eugene braunwald c. michael gibson carolyn h. mccabe tara yoder eugene braunwald c. michael gibson...

Eugene BraunwaldEugene BraunwaldC. Michael GibsonC. Michael Gibson

Carolyn H. McCabeCarolyn H. McCabeTara YoderTara Yoder

Eugene BraunwaldEugene BraunwaldC. Michael GibsonC. Michael Gibson

Carolyn H. McCabeCarolyn H. McCabeTara YoderTara Yoder

TIMI 31

A Phase II, Open-Label, Multi-Center, Dose Escalation Study to Determine the Efficacy, Safety,

Tolerability, Pharmacokinetics and Pharmacodynamics of BB-10153 in ST Segment

Elevation Myocardial Infarction

TIMI 31

A Phase II, Open-Label, Multi-Center, Dose Escalation Study to Determine the Efficacy, Safety,

Tolerability, Pharmacokinetics and Pharmacodynamics of BB-10153 in ST Segment

Elevation Myocardial Infarction

BB 10153 Protocol Version 1, 6/6/02BB 10153 Protocol Version 1, 6/6/02

Limitations of Fibrinolytic Therapy in ST Elevation MILimitations of Fibrinolytic Therapy in ST Elevation MILimitations of Fibrinolytic Therapy in ST Elevation MILimitations of Fibrinolytic Therapy in ST Elevation MI

• Fibrinolytic therapy restores normal TIMI Grade 3 Flow in only 60% of patients• Fibrinolytic therapy restores normal tissue

perfusion in only 30% of patients• Fibrinolytic therapy is associated with

reocclusion• Fibrinolytic therapy is associated with @ a

0.9% risk of ICH

• Fibrinolytic therapy restores normal TIMI Grade 3 Flow in only 60% of patients• Fibrinolytic therapy restores normal tissue

perfusion in only 30% of patients• Fibrinolytic therapy is associated with

reocclusion• Fibrinolytic therapy is associated with @ a

0.9% risk of ICH


60 60 5763

0

20

40

60

80

100

tPA rPA NPA TNK40

60 60 5763

0

20

40

60

80

100

tPA rPA NPA TNK40

The 90 Minute Wall:The 90 Minute Wall:The 90 Minute Wall:The 90 Minute Wall: 60% Rates of TIMI Grade 3 Flow

60% Rates of TIMI Grade 3 Flow

% T

IMI 3

Flo

w%

TIM

I 3 F

low


Combination Therapy Improves TIMI 3 Flow by 8%: Pooled Combination Therapy Improves TIMI 3 Flow by 8%: Pooled Date From Dose Confirmation Phases of Recent TrialsDate From Dose Confirmation Phases of Recent Trials

Combination Therapy Improves TIMI 3 Flow by 8%: Pooled Combination Therapy Improves TIMI 3 Flow by 8%: Pooled Date From Dose Confirmation Phases of Recent TrialsDate From Dose Confirmation Phases of Recent Trials

56

4047

7073

54

645654

7378

0

20

40

60

80

100 Lytic aloneCombination

56

4047

7073

54

645654

7378

0

20

40

60

80

100 Lytic aloneCombination

SPEED60-90 min

SPEED60-90 min

GUSTO I90 min

GUSTO I90 min

T14 tPA90 min

T14 tPA90 min

% p

ts w

ith

TIM

I 3

Flo

w%

pts

wit

h T

IMI

3 F

low

INTRO-AMI60 min

INTRO-AMI60 min

58586363292292 9898 100100 757581818787

T14 rPA90 min

T14 rPA90 min

8888 329329 321321

Pooled60-90 min

Pooled60-90 min


0.50.5 1.81.8

11.411.4 13.713.7

4.04.01.11.1 3.53.5

20.020.024.624.6

5.75.7

00

1010

2020

3030

4040

5050

GUSTO V: Combination Therapy Is Associated GUSTO V: Combination Therapy Is Associated With BleedingWith Bleeding

GUSTO V: Combination Therapy Is Associated GUSTO V: Combination Therapy Is Associated With BleedingWith Bleeding

