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OVERTURE

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OVERTURE

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  1. OVERTURE Milton Packer, M.D., FACCColumbia University College of Physicians and SurgeonsColumbia Presbyterian Medical CenterNew York, NY • FDA Cardiovascular and Renal DrugsAdvisory Committee Meeting • July 19, 2002

  2. Question • Is it possible that NEP inhibition producesan adverse cardiovascular effect that could negate the cardiovascular benefits expected from omapatrilat’s incremental ability tolower blood pressure?

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

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

  5. Omapatrilat versus Enalapril Randomized Trial of Utilityin Reducing Events (OVERTURE)

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

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

  8. OVERTURE • 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 boundof 97.5% one-sided confidence interval was < 1.00) OVERTURE (CV137-068)

  9. Enalapril Omapatrilat 973/2884 914/2886 Primary Endpoint HazardRatio Log-rankp-Value Death or CHFHospitalization 0.94 (0.86,1.03) 0.187 OVERTURE (CV137-068)

  10. HazardRatio Log-rankp-Value Omapatrilat Enalapril CV Death orCV Hospitalization 1178/2886 1275/2884 0.91 (0.84,0.99) 0.024 CV Death or CV Hospitalization OVERTURE (CV137-068)

  11. CV Events by Baseline Systolic BP Subgroup Death or CHF Hospitalization CV Death or CV Hospitalization Favors Oma Favors Ena Favors Oma Favors Ena Systolic BP  140 mmHg Systolic BP 130-139 mmHg Systolic BP 120-129 mmHg Systolic BP 110-119 mmHg Systolic BP < 110 mmHg 0.70 0.85 1.00 1.15 1.30 0.55 0.70 0.85 1.00 1.15 1.30 Hazard Ratios Hazard Ratios OVERTURE (CV137-068)

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

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