cangrelor c angrelor versus standard t h erapy to a chieve optimal m anagement of p latelet i...

Cangrelor

CCangrelor versus standard angrelor versus standard t tHHerapy to erapy to AAchieve chieve optimal optimal MManagement of anagement of PPlatelet latelet IInhibitinhibitiONON TrialsTrials

Rationale and BackgroundRationale and BackgroundRationale and BackgroundRationale and Background

THE THE MEDICINESMEDICINES COMPANY COMPANY®®®®

Cangrelor

• Optimal acute care anti-platelet strategyOptimal acute care anti-platelet strategy

• Profile: IV platelet inhibitor via P2YProfile: IV platelet inhibitor via P2Y1212 receptor receptor

Potent effectPotent effect Titrate up to 100% platelet inhibitionTitrate up to 100% platelet inhibition

Rapid onsetRapid onset Immediate (seconds)Immediate (seconds)

Rapid offset Rapid offset 6 minutes T/26 minutes T/2

ReversibleReversible Return to platelet function within 60 minutesReturn to platelet function within 60 minutes

• Status: Phase III underwayStatus: Phase III underway

• License: AstraZeneca, 2003License: AstraZeneca, 2003


Rationale for Cangrelor• Platelet inhibition accepted practicePlatelet inhibition accepted practice

Aspirin

Plavix 300-600 mg for rapid onset

ACC/AHA & ESC Guidelines

GP IIb/IIIa inhibitors

Activation

Aggregation


Rationale for Cangrelor• Inadequate platelet inhibition in acute settingInadequate platelet inhibition in acute setting

Oral P2Y12 IV GP IIb/IIIa

Delayed onset

Prolonged effect

Unpredictable effect(low responders)

Long infusion (12-18 hrs)

Return to platelet fn(6 hrs to days)

Aggregation inhibition only


CHAMPION Program

• Phase III program underwayPhase III program underway

1O Ischemic superiorityVs. Plavix 600 mg at

the start of PCIVs. Plavix 600 mg at

the end of PCIN = 9,000 pts N = 6,300 pts

Cangrelor

• PharmacologyPharmacology• PharmacologyPharmacology


_

O_

P

O_

O

P

O

O

OP

O

_O

OO

OH OH

N

N

N

N

H2N

4Na+

Chemical structure of ATP

O


Cangrelor metabolism

N N

NN

NH

SCF3

OHOH

OO

PO

O

PP

OO

OClCl

OO

O

S

4Na+

N N

NN

NH

SCF3

OHOH

OOH

S

N N

NN

NH

SCF3

OHOH

OOH

S

N N

NN

NH

SCF3

S

N N

NN

NH

SCF3

S

cangrelor

O

Omain plasma metabolite main biliary metabolite

SC-931- 9017 and SC-100199


_

O_

P

O_

O Cl

ClP

O

O

OP

O

_O

OO

OH OH

N

N

N S F

FF

N

HNS

4Na+

Chemical structure of cangrelor

Stabilised analogue of ATP


Human Metabolism• Independent of renal or hepatic function

• Mechanism of inactivation– sequential dephosphorylation to the nucleoside

– major circulating metabolite 10,000-fold less active than parent

SC-931- 9017 and SC-100199

N N

NN

NH

SCF3

OHOH

OO

PO

O

PP

OO

OClCl

OO

O

S

4Na+

N N

NN

NH

SCF3

OHOH

OOH

S

cangrelor

dephosporylatedmajor metabolite


Pharmacologic effect in vitro• Potent, dose-dependent & selective inhibition of ADP-induced

aggregation

0.01 0.10 1 10 100 1000

[ADP] (M)

% c

on

tro

l a

gg

reg

ati

on

0

20

40

80

100

60

03

1030

100300500

[cangrelor] (nM)

Studies 30144, 30145, 30316, 30139

• IC50 vs ADP: 0.45 nM (human washed platelets)• P1, other P2: 3000-fold selectivity• No effect at unrelated receptors @ 1 - 10 mM


ADP-induced plateletaggregation ex vivo

Cyclic flow reduction - thrombosis

bleeding time

1 10 100 1000 10000

cangrelor ng/kg/min i.v.

