Change in Systolic BP at Week 24 for Patients Receiving Adjuncts After Week 8 All Randomized Patient

1
Change in Systolic BP at Week 24 for Patients
Receiving Adjuncts After Week 8 (All Randomized
Patients)
Other Diuretics(n 690)
Other CCB(n 735)
Beta Blockers(n 890)
HCTZ(n 2476)
Amlodipine(n 695)
ARB(n 274)
Change in SBP (mmHg)
OCTAVE (CV137-120)
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OCTAVE Group 3 Effectiveness of Omapatrilatin
Patients Treated with HCTZ and Amlodipineat
Randomization at Week 24
SBP
DBP
BP Change (mmHg)
OCTAVE (CV137-120)
3
Enalapril Comparison in Severe Hypertension(CV137
-049)
B71
B1
B15
B8
B29
40
20
40 80
Forced titrationto 40, elective to 80
Omapatrilat
C1
Level I
Level II
Level III
Adjunct
SeDBP 115-130mmHg
Forced titration to 20, elective to 40
Enalapril
20
20 40
10
A7
B1
B71
C1
Period A Single-Blind Placebo Lead-In
Period C Long-Term Open-Label
Period B Double-Blind Randomized
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Primary Efficacy ResultsMean Changed from
Baseline in Trough SeDBP,and SeSBP and SePP at
Week 10
CV137-049
5
Most Common Adverse Events
Excluding Angioedema
OCTAVE (CV137-120)
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Definition of Hospitalization for Heart Failure

• OVERTURE Trial
• Included all hospitalizations attributable to
  heart failure as adjudicated by Endpoint
  Committee which required IV treatmentand had a
  duration gt 24 hours
• SOLVD Treatment Trial
• Included all hospitalizations attributable to
  heart failure by the investigator regardless of
  treatment or duration

OVERTURE (CV137-068)
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Study Design (CV137-071)
Single blind
Double blind
Omapatrilat
Placebo
10 mg
40 mg
80 mg
CAD Exertional angina
R
wk 2
wk 1
wk 4
ETT
ETT
Placebo
ETT
ETT
3 Wk (max) Period A
4 Wk Period B
Day 28
Day 29
BMS data on file
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Primary Efficacy ResultsChange in Peak Exercise
Parameters vs Baseline ETT
p lt 0.001
p lt 0.001
p lt 0.001
Increased Time (sec)
Time to Onset of Angina
Maximal Exercise Duration
Time to ST Depression

BMS data on file
CV137-071
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Diabetic Patients (CV137-046)
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Summary of Primary Efficacy Results
Adjusted Geometric Mean Change from Baseline
for Albumin Excretion Rate
Adjusted GM Change from Baseline
Study Week
CV137-046
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Losartan Comparison in LVH (CV137-038)
omapatrilat
20 mg
40 mg
80 mg
HCTZ
80 mg
HCTZ/AML

Baseline EchoLVH
losartan
HypertensionDBP 95-115 mmHgand / orSBP 160-200
mmHg
50 mg
100 mg
100 mg
HCTZ
100 mg
HCTZ/AML
Wk 52(Echo)
Wk 8
Wk 16
Wk 24(Echo)
Force Titration
Open-label adjuncts added to Level III
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Summary of Primary Efficacy Results

Mean Changes from Baseline inEchocardiographic
Measures at Week 24
CV137-038
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BP Changes From Baseline Per Study Week
0 -5 -10 -15 -20 -25 -30 -35
Losartan
Omapatrilat
DBP
Change in BP (mmHg)
SBP
0
24
30
36
44
52
Week
Adjunctive therapy Omapatrilat 6.3 22.2
32.7 32.5 34.4 Losartan 16.5 50.0
54.8 59.3 60.0
CV137-038
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CHOIRS Background(Conduit Hemodynamics
ofOmapatrilat International Research Study)

• Elevated pulse pressure, an indirect measure of
  increased vascular stiffness, associated with
• Myocardial infarction, stroke
• Development and progression of heart failure
• Increased mortality
• Current epidemic of uncontrolled systolic
  hypertension due to a lack of treatments
  thatreduce arterial stiffness
• Natriuretic peptides have a favorable effect on
  largearteries in basic studies although their
  effects in humans have not been elevated

