tra-pci update on the new antiplatelet agents: par-1 inhibitors

David J. Moliterno, MD, MPH Chief, Cardiovascular Medicine

Professor & Vice-Chair of MedicineUniversity of Kentucky

Co-Director - Gill Heart InstituteLexington, KY

TRA-PCITRA-PCIUpdate on the New Antiplatelet Agents:Update on the New Antiplatelet Agents:

PAR-1 InhibitorsPAR-1 Inhibitors

Platelet-Thrombin Platelet-Thrombin InteractionInteraction

ThrombinThrombin

XXaa+V+Vaa+II+II

ThrombusThrombus

FibrinFibrin

FibrinogenFibrinogen

Platelet Platelet ReceptorsReceptors

Platelet

ThrombinThrombin

ADPADP

EpinephrineEpinephrine

CollagenCollagen Anionicphospholipid

surfaces

GPGPIIb/IIIaIIb/IIIa

Platelet

Fibrinogen

GP Ia

P2Y1

GP VI

PAR-4

TBX ATBX A22 TBXA2-R

SerotoninSerotonin 5HT2A

P2Y12

PAR-1

GPGPIIb/IIIaIIb/IIIa

EPI-R

TRA BackgroundTRA Background

SCH 530348 is an oral, potent, selective thrombin receptor SCH 530348 is an oral, potent, selective thrombin receptor antagonist (TRA) being developed for the prevention and antagonist (TRA) being developed for the prevention and treatment of atherothrombosis. treatment of atherothrombosis.

Preclinical and early clinical studies have demonstrated SCH Preclinical and early clinical studies have demonstrated SCH 530348 to have antithrombotic properties, with no increase in 530348 to have antithrombotic properties, with no increase in bleeding time or clotting times (aPTT, PT, ACT).bleeding time or clotting times (aPTT, PT, ACT).

SCH 530348 is an oral, potent, selective thrombin receptor SCH 530348 is an oral, potent, selective thrombin receptor antagonist (TRA) being developed for the prevention and antagonist (TRA) being developed for the prevention and treatment of atherothrombosis. treatment of atherothrombosis.

Preclinical and early clinical studies have demonstrated SCH Preclinical and early clinical studies have demonstrated SCH 530348 to have antithrombotic properties, with no increase in 530348 to have antithrombotic properties, with no increase in bleeding time or clotting times (aPTT, PT, ACT).bleeding time or clotting times (aPTT, PT, ACT).

Galbulimima baccataGalbulimima baccata

Himbicine derivativeHimbicine derivative Bark of the Australian RhododendronBark of the Australian Rhododendron Found in the tropical zones of eastern Found in the tropical zones of eastern

Malaysia, New Guinea, northern Malaysia, New Guinea, northern Australia and the Solomon Islands.Australia and the Solomon Islands.

Study DesignStudy Design

Non-Urgent PCI or Cath possible PCI (All Receive Aspirin)

Randomization #1 — 3:1 SCH530348:Placebo (Single Loading Dose)

Sequential Groups: 1=10 mg; 2=20 mg; 3=40 mg, or Placebo

No PCI** No PCI**

Randomization #2 1:1:1Maintenance Therapy Once Daily for ~ 60 days

SCH 530348 Loading Dose SCH 530348Or Placebo Loading Dose Placebo

Safety: TIMI Major plus Minor BleedingEfficacy: Death/MACE

Safety: TIMI Major plus Minor Bleeding

* Primary Evaluable Cohort* Primary Evaluable Cohort **Secondary Evaluable Cohort**Secondary Evaluable Cohort

Cardiac Catheterization

Planned PCI (All Receive Clopidogrel and Antithrombin)

CABG

Quantify Postoperative Chest-Tube Drainage,

Transfusions, and Re-exploration

Medical Management

0.5 mgn~100

1 mgn~100

2.5 mgn~100

Placebon~100

SCH 530348

PlaceboPlaceboSCH 530348SCH 530348

AllAll 10 mg10 mg 20 mg20 mg 40 mg40 mg

All RandomizedAll Randomized 257257 773773 222222 238238 313313

Primary Cohort (PCI) Primary Cohort (PCI) 151151 422422 129129 120120 173173

Secondary CohortSecondary Cohort 106106 351351 9393 118118 140140

Secondary Cohort Secondary Cohort with CABGwith CABG 2424 5252 1010 1818 2424

MaleMale 80%80% 70%70% 72%72% 66%66% 72%72%

Age (mean, years)Age (mean, years) 6262 6363 6565 6363 6363

Weight (mean, kg)Weight (mean, kg) 9191 9090 8989 9292 9090

Diabetes MellitusDiabetes Mellitus 30%30% 34%34% 37%37% 32%32% 33%33%

Prior MIPrior MI 37%37% 35%35% 35%35% 38%38% 32%32%

Prior RevascularizationPrior Revascularization 47%47% 48%48% 50%50% 46%46% 48%48%