0

20

40

60

80

100

% i

nh

ibit

ion

ag

gn

& t

hro

mb

osi

s

1

2

3

4

5

6

BT

(fo

ld i

ncr

ease

)

Antithrombotic effect: canine model• Dose-related antithrombotic (reduction in CFR) and antiplatelet

effects with little impact on bleeding time

Study PR-40019

Ingall et al. J Med Chem 1999; 42: 213


Adjunct to reperfusion: canine model• Cangrelor administered after t-PA prolongs reperfusion and restores

myocardial tissue perfusion

Wang et al ATVB 2003;23:357-62.

0

45

5

10

15

20

25

30

35

Base Occlusion 20 min 2 h

dB

/sec

.

Time

Placebocangrelor

*

*

Myocardial blood flow assessed by contrast echocardiography

*p=0.05


Effect of cangrelor on ADP-induced platelet aggregation in patients with NSTE ACSWhole blood impedance aggregometry

0

20

40

60

80

100

0.5 1.5 2.5 3.5 5 24 20 mpost

1 h post

Mea

n %

inhi

bitio

n of

pla

tele

t agg

rega

tion

Time after onset of infusion (h) Time after termination of infusion

0.05 g/kg/min

0.2 g/kg/min

0.5 g/kg/min

2g/kg/min

Infusion dose

From Storey RF et al. Thromb Haemost. 2001; 85:401-7.


Effect of cangrelor infusion on Effect of cangrelor infusion on ex vivo ex vivo ADP-induced ADP-induced P-selectin expression in patients with ACSP-selectin expression in patients with ACS

0

10

20

30

40

0 0.3 1 3 10 30

ADP M

% +v

e eve

nts

Baseline

24 hr

Storey RF et al. Thromb Haemost. 2002; 88:488-94.


Effect of cangrelor infusion on Effect of cangrelor infusion on ex vivo ex vivo ADP-induced ADP-induced platelet-monocyte conjugate formation in patients platelet-monocyte conjugate formation in patients with ACSwith ACS

0

10

20

30

0 0.3 1 3 10 30

ADP M

Median

fl (C

D42a

)

Baseline

24 hr

Storey RF et al. Thromb Haemost. 2002; 88:488-94.


0

10

20

30

40

50

60

0 10 30 100 300 1000

AR-C69931MX concentration (nmol/l)

% A

nnex

in V

pos

itiv

e ev

ents

Saline

Aspirin

Effects of Effects of in vitro in vitro cangrelor and aspirin on Annexin V cangrelor and aspirin on Annexin V binding induced by TRAP 20 binding induced by TRAP 20 mol/Lmol/L

Storey et al. Br. J. Haematol. 2000

Cangrelor (nmol/L)


0

5

10

15

20

25

0 10 30 100 300 1000

AR-C69931MX concentration (nmol/l)

% m

icro

part

icle

s

Saline

Aspirin

Effects of Effects of in vitro in vitro cangrelor and aspirin on cangrelor and aspirin on microparticle formation induced by TRAP 20 microparticle formation induced by TRAP 20 mol/Lmol/L

Storey et al. Br. J. Haematol. 2000

Cangrelor (nmol/L)

THE THE MEDICINESMEDICINES COMPANY COMPANY®®®®Storey RF et al. Platelets 2002; 13: 407-413

Variable response to clopidogrel with incomplete Variable response to clopidogrel with incomplete P2YP2Y1212 receptor blockade receptor blockade• ADP-induced platelet aggregation before and after clopidogrel 300 mg followed by 75 mg daily for 4-7 days in patients undergoing PCI

• Cangrelor added in vitro blocks the unblocked receptors

0

20

40

60

80

100

Baseline PostClopidogrel

PostClopidogrel+ cangrelor

Mea

n %

Pla

tele

t A

ggre

gatio

n

*

*

* P<0.05

Wide inter-individual variation in response

Cangrelor

• Clinical ProgramClinical Program• Clinical ProgramClinical Program


Clinical ProgramTwelve Studies Completed to Date

#5014N=40[28]

