Title: IDNT Irbesartan Diabetic Nephropathy Trial
1NDA 21-188
Omapatrilat in the Treatmentof
HypertensionEfficacy and Safety
Elliott Levy, M.D.Vice President, Clinical
Design and EvaluationPharmaceutical Research
Institute
7asdf
FDA Cardiovascular and Renal DrugsAdvisory
Committee Meeting July 19, 2002
2Efficacy
3Omapatrilat 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
4Order of Presentation
- In 4 placebo-controlled trials (2369 patients),
doserelated reduction demonstrated in systolic
and diastolic blood pressure - In 6 active-controlled trials (2742 patients),
omapatrilat80 mg shown to be more effective
monotherapy than lisinopril 40 mg, amlodipine 10
mg, losartan 100 mg - In OCTAVE (25,302 patients), omapatrilat-based
regimen consistently more effective than
enalapril-based regimen - Greater BP reduction preserved in patients with
comorbidity and difficult to control hypertension
5Dose-Related Mean Reductionfrom Baseline in
Trough Blood Pressure
Weeks 6-9CV137-006, -022, -024 and -045
6Changes in Trough Systolic BP versus Active
Comparators at Maximal Recommended Dose
CV137-030(n 492)
CV137-037(n 437)
CV137-077(n 203)
oma 80 mg
aml 10 mg
oma 80 mg
lis 40 mg
oma 80 mg
los 100 mg
SBP Change (mmHg)
-5.2
-3.1
-7.2
Week 10
p 0.05 vs. comparator p lt 0.001 vs.
comparator
7Changes in 24-Hour Average AmbulatorySystolic BP
versus Active Comparatorsat Maximal Recommended
Doses
CV137-032(n 379)
CV137-031(n 317)
CV137-066(n 673)
oma 80 mg
aml 10 mg
oma 80 mg
lis 40 mg
oma 80 mg
aml 10 mg
los 100mg
ASBP Change (mmHg)
-5.4
-6.8
-5.9
-8.9
Week 10
p lt 0.001 vs. comparator
8Effects of Omapatrilat and Amlodipine on
Ambulatory Systolic Blood Pressure, by Hour
Difference in 24-hourAverage ASBP -5.9
ASBP (mmHg)
Week 10
Baseline
Omapatrilat (n 192) Amlodipine (n 187)
Omapatrilat 80 mg Amlodipine 10 mg
CV137-032
p 0.001 vs. Amlodipine
9OCTAVE Rationale
- In 6 active controlled monotherapy trials,
omapatrilat 80 mg reduced blood pressureto a
greater extent than maximal doses of amlodipine,
losartan and lisinopril - OCTAVE was designed to evaluate
whetheromapatrilat would be superior to another
agent (enalapril) in clinical use conditions,
where therapy is titrated electively and
supplementedby other agents to reach BP target - OCTAVE was large enough to characterize efficacy
and safety in important subgroups
10OCTAVE Study Design
Adjunctive Rx
10 mg
20
40
80
Omapatrilat
SBP ? 140 or DBP ? 90
Target BP lt 140/90 mmHg
Enalapril
20
40
10
5 mg
Adjunctive Rx
Titration to Target
Adjunctive Rx to Target
2
4
6
8
16
24
Week
Forced Titration
11OCTAVE Study Groups
JNC VI Stage I-IIIUntreated
JNC VI Stage IDespite Treatment
JNC VI Stage IIDespite Treatment
Replacement (Group 2)
Add-on (Group 3)
Initial (Group 1)
Ena
Oma
Ena
Oma
Ena
Oma
n 9,292
n 11,224
n 4,751
Baseline BP(mmHg)
156 / 96
150 / 91
166 / 97
12OCTAVE Study Endpoints
- Efficacy (Co-Primary)
- Change in systolic blood pressure from baseline
to Week 8, by study group - Use of new adjunctive antihypertensive therapy
between Weeks 8 and 24,by study group - Safety
- Incidence of adverse events
- Incidence and severity of angioedema
13OCTAVE Efficacy Results at Week 8
Change in Systolic BP
Titration to Top Dose(Oma 80 mg, Ena 40 mg)
InitialGroup 1
ReplacementGroup 2
Add-onGroup 3
of Patients
SBP Change (mmHg)
-3.8
-3.2