DemographicDemographicss

PlaceboPlacebo(n = 151)(n = 151)

SCH 530348SCH 530348

All All n = 422n = 422

10 mg 10 mg n = 129n = 129

20 mg20 mgn = 120n = 120

40 mg40 mgn = 173n = 173

AspirinAspirin 148 (98%)148 (98%) 416 (99%)416 (99%) 127 (98%)127 (98%) 117 (98%)117 (98%) 172 (99%)172 (99%)

ClopidogrelClopidogrel

All All 146 (97%)146 (97%) 408 (97%)408 (97%) 127 (98%)127 (98%) 117 (98%)117 (98%) 164 (95%)164 (95%)

75 mg75 mg 73 (48%)73 (48%) 191 (45%)191 (45%) 56 (43%)56 (43%) 52 (43%)52 (43%) 83 (48%)83 (48%)

300 mg300 mg 30 (20%)30 (20%) 85 (20%)85 (20%) 34 (26%)34 (26%) 21 (18%)21 (18%) 30 (17%)30 (17%)

600 mg 600 mg 40 (26%)40 (26%) 125 (30%)125 (30%) 36 (28%)36 (28%) 39 (33%)39 (33%) 50 (29%)50 (29%)

Antithrombin AgentAntithrombin Agent

HeparinHeparin 61 (40%)61 (40%) 181 (43%)181 (43%) 53 (41%)53 (41%) 52 (43%)52 (43%) 76 (44%)76 (44%)

BivalirudinBivalirudin 76 (50%)76 (50%) 196 (46%)196 (46%) 65 (50%)65 (50%) 51 (43%)51 (43%) 80 (46%)80 (46%)

GP IIb/IIIaGP IIb/IIIa 7 (5%)7 (5%) 37 (9%)37 (9%) 7 (5%) 7 (5%) 14 (12%)14 (12%) 16 (9%)16 (9%)

PCI Cohort MedicationsPCI Cohort Medications

TIMI Major/Minor BleedingTIMI Major/Minor Bleeding

4%4%

00

2%2%

All TRAAll TRAn=422n=422

2.8%2.8%

PCI CohortPCI Cohort

1%1%

3%3%

5%5%

PlaceboPlacebon=151n=151

3.3%3.3%

10 mg10 mgn=129n=129

20 mg20 mgn=120n=120

40 mg40 mgn=173n=173

1.6%1.6%

2.5%2.5%

4.0%4.0%

SCH 530348SCH 530348

p = 0.77

p = 0.35

p = 0.70

p = 0.73

p- value relative to placebo

PlaceboPlacebo

(n=24)(n=24)

SCH 530348SCH 530348

AllAll

(n=52)(n=52)10 mg10 mg

(n = 10)(n = 10)20 mg20 mg

(n = 18)(n = 18)40 mg40 mg

(n=24)(n=24)

Any BleedAny Bleed 2424 5252 1010 1818 2424

TIMI Major/MinorTIMI Major/Minor 19 (79%)19 (79%) 48 (92%)48 (92%) 9 (90%)9 (90%) 17 (94%)17 (94%) 22 (92%)22 (92%)

Non-TIMINon-TIMI 8 (33%)8 (33%) 18 (35%)18 (35%) 3 (30%)3 (30%) 6 (33%)6 (33%) 9 (39%)9 (39%)

TransfusionTransfusion

PRBCPRBC 11 (46%)11 (46%) 32 (62%)32 (62%) 8 (80%)8 (80%) 9 (50%)9 (50%) 15 (63%)15 (63%)

>2 Units>2 Units 55 99 22 22 55

Chest Tube Chest Tube Drainage (ml)Drainage (ml) 996996 988988 13931393 10151015 870870

Re-explorationRe-exploration 33 22 11 00 11

CABG Cohort BleedingCABG Cohort Bleeding

PlaceboPlacebon= 151n= 151

SCH 530348SCH 530348

AllAlln=422n=422

10 mg10 mgn= 129n= 129

20 mg20 mgn=120n=120

40 mg40 mgn=173n=173

Death/MACE/StrokeDeath/MACE/Stroke 13 (8.6%)13 (8.6%) 26 (6.2%)26 (6.2%) 12 (9.3%)12 (9.3%) 6 (5.0%)6 (5.0%) 8 (4.6%)8 (4.6%)

