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Omapatrilat in the TreatmentOmapatrilat in the Treatmentof Hypertensionof Hypertension
Efficacy and SafetyEfficacy and Safety
NDA 21-188
FDA Cardiovascular and Renal DrugsFDA Cardiovascular and Renal DrugsAdvisory Committee MeetingAdvisory Committee MeetingJuly 19, 2002July 19, 2002
Elliott Levy, M.D.Vice President, Clinical Design and EvaluationPharmaceutical Research Institute
EfficacyEfficacy
7/19-37/19-3
Omapatrilat Target PopulationOmapatrilat Target Population
Patients with:Patients with:
A high risk of major cardiovascular events*A high risk of major cardiovascular events*
– Cardiovascular disease (e.g., MI, CHF)Cardiovascular disease (e.g., MI, CHF)
– Target organ damage (e.g., LVH, proteinuria)Target organ damage (e.g., LVH, proteinuria)
– 3 or more cardiovascular risk factors 3 or more cardiovascular risk factors
– Diabetes or renal diseaseDiabetes or renal disease andand
Hypertension that is difficult to controlHypertension that is difficult to controlwith existing medicationswith existing medications
*Based on WHO-ISH guidelines
Use with special caution in black patientsUse with special caution in black patientsand current smokersand current smokers
7/19-47/19-4
Order of PresentationOrder of Presentation
In 4 placebo-controlled trials (2369 patients), doseIn 4 placebo-controlled trials (2369 patients), doserelated reduction demonstrated in systolic and diastolic related reduction demonstrated in systolic and diastolic blood pressureblood pressure
In 6 active-controlled trials (2742 patients), omapatrilatIn 6 active-controlled trials (2742 patients), omapatrilat80 mg shown to be more effective monotherapy than 80 mg shown to be more effective monotherapy than lisinopril 40 mg, amlodipine 10 mg, losartan 100 mglisinopril 40 mg, amlodipine 10 mg, losartan 100 mg
In OCTAVE (25,302 patients), omapatrilat-based regimen In OCTAVE (25,302 patients), omapatrilat-based regimen consistently more effective than enalapril-based regimenconsistently more effective than enalapril-based regimen
Greater BP reduction preserved in patients with Greater BP reduction preserved in patients with comorbidity and difficult to control hypertensioncomorbidity and difficult to control hypertension
7/19-57/19-5
Dose-Related Mean ReductionDose-Related Mean Reductionfrom Baseline in Trough Blood Pressurefrom Baseline in Trough Blood Pressure
Weeks 6-9CV137-006, -022, -024 and -045
-20
-15
-10
-5
0
Pbo 10 mg 20 mg 40 mg 80 mg Pbo 10 mg 20 mg 40 mg 80 mgPbo 10 mg 20 mg 40 mg 80 mg Pbo 10 mg 20 mg 40 mg 80 mg
Ch
ang
e in
BP
(m
mH
g)
Ch
ang
e in
BP
(m
mH
g)
SystolicSystolic
-3.4
-11.4
-13.2
-17.0
-19.1
-4.4
-8.4
-10.2-11.8
-14.1
DiastolicDiastolic
7/19-67/19-6 * p 0.05 vs. comparator ** p 0.001 vs. comparator
Changes in Trough Systolic BP versus Active Changes in Trough Systolic BP versus Active Comparators at Maximal Recommended DoseComparators at Maximal Recommended Dose
-20.8
-14.2
-20.9
-17.7
-9.0
-13.7
-30
-25
-20
-15
-10
-5
0
CV137-030(n = 492)
CV137-037(n = 437)
SB
P C
han
ge
(mm
Hg
)
CV137-077(n = 203)
-3.1*-3.1*
-5.2**-5.2**
-7.2**-7.2**
Week 10
oma80 mg
aml10 mg
oma80 mg
lis40 mg
oma80 mg
los100 mg
7/19-77/19-7** p 0.001 vs. comparator
Changes in 24-Hour Average AmbulatoryChanges in 24-Hour Average AmbulatorySystolic BP versus Active ComparatorsSystolic BP versus Active Comparators
at Maximal Recommended Dosesat Maximal Recommended Doses
-20.4-19.0 -18.9
-14.5-12.2
-13.5
-10.0
-30
-25
-20
-15
-10
-5
0
CV137-032CV137-032(n = 379)(n = 379)
CV137-031CV137-031(n = 317)(n = 317)
AS
BP
Ch
ang
