1 Novel Antiplatelet Agents: AZD6140, Cangrelor, TRA

1

Novel Antiplatelet Agents: AZD6140, Cangrelor, TRA

2Meadows TA, Bhatt DL. Circ Res. 2007;100:1261

Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply.3

1. van Giezen JJ, Humphries RG. Semin Thromb Hemost 2005;31:195-204.

AZD6140 Characteristics

The first reversible oral adenosine diphosphate (ADP) receptor antagonist1

New class of P2Y12 inhibitors• Cyclo-pentyl-triazolo-pyrimidine (CPTP)

• Not a thienopyridine or ATP analog

• Direct-acting (not a prodrug); does not require metabolic activation

Reversible binding; degree of inhibition reflects plasma concentration• half-life of approximately 12 h

• More rapid reversal of effect—full recovery of platelet function

Rapid onset (within 2 hours); peak plasma levels within 2 to 3 hours

Greater and more consistent inhibition of ADP-induced platelet aggregation versus clopidogrel

Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51.


Randomization

V1

Day 1

V2 V3 V4 Follow-up

Week 4 Week 8 Week 12 Final Visit+7 days

AZD6140 90 mg bid (n = 334)

AZD6140 180 mg bid (n = 323)

Clopidogrel 75 mg qd (n = 327)

ACS Patients;Onset of chestpain and 48 h maximum torandomization

N = 990

*Of the 990 randomized patients, 984 who received ≥1 dose of study drug and were included in the safety analysis dataset.GP = glycoprotein; LMWH = low-molecular-weight heparin.

DISPERSE2 Main Study Design

All patients received aspirin (≤325 mg first dose, then 75–100 mg qd) and heparin/LMWH and/or a GPIIb/IIIa antagonist

• 50% of AZD6140 patients in each arm received a 270-mg loading dose

• In the clopidogrel group, thienopyridine-naïve patients received a 300-mg loading dose



*p < 0.05 for AZD6140 versus clopidogrel. Mean ± SD.

DISPERSE2 PK/PD Substudy: Inhibition of Platelet Aggregation After Initial Doses on Day 1 in Clopidogrel Naïve patients

0 2 4 6 8 10 120

25

50

75

100

Time postdose (h)

Mea

n %

inh

ibit

ion

*

*

*

**

*

* *

*

**

*

0 2 4 6 8 10 120

20

40

60

80

100

**

**

*

*

**

*

**

*

Time postdose (h)

Mea

n %

inh

ibit

ion

Maximum Aggregation Response Final Aggregation Response

AZD6140 180 mgAZD6140 90 mg Clopidogrel 300 mgAZD6140 270 mg

Storey R, et al. J Am Coll Cardiol 2007;50:1852-6.


*p < 0.05 for AZD6140 versus clopidogrel.

0 2 4 6 8 10 120

20

40

60

80

**

*

*

**

*

**

**

*

Time postdose (h)

Mea

n %

pla

tele

t ag

greg

atio

n

DISPERSE2 PK/PD Substudy: Suppression of Platelet Aggregation in Clopidogrel-Pretreated Patients

Clopidogrel 75 mg

AZD6140 180 mg

AZD6140 90 mg

AZD6140 270 mg

Storey R, et al. J Am Coll Cardiol 2007;50:1852-6.


*Minor bleeding without major bleeding.

Week 4 (Primary End Point)

0

2

4

6

8

10

12

AZD6140 90 mg bid

AZD6140 180 mg bid

Clopidogrel 75 mg qd

Tot

al B

leed

ing

Rat

e, %

Overall

0

2

4

6

8

10

12

AZD6140 90 mg bid

AZD6140 180 mg bid


9.6

7.78.0

10.2 10.29.2

Tot

al B

leed

ing

Rat

e, %

MajorMinor*

DISPERSE2 Protocol-Defined Bleeding Rates (%) Week 4 and Overall (Week 12)

Protocol-defined total bleeding rates were similar for all groups No evidence of dose-response pattern for major bleeds



20%

10%

5%

0

1

15%

Cu

mul

ativ

e R

isk

of

an E

vent

11 21 31 41 51 61 71 81 91

AZD6140 90 mg bidAZD6140 180 mg bidClopidogrel 75 mg daily

Study Day

DISPERSE2 Cumulative Adjudicated Clinical End Point of CV Death/MI/StrokeKaplan-Meier Estimates



Discontinuation rates due to adverse events were low and similar among all groups• 6%, 7%, and 6% discontinued in the AZD6140 90 mg bid, AZD6140 180 mg bid, and clopidogrel 75

mg qd groups, respectively*p < 0.05 vs. clopidogrel. All other values are not significant.