Men

#5014N=40[28]

Men

#5036N=23[15]

Women

#5036N=23[15]

Women

#5109N=24[24]

Renal

#5109N=24[24]

Renal

#5037N=12[12]

Interact’

#5037N=12[12]

Interact’

#5058N=43[39]ACS

NSTEMI

#5058N=43[39]ACS

NSTEMI

#5060N=94[45]ACS

NSTEMI

#5060N=94[45]ACS

NSTEMI

#5092N=25

[0]ACS

NSTEMI

#5092N=25

[0]ACS

NSTEMI

#5129-1N=209[149]

PCI

#5129-1N=209[149]

PCI

#5129-2N=216[105]

PCI

#5129-2N=216[105]

PCI

#5135N=101

[85]ACS

STEMI

#5135N=101

[85]ACS

STEMI

PK-PDVolunteersN=143 [123 drug]

Phase I-IIPatientsN=688 [423 drug]

#9017N=4[4]

Inf

#9017N=4[4]

Inf

#0402N=40[40]

Bolus+Inf

#0402N=40[40]

Bolus+Inf


Human Pharmacokinetics • Linear relationship

0

100

200

300

400

500

600

0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000

Infusion rate (ng/kg/ml)

Pla

sma

co

nce

ntr

atio

n (

ng

/mL

)

SC-931-5014


0.1

1

10

100

1000

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Time (h)

Pla

sm c

on

cen

tra

tion

(n

g/m

L)

Human Pharmacokinetics • Half-life – 3.3 minutes – rapidly metabolized by

dephosphorylation

SC-931-5014


Human Pharmacokinetics• Rapid attainment of steady state following bolus

Bolus Infusion

0

100

200

300

400

500

600

700

800

0 20 40 60 80 100 120 140 160

Time (min)

Can

gre

lor

(ng

/mL

) Group A: 15 mcg/kg bolus + 2 mcg/kg/min (n=9)

Group B: 30 mcg/kg bolus + 4 mcg/kg/min (n=9)

#0402N=40[40]

Bolus+Inf

#0402N=40[40]

Bolus+Inf


• Whole blood impedance aggregometry

Human PharmacokineticsHuman Pharmacokinetics

0

2

4

6

8

10

12

14

16

0 20 40 60 80 100 120 140 160Time (minutes)

Imp

edan

ce (

Oh

ms)

Group A 15 µg/kg bolus + 2 µg/kg/min infusion Group B 30 µg/kg bolus + 4 µg/kg/min infusion

Bolus Infusion


Cangrelor in Renal Impairment*• No effect of renal impairment on cangrelor PK

0

50

100

150

200

250

300

0 2 4 6 8 10

Healthy volunteers (n=4) Renally impaired (n=8)

Time (h)

Pla

sma

Co

nc

(ng

/ml)

SC-931-5109

*Mild to severe, median CLcr = 55 mL/min


Renal ImpairmentNo measurable change in PK

0

50

100

150

200

250

300

0 2 4 6 8 10

Healthy volunteers (n=4) Renally impaired (n=8)

Time (h)

Pla

sma

Co

nc

(ng

/ml)

1Mild to severe, median CLcr = 55 mL/min SC-931-5109


Objectives:Objectives:

• Primary:Primary:

– Test infusion for up to 72 hoursTest infusion for up to 72 hours

• Secondary:Secondary:

– Find dose that gives 100% inhibition of ADP-induced Find dose that gives 100% inhibition of ADP-induced platelet aggregation in >90% of patientsplatelet aggregation in >90% of patients

Phase II study in ACS #5058N=43[39]ACS

NSTEMI

#5058N=43[39]ACS

NSTEMI


Phase II study in ACS

Three part study

Part 1 (n=12)

Part 2 (n=13)

Part 3 (n=14)

Total (n=39)

Dose (g/kg/min)

