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OVERTURE

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

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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.

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