-3.6
InitialGroup 1
ReplacementGroup 2
Add-onGroup 3
p lt 0.001 vs enalapril
14OCTAVE Efficacy Results at Week 24
Change in Systolic BP
Use of NewAdjunctive Therapy
InitialGroup 1
ReplacementGroup 2
Add-onGroup 3
of Patients
SBP Change (mmHg)
-3.1
-3.1
-2.8
InitialGroup 1
ReplacementGroup 2
Add-onGroup 3
p lt 0.001 vs enalapril
15Demographic SubgroupsChange in Systolic BP at
Week 24
OCTAVE (CV137-120)
16Subgroups 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)
17OCTAVE Conclusion
- Greater BP reduction with omapatrilat-based
regimen, despite more frequent use of maximal
doses and adjunctive therapy with enalapril - Highly consistent results regardless of patient
subgroup or manner of use of study drug - Greater BP reduction observed at week 8and
preserved over 24 weeks, despite useof
adjunctive therapy
18Role of Omapatrilat in Difficult to Control
Hypertension
- In many patients, hypertension can be readily
controlled with existing therapy - OCTAVE and other large clinical trials
demonstrate that hypertension is difficult to
control in many patients - In patients not readily controlled with existing
therapies, an omapatrilat-based regimen provides
lasting efficacy advantage
19Efficacy at Week 24 in SubgroupsDefined by
Baseline JNC-VI Stage
Change in Systolic BP JNC-VI
Use of New Adjunctive Antihypertensive
TherapyJNC-VI
Stage I(n 4160) 147
Stage II(n 3864) 160
Stage III(n 983) 178
Baseline SBP (mmHg)
SBP Change (mmHg)
of Patients
-2.6
-3.0
-4.6
Stage I
Stage II
Stage III
p lt 0.001 vs enalapril
Omapatrilat
Enalapril
OCTAVE (CV137-120)Group 1
20Control of BP (lt 140/90 mmHg) in Multi-Drug
Resistant Patients in Group 3 at Week 24
Omapatrilat
Enalapril
Controlled
2 or More Baseline Meds(n 2309)
3 or More Baseline Meds(n 703)
OCTAVE (CV137-120)
21Difficult to Control Hypertension Patients
Uncontrolled with ACE-Inhibitor Regimen
Omapatrilat
20 40 80
Maximal ACE-I (alone or as part of regimen)
SBP ? 140 or DBP ? 90
Lisinopril
20 20 40
Titration 2-4 Weeks
Maintenance 4 Weeks
Enrollment / Lead-In 2 weeks
Randomization D/C ACE-I Continue other
antihypertensives (if any) at established dose
CV137-073
22Changes in Ambulatory Systolic BP in Subjects
Uncontrolled with ACE-Inhibitor Regimen
Average ambulatory difference from Lisinopril
-8.8Trough difference from Lisinopril -7.0
ASBP (mmHg)
Omapatrilat 80 mg (n 124)
Lisinopril 40 mg (n 122)
Week 4 Maintenance p lt 0.001 vs. lisinopril
Hour Post-Dose
CV137-073
23Change 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
Omapatrilat 80 mg
Lisinopril 40 mg
CV137-073
24Efficacy at Week 24 OCTAVE Patients Not at
Target with ACE-Inhibitor Regimens at Baseline
ACE-I 1Antihypertensive Med (n 1368)
ACE-I 2 or More Antihypertensive Meds (n
546)
ACE-I Monotherapy (n 2278)
-5.9
-3.0
SBP Change (mmHg)
-3.5
Group 2 p lt 0.001 vs. enalapril
25Efficacy at Week 24 OCTAVE Patients
withDiabetes Not at Target with
ACE-InhibitorRegimens at Baseline
ACE-I 1 Antihypertensive Med (n 322)
ACE-I 2 or More AntihypertensiveMeds (n 169)
ACE-IMonotherapy (n 466)
-8.5
SBP Change (mmHg)
-6.9
-4.8
Group 2
p lt 0.05 p lt 0.001 vs. enalapril
26Efficacy Conclusions
- Greater antihypertensive efficacy with regimen
based on omapatrilat - Greater efficacy apparent across patient
subgroups and continued over time - Greater efficacy maintained even when physicians
