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Eugene Braunwald C. Michael Gibson Carolyn H. McCabe Tara 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. Eugene Braunwald C. Michael Gibson Carolyn H. McCabe Tara Yoder.

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Eugene Braunwald C. Michael Gibson Carolyn H. McCabe Tara Yoder

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  1. TIMI 31A 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 Eugene Braunwald C. Michael Gibson Carolyn H. McCabe Tara Yoder

  2. Limitations 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

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

  4. Combination Therapy Improves TIMI 3 Flow by 8%: Pooled Date From Dose Confirmation Phases of Recent Trials % pts with TIMI 3 Flow 88 63 58 87 75 321 98 100 81 329 292 Pooled 60-90 min GUSTO I 90 min T14 tPA 90 min T14 rPA 90 min SPEED 60-90 min INTRO-AMI 60 min

  5. Std. Reteplase (n = 8260) Abciximab +  Dose Reteplase (n = 8328) GUSTO V: Combination Therapy Is Associated With Bleeding 50 40 p < 0.0001 30 24.6 p < 0.0001 % of Patients 20.0 20 13.7 11.4 p < 0.0001 p < 0.0001 p < 0.0001 10 5.7 4.0 3.5 1.8 1.1 0.5 0 Severe Bleeding Moderate Bleeding Mild Bleeding Any Bleeding Receiving Transfusions Lancet 2001; 357:1905-14

  6. ICH by Age Group 3 Std. Dose Reteplase (n = 8260) p = 0.069* Abciximab +  Dose Reteplase (n = 8328) 2.1 p = 0.53 2 1.5 % of Patients 1.2 1.1 p = 0.66 1 p = 0.27* 0.5 0.4 0.4 0.3 37/7172 21/6193 24/6230 25/2030 31/2135 28/7179 12/1088 24/1149 0 > 75 yrs < 70 yrs > 70 yrs < 75 yrs * Significant treatment interaction for the age 75 dichotomy; p = 0.033; Lancet 2001; 357:1905-14

  7. Recurrent MI during Index Hospitalization is Associated with Higher Mortality at 2 Years Kaplan - Meier survival estimates, by early reinfarction 1 No early reinfarction 10.1%, n=19,265 Early reinfarction 19.6%, n=836 0.75 Log - rank p<0.0001 0.5 0 0.5 1 1.5 2 Years Gibson CM et al, ACC 2002

  8. TIMI 31: Mechanism of Action of Current Fibrinolytic Agents • 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.

  9. TIMI 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

  10. TIMI 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 insite-selective production of plasmin. • Consequently, thrombus dissolution may be achieved without systemic destruction of haemostatic proteins, thus reducing the potential risk of haemorrhage.

  11. TIMI 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

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

  13. BB-10153:More effective as an antithrombotic than heparinData from a coil model of thrombosis BB-10153 (4 mg/kg) Heparin (100 U/kg) Heparin (500 U/kg)

  14. BB-10153 does not increase the bleeding time

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

  16. TIMI 31: Primary Study Objectives • To assess the angiographic efficacy of BB-10153 in a dose escalation study

  17. TIMI 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

  18. 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 Patient with Acute ST Elevation MI < 6 hours Dose Escalate 3 mg/kg BB-10153 5 mg/kg BB-10153 1 mg/kg BB-10153 2 mg/kg BB-10153 ASA, IV Heparin 1o Endpoint: TIMI Grade 3 Flow 2o Endpoint: ST Resolution (1 & 3 hrs), Pharmacokinetics and Pharmacokinetics Angio 60 Minutes 30 Day Follow-up Death, recurrent MI, recurrent angina

  19. 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

  20. TIMI 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

  21. Are you interested in participating in the evaluation of BB-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 mgibson@perfuse.org

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

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