DISPERSE2 Crude Incidence ofNon-Bleeding Adverse Events (%)

Preferred termAZD6140 90 mg bid

n = 334AZD6140 180 mg bid

n = 323Clopidogrel 75 mg qd

n = 327

Dyspnea* 10.5 15.8 * 6.4

Chest pain 7.5 7.4 8.9

Headache 9.6 6.5 8.6

Nausea 6.6 6.5 3.4

Dyspepsia 4.8 3.1 2.8

Insomnia 5.4 4.6 2.8

Diarrhea 3.0 7.4 * 3.4

Hypotension 4.2 * 3.7 * 0.6

Dizziness 4.2 3.4 3.1

Syncope 1.2 1.5 0.6

Rash 0.9 1.9 0.6



ECG = electrocardiogram; NSVT = nonsustained ventricular tachycardia; VT = ventricular tachycardia.

DISPERSE2 Arrhythmia Events Detected From Post-Hoc Analysis of ECG Monitoring (%)

AZD6140 90 mg bid n = 305

AZD6140 180 mg bid

n = 283


n = 297

Ventricular tachycardia

Patients with sustained VT >30 s 0.0 0.3 0.3

Patients with at least 1 NSVT 22 26 22

Patients with at least 1 triplet 29 27 31

Ventricular pauses

Patients with at least 1 pause >2.5 s 5.5 9.9 4.3

Patients with at least 1 pause >5 s 1.6 2.1 0.3

Ventricular pauses were mostly asymptomatic Continuous ECG monitoring began at randomization for 885 patients (89.4% of patients enrolled) There was no difference in rates of VT among the 3 groups



DISPERSE2 Conclusions AZD6140 had greater platelet inhibition than clopidogrel

AZD6140 shows similar safety and tolerability to clopidogrel

AZD6140, a reversible inhibitor of the P2Y12 receptor, offers potential for flexibility by allowing rapid initiation of surgical procedures following discontinuation of drug

With lack of increased major bleeding and encouraging trends in efficacy, this agent is now being studied in the PLATlet inhibition and patient Outcomes (PLATO) outcomes study


®*

AZD6140 90 mg bid

Clopidogrel 300/600mg load: 75mg od

V1 V2 V3 V4 V5 V6End of

TreatmentFollow-up

Onset of chest pain <24h

1 mo

3 mo

6 mo

6 to 12 mo

EOT + 1 mo

* N=9000 per treatment arm

Study DesignStudy Design

9 mo

12 mo

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

ATP analogue

Molecular weight 800 Daltons

Plasma half-life of 5-9 minutes

20 minutes for return to normal platelet function

NN

NN

NH

SCF

3

OHOH

OO

PO

O

PP

OO

OCl

Cl

OO

O

S

4Na+

Cangrelor Phase II Clinical Data: Compared with

Abciximab in PCIDouble-blind randomized trial performed in US

Incidence of events up to 7 days

5.7%5.4%

2.1%

1.0%

Death, MI, revascularization Major bleed (TIMI criteria)

Abciximab (N=94)

Cangrelor (N=105)

0%

1%

2%

3%

4%

5%

6%P=NS

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

CHAMPION Program

Phase III program underway

1O Endpoint – superiority for ischemic events

vs. clopidogrel 600 mg at the start of PCI

vs. clopidogrel 600 mg at the end of PCI

N = 9,000 pts N = 6,300 pts

TRANSCENDENCE-PCI

Subjects Undergoing Non-Urgent PCI or Cardiac Catheterization

No PCI**

Cardiac Catheterization

Safety: TIMI Major plus Minor BleedingEfficacy: Death/MACE

CABG Medical Management

Quantify Postoperative Chest-

Tube Drainage, Transfusions, and

Re-exploration

Safety: TIMI Major plus Minor Bleeding

No**

0.5 mgn~100

1 mgn~100

2.5 mgn~100

Placebon~100

PCI - Subjects Receive Clopidogrel and Antithrombin

Randomization #2

Randomization #1 3:1 SCH 530348 : PlaceboSingle Loading Dose Prior to Catheterization

TRANSCENDENCE-PCI, Thrombin Receptor Antagonist for Clinical Event Reduction Over Standard Concominant therapies in Percutaneous Coronary Intervention.

Prior MI, Ischemic CVA, or PAD

SCH 530348SCH 530348

PlaceboPlacebo

RANDOMIZE 1:1 DOUBLE BLINDStratify by CAD, CVD or PAD

and intent to use thienopyridine

Follow up VisitsDay 30, Mo 4, Mo 8, Mo 12

Q6 months

Standard care, including oral antiplt rx

Final Visit

Primary EPCV Death, MI, Stroke,

Urgent Coronary Revascularization

Primary EPCV Death, MI, Stroke,

Urgent Coronary Revascularization

Major Secondary EP: CV death, non-fatal MI, non-fatal stroke

Trial FeaturesGlobal: 31 countries~1000 sites~19,500 subjectsDouble-blindEvent-driven

Trial FeaturesGlobal: 31 countries~1000 sites~19,500 subjectsDouble-blindEvent-driven

Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50

Documents

1 Novel Antiplatelet Agents: AZD6140, Cangrelor, TRA