1 Mar 98

TIMI 15A -- An Open-Label,

Randomized, Dose-Response Study

to Evaluate the Pharmacodynamic

Response, Safety and Pharmaco-

kinetics of KlervalTM (RPR 109891)

Administered Intravenously for 24 to

96 hours in Patients with Recent

Acute Coronary Syndromes

2 Mar 98

Background

• Ischemic complications high through 1 yr

post acute coronary syndrome (ACS):

– Mortality (8-15%)

– Reinfarction (8-12%)

– Rehospitalization (15-30%)

• GP IIb/IIIa inhibitors are efficacious as

adjunct in percutaneous interventions

• GP IIb/IIIa inhibitors promising in acute Rx

of ACS, but role in 2o prevention unknown

3 Mar 98

KlervalTM (RPR 109891)

Characteristics

• Small molecule (pseudopeptide), specific,

reversible GP IIb/IIIa receptor antagonist

• Availability of IV and oral formulation

• Inhibits platelet aggregation within 10 min

of IV bolus

• Half-life of IV formulation: 1.1 - 1.6 hours

4 Mar 98

TIMI 15A Trial

Design and Objectives

• Randomized, open-label, phase II

• Bolus + infusion for 24-96 hours

• Primary Objectives1. Evaluate inhibition of platelet aggregation (IPA)

2. Safety and tolerability

• Secondary Objectives1. Correlate plasma conc. with efficacy, safety

2. Correlate Receptor Occupancy (RO) and IPA

3. Evaluate platelet activation

5 Mar 98

Eligibility CriteriaInclusion • Age 18-75, male or female• Acute Coronary Syndrome within 48 hours

UA - ST changes, prior CAD, Sx and age > 65MI - non-ST-elevation or STE-MI (24 hrs post lysis)

• Creatinine clearance > 50 mL/m

Major Exclusions• Increased bleeding risk

• ReoPro, Ticlid, Persantine within 14 days

• Planned CABG < 24 h of randomization

• Platelets < 150K, anemia

• Other serious concomitant illness

6 Mar 98

45/0.6 60/0.8

Protocol Design

ACS within 0-48h

30/0.4

Aspirin

Heparin (opt) Other

Doses

60/0.5

75/0.2

75/0.4

90/0.2

100/0.

Bolus/Infusion (mg/kg) (mg/kg/m)

for 24-96 h PK/PD at 0, 20m, 1-4h

QD, pre-stop, 2-4h &

8-24h post stop

Clinical f/u at 14d

7 Mar 98

Baseline Characteristics

Number of patients 91*

Mean Age + SD 55.4 + 9.9 yrs

Male 76%

White 79%

Prior MI 39%

Prior CABG or PTCA 12%

Prior Aspirin 68%

Diagnosis (STE-MI/nSTE-MI/UA) 28%, 25%, 47%

Treatment (Lytic/PTCA/Neither) 13%, 19%, 68%

Adjunctive heparin 86%

* 2 additional pts randomized but did not receive study drug (data not shown)

8 Mar 98

Mean Inhibition (SD) of Platelet

Aggregation* 20 min after Bolus

0

10

20

30

40

50

60

70

80

90

100

30 45 60 75 90 100 120

Bolus Dose (mg/kg)*ADP 20 mM

in P-PACK

N: 11 10 22 14 3 9 11

9 Mar 98

Mean Inhibition of Platelet

Aggregation During Infusion

0

10

20

30

40

50

60

70

80

90

100

1-4h 24h 48-96h Pre-

stop

2-4h

post

8-16h

post

17-24h

post

0.80 ug/kg/min : N=13

0.60 ug/kg/min : N=12

0.50 ug/kg/min : N=20

0.40 ug/kg/min : N=34

0.20 ug/kg/min : N=10

* *

* Only 1 specimen for each pt 8-24h post drug

% IPA

10 Mar 98

% Patients with a Mean Steady State

Average Within and Outlying 80 - 95 % IPA

0.4 (n=34) 0.5 (n=20) 0.6 (n=12)0

10

20

30

40

50

60

70

80

90

100

0.4 (n=34) 0.5 (n=20) 0.6 (n=12)

<80% IPA

80-95% IPA

>95% IPA

Infusion (mg/kg/min)

% o

f P

ati

en

ts

11 Mar 98

Mean Inhibition of Platelet Aggregation and

Receptor Occupancy with KlervalTM 100/0.5

N: 9* 11* 11 4 1 11 8* 2 9

*N for RO at these timepoints 10, 12,7 respectively

H Only 1 specimen for each pt 8-24h post drug

0

10

20

30

40

50

60

70

80

90

100

20m

1-4

h

24h

48h

72h

Pre

-sto

p

2-4

h p

ost

8-1

6h

po

st

17-2

4h

po

st

% I

PA

/ R

O

% R-Occ ADP 5uM

ADP 20uM TRAP 5uM

H H

12 Mar 98

Hemorrhagic EventsRx period* Day 0-14

N (%) N (%)