Death/MACE*Death/MACE* 13 (8.6%)13 (8.6%) 25 (5.9%)25 (5.9%) 11 (8.5%)11 (8.5%) 6 (5.0%)6 (5.0%) 8 (4.6%)8 (4.6%)

Death/MIDeath/MI 11 (7.3%)11 (7.3%) 19 (4.5%)19 (4.5%) 7 (5.4%)7 (5.4%) 5 (4.2%)5 (4.2%) 7 (4.0%)7 (4.0%)

DeathDeath 00 2 (0.5%)2 (0.5%) 1 (0.8%)1 (0.8%) 00 1 (0.6%)1 (0.6%)

MACEMACE 13 (8.6%)13 (8.6%) 24 (5.7%)24 (5.7%) 11 (8.5%)11 (8.5%) 6 (5.0%)6 (5.0%) 7 (4.0%)7 (4.0%)

MIMI 11 (7.3%)11 (7.3%) 18 (4.3%)18 (4.3%) 7 (5.4%)7 (5.4%) 5 (4.2%)5 (4.2%) 6 (3.5%)6 (3.5%)

Recurrent ischemiaRecurrent ischemia 1 (0.7%)1 (0.7%) 1 (0.2%)1 (0.2%) 1 (0.8%)1 (0.8%) 00 00

RevascularizationRevascularization 1 (0.7%)1 (0.7%) 6 (1.4%)6 (1.4%) 3 (2.3%)3 (2.3%) 1 (0.8%)1 (0.8%) 2 (1.2%)2 (1.2%)

StrokeStroke 00 1 (0.2%)1 (0.2%) 1 (0.8%)1 (0.8%) 00 00MACE = Major Adverse Cardiac Event (myocardial infarction, ischemia requiring hospitalization, coronary revascularization) MI = Myocardial Infarction * = primary efficacy endpoint

PCI Cohort MACE ResultsPCI Cohort MACE Results

60-Day Death or MACE60-Day Death or MACE

8%8%

00

4%4%



2%2%

6%6%

10%10%


8.6%8.6%

10 mg10 mgn=129n=129

20 mg20 mgn=120n=120

40 mg40 mgn=173n=173

8.5%8.5%

5.0%5.0%4.6%4.6%

SCH 530348SCH 530348

5.9%5.9%p = 0.26

p = 0.98

p = 0.25p = 0.15


60-Day Death or MI60-Day Death or MI

8%8%

00

4%4%


4.5%4.5%


2%2%

6%6%

10%10%


7.3%7.3%

10 mg10 mgn=129n=129

20 mg20 mgn=120n=120

40 mg40 mgn=173n=173

5.4%5.4%

4.2%4.2%4.0%4.0%

SCH 530348SCH 530348

p = 0.19p = 0.53

p = 0.28p = 0.20


PCI PCI CohortCohort

Myocardial InfarctionMyocardial Infarction

8%8%

00

4%4%

2%2%

6%6%

10%10%

PlaceboPlacebo 40mg40mg20mg20mg10mg10mg

11 7722 33 44 55 6600

DaysDays

p = 0.52

p = 0.28

p = 0.12

80%80%

00

40%40%

Platelet Aggregation SubstudyPlatelet Aggregation Substudy

20%20%

60%60%

100%100%


10 mg10 mgn=15n=15

20 mg20 mgn=18n=18

40 mg40 mgn=33n=33

2929

SCH 530348SCH 530348

00 00 00 00 00 00

5353

6868

8282

9696

46465454

66

4343

2121

30 minutes30 minutes




Subjects with >80% IPA to 15 Subjects with >80% IPA to 15 M TRAPM TRAP

PlaceboPlacebo

SCH 530348SCH 530348

AllAll 0.5 mg0.5 mg 1.0 mg1.0 mg 2.5 mg2.5 mg

NumberNumber 149149 413413 136136 139139 138138

TIMI Major/MinorTIMI Major/Minor 00 4 (1.0%)4 (1.0%) 2 (1.5%)2 (1.5%) 00 2 (1.4%)2 (1.4%)

TIMI MajorTIMI Major 00 2 (0.5%)2 (0.5%) 1 (0.7%)1 (0.7%) 00 1 (0.7%)1 (0.7%)

TIMI MinorTIMI Minor 00 2 (0.5%)2 (0.5%) 1 (0.7%)1 (0.7%) 00 1 (0.7%)1 (0.7%)