% o

f P

atie

nts

% o

f P

atie

nts

Std. Reteplase (n = 8260)Std. Reteplase (n = 8260)Abciximab + Dose Reteplase (n = 8328)Abciximab + Dose Reteplase (n = 8328)

p < 0.0001p < 0.0001p < 0.0001p < 0.0001

MildBleeding

MildBleeding

ModerateBleedingModerateBleeding

SevereBleedingSevere

Bleeding

p < 0.0001p < 0.0001

AnyBleeding

AnyBleeding

ReceivingTransfusions

ReceivingTransfusions

p < 0.0001p < 0.0001

p < 0.0001p < 0.0001

Lancet 2001; 357:1905-14Lancet 2001; 357:1905-14


0.5

1.1

0.4

1.2

0.3

1.5

0.4

2.1

0

1

2

3

% o

f P

atie

nts

% o

f P

atie

nts

Std. Dose Reteplase (n = 8260)

Abciximab + Dose Reteplase (n = 8328)

p = 0.66

< 70 yrs< 70 yrs > 75 yrs> 75 yrs> 70 yrs> 70 yrs < 75 yrs< 75 yrs

ICH by Age GroupICH by Age GroupICH by Age GroupICH by Age Group

* Significant treatment interaction for the age 75 dichotomy; p = 0.033; * Significant treatment interaction for the age 75 dichotomy; p = 0.033;

p = 0.53

p = 0.27*

p = 0.069*

12/1088 24/114928/717937/717225/2030 31/213521/619324/6230

Lancet 2001; 357:1905-14Lancet 2001; 357:1905-14


Recurrent MI during Index Hospitalization is Recurrent MI during Index Hospitalization is Associated with Higher Mortality at 2 YearsAssociated with Higher Mortality at 2 Years

Recurrent MI during Index Hospitalization is Recurrent MI during Index Hospitalization is Associated with Higher Mortality at 2 YearsAssociated with Higher Mortality at 2 Years

Kaplan-Meier survival estimates, by early reinfarction

Years 0 0.5 1 1.5 2

0.5

0.75

1 No early reinfarction

10.1%, n=19,265

Early reinfarction19.6%, n=836

Log-rank p<0.0001

Gibson CM et al, ACC 2002Gibson CM et al, ACC 2002


TIMI 31: Mechanism of Action of Current Fibrinolytic TIMI 31: Mechanism of Action of Current Fibrinolytic AgentsAgents

TIMI 31: Mechanism of Action of Current Fibrinolytic TIMI 31: Mechanism of Action of Current Fibrinolytic AgentsAgents

• The fibrinolytic system contains an inactive pro-enzyme, plasminogen, which is converted to the active enzyme, plasmin, by the action of plasminogen activators.

• Plasmin in turn digests fibrin to soluble products and thus induces thrombolysis.

• The fibrinolytic system contains an inactive pro-enzyme, plasminogen, which is converted to the active enzyme, plasmin, by the action of plasminogen activators.

• Plasmin in turn digests fibrin to soluble products and thus induces thrombolysis.


TIMI 31: Mechanism of Action of BB10153TIMI 31: Mechanism of Action of BB10153TIMI 31: Mechanism of Action of BB10153TIMI 31: Mechanism of Action of BB10153

• Natural state of affairs: Enzymes responsible for forming a clot do not activate the enzymes responsible for dissolving the clot

• Effect of BB-10153: Enzymes (thrombin) responsible for forming clot instead activate the enzymes responsible for dissolving the clot


TIMI 31: Potential Advantages of BB10153TIMI 31: Potential Advantages of BB10153TIMI 31: Potential Advantages of BB10153TIMI 31: Potential Advantages of BB10153

• In contrast to current agents, BB10153 is a recombinant variant of human plasminogen, which has been genetically modified so that it is activated to plasmin by thrombin, rather than by plasminogen activator enzymes. • As thrombin is the key enzyme involved in thrombus formation, and thrombin activity is localised at the site of the thrombus formation, intravenous (i.v.) administration of BB-10153 results in site-selective production of plasmin.• Consequently, thrombus dissolution may be achieved without systemic destruction of haemostatic proteins, thus reducing the potential risk of haemorrhage.

