/kg/hour)

Clopidogrelcapsules(600mg)

Placebobolus & infusion

(to match)

1º Endpoint: Death, MI, and uRevasc at 48 hours

2 º Endpoints:Death, MI, uRevasc at 30 daysDeath at 6 months and 1 year

Index ProcedureStudy drug infusion (for at least 2 hours or

the duration of the procedure, whichever is longer)

Clopidogrelcapsules(600 mg)

Placebocapsules(to match)

Clopidogrel Maintenance(at physician discretion)

+ +

Platelet StimuliPlatelet Stimuli

GP IIb/IIIa integrinGP IIb/IIIa integrinGP IIb/IIIa integrinGP IIb/IIIa integrin

ADPADP

EpinephrineEpinephrine

CollagenCollagen

ThrombinThrombin

Platelet AggregationPlatelet AggregationPlatelet AggregationPlatelet Aggregation

SerotoninSerotoninShear rateShear rate

AA

TxA2

COX-1

ThrombinThrombin

ThrombinThrombin

ThrombinThrombin

TxATxA22TxATxA22

Thrombin

ADPADP

TXATXA22

ADP P2Y12

ADPADP

(fibrinogen(fibrinogenreceptor)receptor)

GP IIb/IIIaGP IIb/IIIaActivation

COX-1

clopidogrel bisulfate

aspirin

cAMP

Oral Anti-PAR-1 receptors

SCH 530348E 5555

adapted from Schafer AI. Am J Med. 1996;101:199-209.

TRA (SCH 530348) Program(29,500 pts)

1o EP: Composite of CV death, MI, Stroke, and urgent

revascularization

TRA (SCH 530348) ProgramEvaluation of Efficacy and Safety in Acute and Chronic Atherothrombosis

CER

NSTEACS10,000 pts

2º Prevention19,500 pts

SCH 530348 Placebo SCH 530348 Placebo

F/U: 30 days, 4,8,12 months, and 6 months thereafter

F/U 1 yr minimum

1o EP: Composite of CV death, MI, Stroke, urgent

revascularization and Recurrent Ischemia w/ Rehosp

…………. to be continued !!!!!!!!!!!. to be continued !!!!!!!!!!!

Dominick J. Angiolillo, MD, PhD, FACC, FESC Director of Cardiovascular Research Assistant Professor...

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Transcript of Dominick J. Angiolillo, MD, PhD, FACC, FESC Director of Cardiovascular Research Assistant Professor...