e (m
mH
g)
CV137-066CV137-066(n = 673)(n = 673)
-5.9**-5.9** -6.8**-6.8** -5.4**-5.4**
Week 10
-8.9**-8.9**
oma80 mg
aml10 mg
oma80 mg
lis40 mg
oma80 mg
aml10 mg
los100mg
7/19-87/19-8
Effects of Omapatrilat and Amlodipine on Effects of Omapatrilat and Amlodipine on Ambulatory Systolic Blood Pressure, by HourAmbulatory Systolic Blood Pressure, by Hour
AS
BP
(m
mH
g)
Hour Post-Dose
2 4 6 8 10 12 14 16 18 20 22 24110
120
130
140
150
160Difference in 24-hourAverage ASBP = -5.9**
CV137-032
** p 0.001 vs. Amlodipine
Omapatrilat (n = 192)Amlodipine (n = 187)
Omapatrilat 80 mgAmlodipine 10 mg
Baseline Week 10
7/19-97/19-9
OCTAVE: RationaleOCTAVE: Rationale
In 6 active controlled monotherapy trials, In 6 active controlled monotherapy trials, omapatrilat 80 mg reduced blood pressureomapatrilat 80 mg reduced blood pressureto a greater extent than maximal doses of to a greater extent than maximal doses of amlodipine, losartan and lisinoprilamlodipine, losartan and lisinopril
OCTAVE was designed to evaluate whetherOCTAVE was designed to evaluate whetheromapatrilat would be superior to another agent omapatrilat would be superior to another agent (enalapril) in clinical use conditions, where (enalapril) in clinical use conditions, where therapy is titrated electively and supplementedtherapy is titrated electively and supplementedby other agents to reach BP targetby other agents to reach BP target
OCTAVE was large enough to characterize OCTAVE was large enough to characterize efficacy and safety in important subgroupsefficacy and safety in important subgroups
7/19-107/19-10
OCTAVE: Study DesignOCTAVE: Study Design
10 mg10 mg
5 mg5 mg
SBP SBP 140 140 or or DBP DBP 90 90
22 44 66 88 1616 2424
2020
1010
4040
2020
8080
4040 + Adjunctive Rx+ Adjunctive Rx
+ Adjunctive Rx+ Adjunctive Rx
Week:Week:
OmapatrilatOmapatrilat
EnalaprilEnalapril
Titration to TargetTitration to Target Adjunctive Rx to TargetAdjunctive Rx to Target
Target BP: 140/90 mmHg
*
*Forced Titration
7/19-117/19-11
JNC VI Stage I-IIIJNC VI Stage I-IIIUntreatedUntreated
JNC VI Stage IJNC VI Stage IDespite Treatment Despite Treatment
ReplacementReplacement(Group 2)(Group 2)
Add-onAdd-on(Group 3)(Group 3)
InitialInitial(Group 1)(Group 1)
RR
n = 9,292n = 9,292 n = 11,224n = 11,224 n = 4,751n = 4,751
EnaEnaOmaOma EnaEnaOmaOma EnaEnaOmaOma
OCTAVE: Study GroupsOCTAVE: Study Groups
RR RR
JNC VI Stage IIJNC VI Stage IIDespite Treatment Despite Treatment
Baseline BPBaseline BP(mmHg)(mmHg) 156 / 96 150 / 91 166 / 97
7/19-127/19-12
OCTAVE: Study EndpointsOCTAVE: Study Endpoints
Efficacy (Co-Primary)Efficacy (Co-Primary) Change in systolic blood pressure from Change in systolic blood pressure from
baseline to Week 8, by study groupbaseline to Week 8, by study group
Use of new adjunctive antihypertensive Use of new adjunctive antihypertensive therapy between Weeks 8 and 24,therapy between Weeks 8 and 24,by study groupby study group
SafetySafety Incidence of adverse eventsIncidence of adverse events
Incidence and severity of angioedemaIncidence and severity of angioedema
7/19-137/19-13
OCTAVE: Efficacy Results at Week 8OCTAVE: Efficacy Results at Week 8
% o
f P
atie
nts
% o
f P
atie
nts
Change in Systolic BPChange in Systolic BPTitration to Top DoseTitration to Top Dose
(Oma 80 mg, Ena 40 mg)(Oma 80 mg, Ena 40 mg)
-21.5
-11.4
-23.2
-18.3-19.6
-7.6
-30
-25
-20
-15
-10
-5
0
44
35
25
33
52
44
0
10
20
30
40
50
60
Omapatrilat Enalapril
InitialInitialGroup 1Group 1
ReplacementReplacementGroup 2Group 2
Add-onAdd-onGroup 3Group 3
-3.2**-3.2**
-3.8**-3.8**
-3.6**-3.6**
InitialInitialGroup 1Group 1