• In contrast to current agents, BB10153 is a recombinant variant of human plasminogen, which has been genetically modified so that it is activated to plasmin by thrombin, rather than by plasminogen activator enzymes. • As thrombin is the key enzyme involved in thrombus formation, and thrombin activity is localised at the site of the thrombus formation, intravenous (i.v.) administration of BB-10153 results in site-selective production of plasmin.• Consequently, thrombus dissolution may be achieved without systemic destruction of haemostatic proteins, thus reducing the potential risk of haemorrhage.


TIMI 31: Potential Advantages of BB10153TIMI 31: Potential Advantages of BB10153TIMI 31: Potential Advantages of BB10153TIMI 31: Potential Advantages of BB10153

• Retains the fibrin binding of the parent molecule but is thrombus selective. • Acts only on newly forming thrombi, may reduce the risk of haemorrhage

• Long half life (3 hours), single bolus

• As a result of above may be associated with lower risk of reocclusion

• Retains the fibrin binding of the parent molecule but is thrombus selective. • Acts only on newly forming thrombi, may reduce the risk of haemorrhage

• Long half life (3 hours), single bolus

• As a result of above may be associated with lower risk of reocclusion


BB-10153 BB-10153 has thrombolytic activity has thrombolytic activity andand prevents reocclusion: prevents reocclusion: Data from a coil model of thrombosis

BB-10153 BB-10153 has thrombolytic activity has thrombolytic activity andand prevents reocclusion: prevents reocclusion: Data from a coil model of thrombosis

0 60 120 180 240

BB-10153(5mg/kg)

tPA (3mg/kg)

tPA (1mg/kg)

Time (min)

No blood flow

Blood flow


BB-10153:BB-10153: More effective as an antithrombotic than heparin Data from a coil model of thrombosis

BB-10153:BB-10153: More effective as an antithrombotic than heparin Data from a coil model of thrombosis

0 50 100 150 200 250

Control

2

4

6

8

10

12

14

16

18

Time after coil insertion (mins)0 50 100 150 200 250

6

5

4

3

2

1

Control

Time after coil insertion (mins)

BB-10153 (4 mg/kg) Heparin (100 U/kg)

0 50 100 150 200 250

7

6

5

4

3

2

1

Control

Time after coil insertion (mins)

Blood flow

No blood flow

Heparin (500 U/kg)


BB-10153 BB-10153 does not increase the bleeding timedoes not increase the bleeding timeBB-10153 BB-10153 does not increase the bleeding timedoes not increase the bleeding time

0

10

20

30

40

Control 30 120Time after dosing (min)

Ble

edin

g tim

e (m

in)

Vehicle (tPA) n=4

tPA 3mg/kg n=4

Vehicle (BB-10153)n=4BB-10153 10mg/kgn=4


BB-10153 is targeted to thrombus: There is no rise in BB-10153 is targeted to thrombus: There is no rise in plasmin activity in the blood with BB-10153plasmin activity in the blood with BB-10153

BB-10153 is targeted to thrombus: There is no rise in BB-10153 is targeted to thrombus: There is no rise in plasmin activity in the blood with BB-10153plasmin activity in the blood with BB-10153

0

10

20

30

40

50

60

-15 0 30 60 120 180 240

Time after dosing (min)

Pla

sm

in a

cti

vit

y in

the

blo

od

BB-10153(5mg/kg)

tPA (3mg/kg)


TIMI 31: Primary Study ObjectivesTIMI 31: Primary Study ObjectivesTIMI 31: Primary Study ObjectivesTIMI 31: Primary Study Objectives

• To assess the angiographic efficacy of BB-10153 in a dose escalation study• To assess the angiographic efficacy of BB-10153 in a dose escalation study


TIMI 31: Secondary Study ObjectivesTIMI 31: Secondary Study ObjectivesTIMI 31: Secondary Study ObjectivesTIMI 31: Secondary Study Objectives

