Baran KW August 28, 2000 Kenneth W. Baran MD for the LIMIT AMI Investigators St. Paul Heart Clinic, St. Paul, MN, USA Sponsor: Genentech Inc., South San Francisco, USA LIMIT AMI (LImitation of Myocardial Injury following Thrombolysis in Acute Myocardial Infarction) An angiographic safety and efficacy trial of a novel anti-CD18 therapy in acute myocardial infarction in conjunction with thrombolysis

Baran KW August 28, 2000

rhuMAb CD18 â Antibody fragment [F(ab’) 2 ] â Single dose administered as IV bolus â Plasma half-life 7 to 10 hours â  90% CD18-containing receptor saturation maintained for ~ 24 hours (0.5 mg/kg) and ~ 48 hours (2.0 mg/kg)

Baran KW August 28, 2000 The LIMIT AMI Trial of rhuMAb CD18 ST elevation > 2 leads Symptoms < 12 hrs No prior coronary surgery No cardiogenic shock No thrombolytic exclusions No major immune-related risks ScreeningScreening

Baran KW August 28, 2000 The LIMIT AMI Trial of rhuMAb CD18 ST elevation > 2 leads Symptoms < 12 hrs No prior coronary surgery No cardiogenic shock No thrombolytic exclusions No major immune-related risks ScreeningScreening Randomization 1:1:1 with administration prior to full-dose tPA 2 mg/kg0.5 mg/kg Placebo + usual care including aspirin, IV heparin

Baran KW August 28, 2000 The LIMIT AMI Trial of rhuMAb CD18 ST elevation > 2 leads Symptoms < 12 hrs No prior coronary surgery No cardiogenic shock No thrombolytic exclusions No major immune-related risks ScreeningScreening Coronary angiography 90 minutes from tPA initiation Randomization 1:1:1 to study drug or placebo then full-dose tPA 2 mg/kg0.5 mg/kg Placebo Corrected TIMI Frame Count, TIMI Flow Grade TIMI Myocardial Perfusion Grade Angioplasty ± Gp IIb/IIIa inhibitors as required + usual care including aspirin, IV heparin

Baran KW August 28, 2000 The LIMIT AMI Trial of rhuMAb CD18 Infarct size sestamibi at rest, day 6-9 CKMB 0-72 hours ECG ST segment resolution 180 minutes Fever Antibiotic use General Safety Other endpoints

Baran KW August 28, 2000 Statistical Analysis â Efficacy endpoint data analyzed by independent and blinded Core Laboratories â Time windows were used for efficacy endpoints using imputation for missing data where possible â “As treated” analysis of the evaluable cohort â Sensitivity analyses â p values: non parametric tests

Baran KW August 28, 2000 Results â Enrollment from September 1998 to March 2000 â 413 subjects randomized â 394 treated with rhuMAb CD18 or placebo â 19 randomized but not treated Ý mainly due to review of exclusion criteria â 60 centers in US and Canada

Baran KW August 28, 2000 Baseline characteristics

Baran KW August 28, 2000 Concomitant Interventions

Baran KW August 28, 2000 Change in peripheral venous blood white cell counts - mean values

Baran KW August 28, 2000 Primary Endpoint: Corrected TIMI Frame minutes Corrected TIMI Frame Count Placebo0.5 mg/kg2.0 mg/kg Treatment Received p = 0.2 p = 1.0meanmedian

Baran KW August 28, 2000 % TIMI Grade 3 flow Expected per protocol: placebo 55%, treatment 70% N=114 N=111N=108 66% 58% 63%

Baran KW August 28, 2000 TIMI Flow Grades (all grades) N=114 N=111 N=108

Baran KW August 28, 2000 TIMI Myocardial Perfusion Grade N=107 N=101 N=102

Baran KW August 28, 2000 ECG ST segment elevation resolution at 180 minutes N=109 N=103 N=106

Baran KW August 28, 2000 Infarct Size by sestamibi scan Day 6-9 LV defect % Placebo 0.5 mg/kg 2.0 mg/kg Treatment Receivedmeanmedian

Baran KW August 28, 2000 Clinical outcomes at Day 30 * Adverse Event report, complications CRF, or readmission diagnosis ** CHF Killip III or IV, or CHF readmission, or CHF Adverse Event (serious or severe or cardiogenic shock) *** Death, CHF or recurrent AMI

Baran KW August 28, 2000 Safety - fever and antibiotic use N=129 N=131 N=134

Baran KW August 28, 2000 Safety - Likely bacterial infections N=134 N=129 N=131 95% CI

Baran KW August 28, 2000 General Safety â No effect on fibrinogen or d-dimer levels â No increase in “serious and life-threatening bleeding” â Slight trend towards increases in overall bleeding adverse events (  10%) and transfusions (  20%) â Small number of mild thrombocytopenia cases < 100,000/mm 3 : placebo 2 cases, 0.5 mg/kg 1 case, 2.0 mg/kg 5 cases â No specific anti-rhuMAb CD18 antibody formation* * Except for one 30 Day sample with possible low level anti-CDR activity still under investigation.

Baran KW August 28, 2000 Conclusions ârhuMAb CD18, in conjunction with thrombolysis, had no effect on coronary flow, infarct size or ECG ST segment resolution âThese results are consistent with the findings of another Phase II study of an anti-CD18 antibody in Primary Angioplasty on infarct size (HALT MI*) âThere may be non CD18- dependent leukocyte binding and transmigration in AMI âLeukocytes may not be key to ischemia- reperfusion injury in human AMI * Faxon D, Annual Meeting of the American Heart Association, Atlanta, November 1999