Major 1 (1.1%)1 2 (2.2%)2

# Provoked 0 0

Significant minor 1 (1.1%)3 2 (2.2%)4

# Provoked 1 1

1, 2, 4 = GI bleed 3 = Catheter-related hematuria,

Insignificant minor bleeding in 44% pts most (>80%)

related to trauma, procedure

*Rx period = after bolus dose through 24 hrs post end of infusion

13 Mar 98

Thrombocytopenia

Plt count < 50,000 0 (0%)

Plt count < 90,000 1* (1.1%)

Plt count <100,000 or > 40% 9 (9.9%)

Post-CABG 6 (6.6%)

Non-CABG related 3** (3.3%)

* Post-CABG platelet count 83,000, 13 days post-drug

** 3 on study drug: 1 at end of infusion (day 2), 1 on day 1 due to clumping

(subsequent counts normal), & 1 on day 1 (subsequent counts normal)

14 Mar 98

Clinical Events

Randomization Through Day 14

N (%)

Death 1 (1.1%)

Myocardial infarction 2 (2.2%)

Recurrent angina 17 (19%)

PTCR (All) 30 (33%)

elective / urgent* 27 / 3

CABG (All) 6 (6.6%)

elective / urgent* 6 / 0

* urgent = due to recurrent ischemia

15 Mar 98

Conclusions and Future Plans

• IV KlervalTM demonstrated a dose-related

inhibition of platelet aggregation

• At the IV doses studied, no major safety or

tolerability issues noted

• Receptor occupancy correlated well with

degree of platelet inhibition

• PK, P-selectin data being reviewed

• Double-blind, placebo-controlled trial

(TIMI 15B) now underway with IV (100/0.5)

followed by oral KlervalTM for 4 weeks

16 Mar 98

TIMI 15B PROTOCOL DESIGN

Unstable Angina

or non-STE-MI(0 - 72 hrs)

Klerval 175 BIDpo x 4wks

Klerval 200 BIDpo x 4 wks

Klerval 150 TIDpo x 4 wks

IV Klerval 100 ug/kg bolus

0.50 ug/kg/min infusion

for 24-96 hrs

Placebo BIDpo x 4 wks

Placebo TIDpo x 4 wks

IV PlaceboBolus + infusion

for 24-96 h

RANDOMIZE

Aspirin

Panel 1: Heparin (opt)

Panel 2: Enoxaparin

STE-MI

(no lytic)(0 - 72 hrs)

STE-MI

(with lytic)(6-72 hrs)

NB: One Klerval dose (& matching placebo) in panel 2

17 Mar 98

Trial Organization

Study Chairman’s Office Eugene Braunwald, MD

Brigham & Women’s Hospital Robert P Giugliano, MD, SM

Boston, MA Carolyn McCabe, BS

Sponsor Jean-Francois Tamby, MD

Rhone-Poulenc Rorer Karen Ramsey, RPh

Collegeville, PA Mary Jacoski, MS

Teresa Rumor, PhD

Stephen May, BS

Platelet Aggregation Robert Wise, MD, PhD

Brigham & Women’s Hosp

Receptor Occupancy Lisa K Jennings, PhD

U Tenn, Memphis

18 Mar 98

Participating Centers

Center PI/RC #Pts

U of Miami Dr. Rafael Sequeira 25

Dr. Gayateri Girwarr

Hennepin Dr. Timothy Henry 18

Ms. Lorrie Knox

Ms. Charlene Boisjolie

Brigham & Dr. Robert Piana 18

Women’s Ms. Michele Po

19 Mar 98

Participating Centers (cont)

Baystate Dr. Marc Schweiger 12Ms. Diane Rondeau

Montefiore Dr. Hiltrud Mueller 8Mr. Joseph CosicoMs. Kelly Schneider

U Vermont Dr. Marc Tischler 6Ms. Michaelanne Rowen

Henry Ford Dr. Steven Borzak 4Ms. Lorri Douthat

20 Mar 98

Percentage of Patients Above 80 % IPA

Following Administration of Bolus

* Two patients did not have 20 min sample

** One patient did not have 20 min sample

Regimen Time > 80% IPA

60 mg + 0.5 mg/kg/min 20 min 56%

(n=9) 1-4 hr 22%

75 mg + 0.4 mg/kg/min 20 min 60%

(n=10) 1-4 hr 0%

100 mg + 0.5 mg/kg/min 20 min 89%

(n=11*) 1-4 hr 55%

120 mg + 0.4 mg/kg/min 20 min 82%

(n=12**) 1-4 hr 58%