1. OVERTURE FDA Cardiovascular and Renal Drugs Advisory Committee Meeting July 19, 2002 Milton Packer, M.D., FACC Columbia University College of Physicians and Surgeons Columbia Presbyterian Medical Center New York, NY

2. 52-2 Question Is it possible that NEP inhibition produces an adverse cardiovascular effect that could negate the cardiovascular benefits expected from omapatrilat’s incremental ability to lower blood pressure?

3. 52-3 Cardiovascular Events Up to 6 Months Post Randomization OCTAVE (CV137-120)

4. 52-4 Cumulative Incidence (%) Cumulative Incidence of CV Events Days Since First Dose Omapatrilat Enalapril OCTAVE (CV137-120) Hazard Ratio: 0.87 (95% CI: 0.67, 1.13)

5. 52-5 Omapatrilat versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE)

6. 52-6 5770 patients with class II, III or IV symptoms of heart failure  2 months due to ischemic or nonischemic cardiomyopathy 5770 patients with class II, III or IV symptoms of heart failure  2 months due to ischemic or nonischemic cardiomyopathy LV ejection fraction  30% LV ejection fraction  30% Hospitalized for heart failure within 12 months Hospitalized for heart failure within 12 months Receiving diuretics (  digitalis, ACE inhibitor, beta-blocker or spironolactone) Receiving diuretics (  digitalis, ACE inhibitor, beta-blocker or spironolactone) Study Description OVERTURE (CV137-068)

7. 52-7 Study Design OVERTURE (CV137-068) Enalapril 10 mg BID Omapatrilat 40 mg QD Baseline 2.5 mg BID 5 mg BID 10 mg QD 20 mg QD Prior ACE inhibitor discontinued Randomization

8. 52-8 Primary endpoint (combined risk of all-cause mortality or CHF hospitalization) was prospectively used to test two hypotheses: Primary endpoint (combined risk of all-cause mortality or CHF hospitalization) was prospectively used to test two hypotheses: –Non-inferiority vs enalapril (achieved if upper bound of 97.5% one-sided confidence interval was  1.09) based on SOLVD Treatment Trial as reference –Superiority vs enalapril (achieved if upper bound of 97.5% one-sided confidence interval was  1.00) OVERTURE OVERTURE (CV137-068)

9. 52-9 Death or CHF Hospitalization 0.94 (0.86,1.03) 0.187 Log-rank p-Value 973/2884 Enalapril 914/2886 Omapatrilat Primary Endpoint Hazard Ratio OVERTURE (CV137-068)

10. 52-10 CV Death or CV Hospitalization 0.91 (0.84,0.99) 0.024 Log-rank p-Value 1178/2886 Omapatrilat 1275/2884 Enalapril Hazard Ratio OVERTURE (CV137-068)

11. 52-11 1.000.701.150.85 Hazard Ratios Systolic BP  140 mmHg Systolic BP 130-139 mmHg Systolic BP 120-129 mmHg Systolic BP 110-119 mmHg Systolic BP  110 mmHg 1.30 Death or CHF Hospitalization 1.000.701.150.85 Hazard Ratios 1.30 CV Death or CV Hospitalization CV Events by Baseline Systolic BP Subgroup OVERTURE (CV137-068) 0.55 Favors Oma Favors Ena Favors Oma Favors Ena

12. 52-12 Heart failure Hypotension Dizziness Impaired renal function Angioedema Enalapril 737 (25.6%) 332 (11.5%) 401 (13.9%) 104 (3.6%) 14 (0.5%) Omapatrilat 653 (22.6%) 564 (19.5%) 561 (19.4%) 66 (2.3%) 24 (0.8%) OVERTURE (CV137-068) Selected Adverse Events

13. 52-13 Conclusion These data provide considerable reassurance that NEP inhibition does not detract from the cardiovascular benefits expected from the incremental anti- hypertensive effects of omapatrilat.