encouraged to add adjunctto achieve BP goal - In patients with difficult to control
hypertension, omapatrilat provides
antihypertensive effect not achievedwith current
drugs
27Safety
28Omapatrilat Safety Database
- Overall
- 34,780 hypertensive patients
- 18,723 exposed to omapatrilat
- Patients exposed by omapatrilat dose
- 10 mg 15,058
- 20 mg 16,655
- Patients exposed to omapatrilat by duration
- gt 3 months 12,995
- gt 1 year 1,478
- Heart Failure (OVERTURE)
40 mg 11,317 80 mg 6,922
29Safety Summary
- Safety well-characterized through
extensiveprogram - Overall incidence of AE, SAE, D/C due to AE
comparable for omapatrilat and ACE-I - Angioedema 3 times more common withomapatrilat
30Angioedema Clinical Overview
Allen Kaplan, M.D.Medical University of South
CarolinaCharleston, SC
FDA Cardiovascular and Renal DrugsAdvisory
Committee Meeting July 19, 2002
31Angioedema Background Information
- Localized edema in a variety of anatomical sites
- Superficial (e.g., eyelids, lips, face)
- Oropharyngeal (e.g., tongue, pharynx)
- Lower airway (e.g., larynx)
- Other (e.g., hands)
- Most common etiologies are inherited and
drug-induced - Bradykinin is the mediator of inherited and
ACE-Iinduced angioedema - ACE-I are the most common cause of
drug-inducedangioedema - Anaphylaxis and angioedema are differentclinical
syndromes
32Angioedema Clinical Information
- Generally develops over several hours but may
progress over 1-2 hours in severe cases - Patients are aware of the swelling of angioedema
- In contrast to antihistamines, treatmentwith
epinephrine can halt furtherprogression of
episode - Laryngeal edema without other symptoms is very
rare
33Anaphylaxis Compared with Angioedema
Drug-Induced or Inherited Angioedema
Anaphylaxis
- Time Course
- Symptoms
- MediatorsTreatment
Rapid evolution typically occursover several
minutes afterantigen exposure Mucocutaneous -
swelling, erythema, urticaria Cardiovascular -
hypotension, shock Respiratory - laryngeal edema,
bronchial constriction Multiple inflammatory
mediators including histamine Epinephrine,
steroids,anti-histamine
Evolves over hours Mucocutaneous - localized
edema of face, oropharynx Cardiovascular -
none Respiratory - laryngeal edema Bradykinin
Epinephrine observation
34Safety of Omapatrilat
35Angioedema with OmapatrilatFindings Prior to
OCTAVE
- Angioedema reported as adverse event
- Precise incidence of angioedema difficultto
determine - ICD-9 based coding system assignedpotential
angioedema events to severalterms (angioedema,
head/neck edema) - AE reports generally did not providesufficient
detail to further assess cases
36Frequency of Angioedema andHead and Neck Edema
with Omapatrilat(Prior to OCTAVE)
Adverse Event
lt 20 mg (N 1544)
? 20 mg (N 2740)
Total (N 4284)
Angioedema,n ()
7 (0.45)
37 (1.35)
44 (1.03)
Head and Neck Edema,n ()
11 (0.71)
29 (1.06)
40 (0.93)
Airway Compromise,n ()
0 (0)
4 (0.15)
4 (0.09)
Randomized controlled HTN studies
37Description of Airway Compromise Cases (Prior to
OCTAVE)
Patient 4
(CV137-042094-009)
Race
White
Black
Black
White
Current Smoker
Yes
No
Yes
No
ClinicalPresentation
Initial dose (20 mg)2 hours post
doseexperienced flushing, swelling of face,
tongue and lips. Presented to ER and following
many interventions, developed stridor and
desatrurated.