0.05-2.0 0.05-2.0 0.20-4.0

Duration (hr) 24 72 72

Male (%) 8 (67%) 10 (77%) 12 (86%) 30 (77%)

Age (mean) 61 63 63 62

Age (range) 42-75 41-76 41-77 41-77

#5058N=43[39]ACS

NSTEMI

#5058N=43[39]ACS

NSTEMI


Platelet aggregation results

Phase II study in ACS

Part 1 (n=12)

Part 2 (n=13)

Part 3 (n=14)

Mean Inhibition of Aggregation at 24h

96.0% 94.9% 98.7%

Patients with 100% Inhibition of Aggregation During Infusion

64% 77% 86%

#5058N=43[39]ACS

NSTEMI

#5058N=43[39]ACS

NSTEMI


Phase II Study in PCIObjective: Objective: • Assess safety of 3 doses vs. placebo,Assess safety of 3 doses vs. placebo,

– 18-to 24-hour infusions18-to 24-hour infusions

MethodsMethods– Double-blind, multicenterDouble-blind, multicenter

– Aspirin, heparin and nitrate co-medsAspirin, heparin and nitrate co-meds

– Clopidogrel or ticlopidine not usedClopidogrel or ticlopidine not used

– Part 1 dose finding vs. placeboPart 1 dose finding vs. placebo

– Part 2 vs. abciximabPart 2 vs. abciximab

#5129-1N=209[149]

PCI

#5129-1N=209[149]

PCI

#5129-2N=216[105]

PCI

#5129-2N=216[105]

PCI


Phase II Study in PCI

Part I: Dose finding

Cangrelor dose (µg/kg/min)Placebo Total

1.0 2.0 4.0

No. randomized 53 52 51 53 209

No. Treated 49 52 48 51 200

Males/Females 37/12 35/12 29/19 41/10 142/58

Mean age yrs (range)

61 (37-83) 63 (44-79) 65 (43-79) 62 (38-78) 63 (37-83)

Median inhib. platelet aggr. at 23.50 h

93% 98% 100% 13%

#5129-1N=209[149]

PCI

#5129-1N=209[149]

PCI



Part I: Dose finding

Bleed category

Cangrelor dose (µg/kg/min)Placebo (n=51)

Total (n=200)1.0 (n=49) 2.0 (n=52) 4.0 (n=48)

Any bleeding 39 (80%) 38 (73%) 38 (79%) 30 (59%) 145 (73%)

Major bleed 0 (0%) 0 (0%) 4 (8%) 0 (0%) 4 (2%)

Minor bleed 4 (8%) 6 (12%) 5 (10%) 4 (8%) 19 (10%)

#5129-1N=209[149]

PCI

#5129-1N=209[149]

PCI


Phase II Study in PCIDose-dependent effect

Study SC-931-5129. Table 14.2.20Inhibition of 20mol ADP-induced platelet aggregation

7, 9, 6 and 5 patients in groups 0, 1, 2 and 4 respectively

13%

93%98% 100%

0%

20%

40%

60%

80%

100%

0 1 2 3 4

Cangrelor dose (ug/kg)

Med

ian

(ran

ge)

inhi

bitio

n#5129-1N=209[149]

PCI

#5129-1N=209[149]

PCI


5.7%

1.0%

5.7%5.4%

2.1%

7.4%

0%

2%

4%

6%

8%

Death/MI/revasc TIMI major bleed TIMI minor bleed

Cangrelor (N=105)

Abciximab (N=93)


Comparable results to abciximab in PCI

• Phase II randomized double-blind trial

Events at 7-days

#5129-2N=216[105]

PCI

#5129-2N=216[105]

PCI


Summary

Cangrelor

• Potent direct platelet P2Y12 antagonist

• Onset of effect in seconds to 100% effect

• Predictable steady-state dose-concentration-effect relationship

• Plasma t0.5 (3.3 min) - clearance independent of renal or hepatic function

• Platelet recovery ~1 hour

• Clinical effects similar to abciximab in PCI

cangrelor c angrelor versus standard t h erapy to a chieve optimal m anagement of p latelet i...

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