OVERTURE

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
  omapatrilats 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
  lt 1.09) based on SOLVD Treatment Trial as
  reference
• Superiority vs enalapril (achieved if upper
  boundof 97.5 one-sided confidence interval was
  lt 1.00)

OVERTURE (CV137-068)
9
Primary Endpoint
Log-rankp-Value
HazardRatio
Death or CHFHospitalization
0.94 (0.86,1.03)
0.187
OVERTURE (CV137-068)
10
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 lt 110 mmHg
1.00
0.70
1.15
0.85
1.30
1.00
0.70
1.15
0.85
1.30
0.55
Hazard Ratios
Hazard Ratios
OVERTURE (CV137-068)
12
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.