11 days sincerandomization(20 mg) 2-3
hourspost doseexperienced facialand
glosso-pharyngeal edemaand difficultybreathing
6 days sincerandomization(20 mg)
hospitalizedfor LOC with head injury. While
underobservation developed subsequent glottis
and laryngeal edema,tongue swelling
anddifficulty speaking.
Within 1 hour offirst dose (20 mg)
experiencedswelling of lips, throat, and
dyspnea. Evaluated in ER, treated and released.
Presented to ER 3 hr later with difficulty
breathing.
Treatment
Epi, steroids,diphenhydramine,lidocaine,tracheo
stomy
Epi, steroids,diphenhydramine,diltiazem,
intubation
Epi, steroids,diphenhydramine,albuterol
nebulizer tx, intubated
Steroids, Amoxicillincricothyrotomy
withsubsequenttracheostomy
4 patients required airway protection in
previous NDA submission
38OCTAVE Assessment of Angioedema
- Compare incidence of angioedema withomapatrilat
(10-80 mg) and enalapril (5-40 mg) - Incidence of angioedema with a starting doseof
10 mg vs. 20 mg omapatrilat was not tested - Special process created for evaluationof
angioedema - Active collection of all potential events
- Detailed follow-up information collectedon
structured questionnaire - Potential angioedema cases adjudicatedby expert
committee without knowledgeof treatment
assignment
39OCTAVE Incidence of Angioedema
Omapatrilat
Enalapril
(N 12,609)
(N 12,557)
Patients with
274 (2.17)
86 (0.68)
Angioedema, n ()
Risk Ratio (95 CI)
3.17 (2.52, 4.12)
40OCTAVE Pre-specified Severity Scale
Severity
I
No treatment administered or antihistaminesonly
Treated with catecholamines or steroids
II
Hospitalized but no mechanical airwayprotection
III
IIIa No airway compromise
IIIb With airway compromise
IV
Mechanical airway protection or death fromairway
compromise
41OCTAVE Pre-specified Severity Scale
Number () of Patients
Severity
Omapatrilat
Enalapril
(N 12,609)
(N 12,557)
I
No treatment administered or antihistaminesonly
161 (1.28)
65 (0.52)
Treated with catecholamines or steroids
94 (0.75)
19 (0.15)
II
Hospitalized but no mechanical airwayprotection
18 (0.14)
2 (0.02)
III
IIIa No airway compromise
17
2
IIIb With airway compromise
1
0
IV
Mechanical airway protection or death fromairway
compromise
1 (0.01)
0 (0.00)
274 (2.17)
Total
86 (0.68)
No deaths occurred from angioedema
42Risk of Angioedema withAirway Compromise
N
Number ofevents ()
Rate of Angioedema Events with Airway Compromise
per 10,000 treated (95 CI)
Treatment
Duration (weeks)
12,557
OCTAVE
0
0 (0.0, 2.9)
Enalapril
24
12,609
OCTAVE
2
1.6 (0.2, 5.7)
Omapatrilat
24
18,723
Combined OCTAVE/Pre-OCTAVE Studies
6
3.2 (1.2, 7.0)
Omapatrilat
8 - 24
43OCTAVE Angioedema with Airway Compromise
Did Not Require Airway Protection (n 1)
Required Airway Protection (n 1)
Race
White
Black
Current Smoker
Yes
No
ClinicalPresentation
- Edema of the
- Eyelid(s)
- Lip(s)
- Neck
- Difficulty speaking
- Difficulty swallowing
- Dyspnea
- Hoarseness
- Hypotensive
- Cyanotic
- Edema of the
- Eyelid(s)
- Face
- Lip(s)
- Mucous Membranes
- Neck
- Pharynx
- Tongue
- Difficulty speaking
- Difficulty swallowing
Treatment
Epinephrine
Epinephrine, Steroids, Tracheostomy
44Angioedema Hospitalizations withoutAirway