• To assess the safety and tolerability of BB-10153

• To assess the pharmacokinetic activity of BB-10153

• To assess the pharmacodynamic activity of BB-10153

• To assess the safety and tolerability of BB-10153

• To assess the pharmacokinetic activity of BB-10153

• To assess the pharmacodynamic activity of BB-10153

ASA, IV HeparinASA, IV Heparin

Dose EscalateDose Escalate

30 Day Follow-upDeath, recurrent MI, recurrent angina

30 Day Follow-upDeath, recurrent MI, recurrent angina

2 mg/kgBB-101532 mg/kg

BB-10153

Patient with Acute ST Elevation MI < 6 hours Patient with Acute ST Elevation MI < 6 hours Patient with Acute ST Elevation MI < 6 hours Patient with Acute ST Elevation MI < 6 hours


BB-10153

Angio 60 MinutesAngio 60 Minutes

TIMI 31: A Phase II, Open-Label, Multi-Center, Dose Escalation Study to Determine the Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BB-10153

in ST Segment Elevation Myocardial Infarction

TIMI 31: A Phase II, Open-Label, Multi-Center, Dose Escalation Study to Determine the Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BB-10153

in ST Segment Elevation Myocardial Infarction


BB-101535 mg/kg

BB-101535 mg/kg

BB-10153

1o Endpoint:TIMI Grade 3 Flow2o Endpoint:ST Resolution (1 & 3 hrs),Pharmacokinetics and Pharmacokinetics

1o Endpoint:TIMI Grade 3 Flow2o Endpoint:ST Resolution (1 & 3 hrs),Pharmacokinetics and Pharmacokinetics


TIMI 31 Study Endpoints:TIMI 31 Study Endpoints:TIMI 31 Study Endpoints:TIMI 31 Study Endpoints:

• Primary: TIMI flow grade 3 at 60 minutes

• Secondary – Angiographic

• TIMI Frame Count• TIMI Perfusion Grade• Thrombus Grade• MLD• Percent Stenosis

– ECG• Proportion of patient s with ≥50% ST res at 60 minutes• Median %ST res at 60 minutes• ST res at 3 hours, specifically in patients undergoing rescue PCI

• Primary: TIMI flow grade 3 at 60 minutes

• Secondary – Angiographic

• TIMI Frame Count• TIMI Perfusion Grade• Thrombus Grade• MLD• Percent Stenosis

– ECG• Proportion of patient s with ≥50% ST res at 60 minutes• Median %ST res at 60 minutes• ST res at 3 hours, specifically in patients undergoing rescue PCI


TIMI 31 Study Endpoints: Safety, PK and PDTIMI 31 Study Endpoints: Safety, PK and PDTIMI 31 Study Endpoints: Safety, PK and PDTIMI 31 Study Endpoints: Safety, PK and PD

Safety and Tolerability• Tabulating and listing the incidence of adverse events• Hematological, biochem, urinalysis parameters subject to clinical

review• Physical examination and vital signs• Bleeding rates

Pharmacokinetic parameters for BB-10153• AUC 0-∞, Cmax, T½, volume of distribution and clearance

Pharmacodynamic parameters• Core lab coagulation parameters• Cardiac biomarker assessments• aPTT assessment• TAS

Safety and Tolerability• Tabulating and listing the incidence of adverse events• Hematological, biochem, urinalysis parameters subject to clinical

review• Physical examination and vital signs• Bleeding rates

Pharmacokinetic parameters for BB-10153• AUC 0-∞, Cmax, T½, volume of distribution and clearance

Pharmacodynamic parameters• Core lab coagulation parameters• Cardiac biomarker assessments• aPTT assessment• TAS


Are you interested in participating in the evaluation of BB-Are you interested in participating in the evaluation of BB-10153?10153?

Are you interested in participating in the evaluation of BB-Are you interested in participating in the evaluation of BB-10153?10153?

•Yes. I am interested in participating in an upcoming trial of BB-10153

•Name: ________________________•Center: ________________________•Phone: _________________________•FAX: __________________________•Email: _________________________

•Fax to Dr. C. Michael Gibson at 617-632-1411 or email [email protected]


•For more information about the sponsor of the trial, British Biotech, visit www.britishbiotech.com

eugene braunwald c. michael gibson carolyn h. mccabe tara yoder eugene braunwald c. michael gibson...

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