Non-TIMI bleedingNon-TIMI bleeding 8 (5.4%)8 (5.4%) 25 (6.1%)25 (6.1%) 8 (5.9%)8 (5.9%) 6 (4.3%)6 (4.3%) 11 (8.0%)11 (8.0%)

PCI Cohort Results after Day 60PCI Cohort Results after Day 60

80%80%

00

40%40%

Platelet AggregationPlatelet Aggregation

20%20%

60%60%

100%100%

0.5 mg0.5 mg 1.0 mg1.0 mg 2.5 mg2.5 mg

SCH 530348SCH 530348

100100 10010030 days30 days

60 days60 days

Subjects with >80% IPA to 15 Subjects with >80% IPA to 15 M TRAPM TRAP

100100 100100

9191 9191

PlaceboPlacebo

111199

ConclusionConclusionss TRA was not associated with an increase inTRA was not associated with an increase in

TIMI major, minor, or non-TIMI bleedingTIMI major, minor, or non-TIMI bleeding

Using 15 Using 15 M TRAP-induced platelet aggregation:M TRAP-induced platelet aggregation: 40 mg loading dose of SCH 530348 achieved40 mg loading dose of SCH 530348 achieved

≥ 80% IPA in 1-2 hours in 68-96% subjects≥ 80% IPA in 1-2 hours in 68-96% subjects 1 mg and 2.5 mg maintenance doses sustained 1 mg and 2.5 mg maintenance doses sustained

≥ 80≥ 80% IPA at 30 and 60 days in all subjects% IPA at 30 and 60 days in all subjects

While not statistically significant, SCH 530348 While not statistically significant, SCH 530348 was associated with:was associated with: Death/MACE: Death/MACE: 32% overall; 32% overall; 46% with 40 mg46% with 40 mg MI: MI: 41% overall; 41% overall; 52% with 40 mg52% with 40 mg

TRA was not associated with an increase inTRA was not associated with an increase inTIMI major, minor, or non-TIMI bleedingTIMI major, minor, or non-TIMI bleeding

Using 15 Using 15 M TRAP-induced platelet aggregation:M TRAP-induced platelet aggregation: 40 mg loading dose of SCH 530348 achieved40 mg loading dose of SCH 530348 achieved

≥ 80% IPA in 1-2 hours in 68-96% subjects≥ 80% IPA in 1-2 hours in 68-96% subjects 1 mg and 2.5 mg maintenance doses sustained 1 mg and 2.5 mg maintenance doses sustained

≥ 80≥ 80% IPA at 30 and 60 days in all subjects% IPA at 30 and 60 days in all subjects

While not statistically significant, SCH 530348 While not statistically significant, SCH 530348 was associated with:was associated with: Death/MACE: Death/MACE: 32% overall; 32% overall; 46% with 40 mg46% with 40 mg MI: MI: 41% overall; 41% overall; 52% with 40 mg52% with 40 mg

TRATRA••CERCER

• • 1-Year Cardiovascular Death, MI, Stroke, Recurrent 1-Year Cardiovascular Death, MI, Stroke, Recurrent Ischemia with Rehosp, Urgent Coronary Revas •Ischemia with Rehosp, Urgent Coronary Revas •


www.clinicaltrials.govwww.clinicaltrials.gov

NSTEACSNSTEACSN = 10,000N = 10,000

SCH 530348SCH 53034840 mg bolus, 2.5 mg daily40 mg bolus, 2.5 mg daily

n=5000n=5000

PlaceboPlacebo(and usual therapy)(and usual therapy)

n=5000n=5000

TThrombin hrombin RReceptor eceptor AAntagonist for ntagonist for CClinical linical EEvent vent RReduction in Acute Coronary Syndromeeduction in Acute Coronary Syndrome

TRATRA••2P—TIMI 502P—TIMI 50



www.clinicaltrials.govwww.clinicaltrials.gov

Hx MI, CVA, PVDHx MI, CVA, PVDN ~ 18,000N ~ 18,000

SCH 530348SCH 5303482.5 mg daily2.5 mg daily

N~9,000N~9,000

PlaceboPlacebo(and usual therapy)(and usual therapy)

N~9000N~9000

TThrombin hrombin RReceptor eceptor AAntagonistntagonistfor for 22º º PPreventionrevention

tra-pci update on the new antiplatelet agents: par-1 inhibitors

Documents

pci cohort1

placebono pci

loading dose sch

primary evaluable cohort

cath possible pci

study designnonurgent

p value relative

timi majorminor bleeding4