Compromise
Omapatrilat (n 17)
Enalapril (n 2)
Airway compromise
None
None
Signs/Symptoms
8 tongue swelling
1 tongue swelling
9 lip swelling
2 lip swelling
Other Indicationsfor observation
7 late hour
1 comorbid conditions
3 social factors
2 comorbid conditions
Progression inHospital
None
None
Treatment
Epi (5) / steroids (16)
Epi (1) / steroids (2)
Time to Discharge
14 next day
1 next day
3 after 2 days
1 after 6 days
45Patient Response to Symptomsof Angioedema
OCTAVE Class II-IV Patients
- Most (80.5) angioedema events occurred outside
the physicians office - Most (63.7) patients with angioedema occurring
outside of physicians officepresented to
medical facilities more than one hour after onset
of symptoms - Many (28.6) patients presented to medical
facilities more than 6 hours after onset of
symptoms
46Patients Abilityto Recognize Angioedema
- Patients with airway compromise were highly
symptomatic with a constellation of symptoms - Patients without airway compromise alsohad
clinically overt presentation with visible
swelling /- functional complaints - No patients with angioedema had non-specific
lower airway complaints (stridor, dyspnea,
hoarseness) alone
47OCTAVE Incidence of Angioedema by Time Period
OCTAVE (CV137-120)
48OCTAVE Summary of Angioedema Riskwith
Omapatrilat in Subgroups
Subgroup
Relative Risk
Incidence
Black race Current smoker Renal
disease Seasonal allergies Female gender Former
smoker Age ? 65 years ACE-I use Diabetes Atheros
clerotic disease
72 (5.5) 89 (3.9) 11 (3.6) 55
(3.3) 153 (2.5) 78 (2.1) 70 (2.0) 90
(2.0) 23 (1.3) 14 (1.2)
Decreased Risk
Increased Risk
(vs. those without characteristics)
Multivariate logistic regression model with
angioedema as the dependent variable and all
other listed variables as independent
variables. vs those who never smoked.
49Angioedema Safety Summary
- Incremental risk of angioedema relative to ACE-I
treatment - Angioedema has wide spectrum of severity
- Current smokers and black patients have a higher
incidence of angioedema - Life-threatening in 1.6/10,000 (95 CI 0.2-5.7)
- Symptomatic event with characteristic
presentation - Onset rapid but not fulminant
- Effective treatment exists for angioedema
50Risk Management
- Angioedema has clinical features which
facilitateits management through patient
education - Symptomatic, recognizable clinical presentation
- Rapid but not fulminant progression
- Effective therapy exists which can preventpoor
outcomes
51Risk Management
- Labeling and packaging
- Indication, warning, risk factors, etc.
- Unit of use packaging
- Comprehensive educational program
- Includes mandatory patient counseling
- Multiple points of contact (physicians,patients,
pharmacists) - Post-marketing surveillance
- Includes prospective observational cohort study
- Ongoing assessment of program effectiveness
- Expert panel
52Projected Reduction in CV Events Per annum per
10,000 Treated
Projected Reduction in CV Events
BPReduction3/2 mmHg
BPReduction5/3 mmHg
Projected CV Events
CV Risk Category
Observed incidence of angioedema with airway
compromise over 24 weeks in OCTAVE 1.6 (95 CI
0.2 -- 5.7) per 10,000