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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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Overture

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


Question

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?


Cardiovascular events up to 6 months post randomization

Cardiovascular Events Up to 6 Months Post Randomization

OCTAVE (CV137-120)


Cumulative incidence of cv events

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)


Overture

Omapatrilat versus Enalapril Randomized Trial of Utilityin Reducing Events

(OVERTURE)


Overture

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)


Overture

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)


Overture

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)


Overture

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)


Overture

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)


Overture

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)


Overture

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)


Conclusion

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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