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CHOIRS Study Design
Baseline hemodynamic study (n 213)SBP ? 160
mmHg
Randomize Force-titrationWks 0, 2, 4
Omapatrilat 10 / 40 / 80 mg daily (n 104)
Enalapril 10 / 20 / 40 mg daily (n 109)
Withdrawn (n 22)
Withdrawn (n 24)
8 Wks at maximal dose
Trough (24 Hr)Hemodynamic Study (n 80)
Trough (24 Hr)Hemodynamic Study (n 87)
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Central and Peripheral Pulse Pressure


lt 0.005 lt 0.05 Mitchell, et al.,
Circulation 2002 1052955
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Omapatrilat Target Population

• Patients with
• A high risk of major cardiovascular events
• Cardiovascular disease (e.g., MI, CHF)
• Target organ damage (e.g., LVH, proteinuria)
• 3 or more cardiovascular risk factors
• Diabetes or renal disease
• and
• Hypertension that is difficult to controlwith
  existing medications

Use with special caution in black patientsand
current smokers
Based on WHO-ISH guidelines
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Subgroups at Increased CV RiskChange in
Systolic BP at Week 24
Adjusted SBP Changeat Week 24 (mmHg) Omapatrilat
Enalapril

Difference(oma / ena)
-18.7 -36.6
Severe Hypertension (n 7197) Group 1 (n
983)
-2.7-4.6
-15.9 -32.0
-17.6
Diabetes Mellitus (n 3275)
-4.2
-13.4
-20.7
Atherosclerotic Disease (n 2283)
-2.7
-18.0
-22.2
ISH (n 1332)
-4.5
-17.7
-17.0
Renal Disease (n 582)
-3.6
-13.4
-20.9
Heart Failure (n 233)
-4.5
-16.4
Includes chronic stable angina, unstable
angina, myocardial infarction, and stroke / TIA
OCTAVE (CV137-120)
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Target Population Baseline Demographics
(Diabetes, Renal Disease, Athero Disease, HF)
OCTAVE (CV137-120)
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OCTAVE Efficacy in Target Population at Week 24
(Diabetes, Renal Disease, Athero Disease, HF)
Use of NewAdjunctive Therapy
Change in Systolic BP
of Patients
SBP Change (mmHg)

-3.6
p lt 0.001 vs enalapril
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Target Population Severity of Angioedema
Events, Week 24 (Diabetes, Renal Disease, Athero
Disease, HF)
Number () of Patients
Omapatrilat (n 2842)
Enalapril (n 2807)
Severity
28 (0.99)
14 (0.50)
I. No Treatment Administered or Antihistamines
Only
15 (0.53)
2 (0.07)
II. Treated with Catecholamines or Steroids
III. Hospitalized but no Mechanical Airway
Protection
2 (0.07)
1 (0.04)

IIIa. No Airway Compromise
2
1

0
0
IIIb. With Airway Compromise
0 (0)
0 (0)
IV. Mechanical Airway Protection or Death from
Airway Compromise
45 (1.58)
17 (0.61)
Total
OCTAVE (CV137-120)
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Change in 24-Hour Average AmbulatorySystolic BP
in Patients Uncontrolledwith ACE-Inhibitor
Regimens at Baseline
ACE-I Monotherapy(n 171)
ACE-ICombination(n 75)
ASBP Change (mmHg)
-11.5
-7.6
Week 4 Maintenance p lt 0.001 vs. lisinopril
CV137-073
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Difficult to Control Patients
Difficult to Control Patients
Patients uncontrolled witha regimen not
including an ACE-I
Untreated patients with severe hypertension
Patients uncontrolled witha regimen including an
ACE-I

• Omapatrilat provides consistent benefit in BP
  reduction over enalapril in each of these
  difficultto control populations.

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BP Control in Uncontrolled Patients at Sites with
Highest Adjunct Use (64.0 - 100) at Week 24
Change in SBP (mmHg)
BP Control n / N ()
Difference
Omapatrilat (n 967) Enalapril (n 966)
544 / 907 (60.0) 466 / 903 (51.6)
-19.1 -15.7
-3.4
OCTAVE (CV137-120)
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Omapatrilat Educational Program
Counseling PharmacistEducation
MD Education
Initial MD-Patient ConsultationPatient
BrochureRx Given
Mandatory Counseling Service
Retail PharmacistEducation
Follow-up MD Patient ConsultationRx Given