ReplacementReplacementGroup 2Group 2
Add-onAdd-onGroup 3Group 3
SB
P C
han
ge
(mm
Hg
)
** p** p 0.001 vs enalapril0.001 vs enalapril
****
****
****
7/19-147/19-14
OCTAVE: Efficacy Results at Week 24OCTAVE: Efficacy Results at Week 24
Change in Systolic BPChange in Systolic BPUse of NewUse of New
Adjunctive TherapyAdjunctive Therapy
-23.6
-14.0
-25.6
-20.5-22.8
-10.9
-30
-25
-20
-15
-10
-5
0
17
25
13
1922
35
0
5
10
15
20
25
30
35
40
45
50
InitialInitialGroup 1Group 1
ReplacementReplacementGroup 2Group 2
Add-onAdd-onGroup 3Group 3
-3.1**-3.1**
-3.1**-3.1**
-2.8**-2.8**
InitialInitialGroup 1Group 1
ReplacementReplacementGroup 2Group 2
Add-onAdd-onGroup 3Group 3
SB
P C
han
ge
(mm
Hg
)
** p** p 0.001 vs enalapril0.001 vs enalapril
**
**
**% o
f P
atie
nts
% o
f P
atie
nts
Omapatrilat Enalapril
7/19-157/19-15
Demographic Subgroups:Demographic Subgroups:Change in Systolic BP at Week 24Change in Systolic BP at Week 24
Adjusted SBP Changeat Week 24 (mmHg)
Omapatrilat EnalaprilDifference(oma / ena)
Age, n (%)
65 years (n = 17,569)
65 years (n = 6887)
75 years (n = 2026)
-20.0
-19.0
-18.9
-16.9
-16.1
-15.7
-3.1
-2.9
-3.2
Gender, n (%)
Male (n = 12,717)
Female (n = 11,739)
-19.1
-20.4
-16.2
-17.2
-2.9
-3.2
Race, n (%)
White (n = 21,651)
Black (n = 2420)
-20.3
-14.5
-17.3
-10.9
-3.0
-3.6
OCTAVE (CV137-120)
7/19-167/19-16
Subgroups at Increased CV Risk:Subgroups at Increased CV Risk:Change in Systolic BP at Week 24Change in Systolic BP at Week 24
Adjusted SBP Changeat Week 24 (mmHg)
Omapatrilat EnalaprilDifference(oma / ena)
-18.7-36.6
Severe Hypertension (n = 7197) Group 1 (n = 983)
-2.7-4.6
-17.6Diabetes Mellitus (n = 3275) -4.2
-20.7Atherosclerotic Disease* (n = 2283) -2.7
-22.2 ISH (n = 1332) -4.5
-17.0Renal Disease (n = 582) -3.6
-20.9Heart Failure (n = 233) -4.5
-15.9 -32.0
-13.4
-18.0
-17.7
-13.4
-16.4
*Includes chronic stable angina, unstable angina, myocardial infarction, and stroke / TIA OCTAVE (CV137-120)
7/19-177/19-17
OCTAVE ConclusionOCTAVE Conclusion
Greater BP reduction with omapatrilat-based Greater BP reduction with omapatrilat-based regimen, despite more frequent use of maximal regimen, despite more frequent use of maximal doses and adjunctive therapy with enalaprildoses and adjunctive therapy with enalapril
Highly consistent results regardless of patient Highly consistent results regardless of patient subgroup or manner of use of study drugsubgroup or manner of use of study drug
Greater BP reduction observed at week 8Greater BP reduction observed at week 8and preserved over 24 weeks, despite useand preserved over 24 weeks, despite useof adjunctive therapyof adjunctive therapy
7/19-187/19-18
Role of Omapatrilat in Role of Omapatrilat in Difficult to Control HypertensionDifficult to Control Hypertension
In many patients, hypertension can be readily In many patients, hypertension can be readily controlled with existing therapycontrolled with existing therapy
OCTAVE and other large clinical trials demonstrate OCTAVE and other large clinical trials demonstrate that hypertension is difficult to control in many that hypertension is difficult to control in many patients patients
In patients not readily controlled with existing In patients not readily controlled with existing therapies, an omapatrilat-based regimen provides therapies, an omapatrilat-based regimen provides lasting efficacy advantagelasting efficacy advantage
7/19-197/19-19
Efficacy at Week 24 in SubgroupsEfficacy at Week 24 in SubgroupsDefined by Baseline JNC-VI StageDefined by Baseline JNC-VI Stage
Omapatrilat Enalapril
SB
P C
han
ge
(mm
Hg
)
-18.0
-26.2
-36.6
-15.4
-32.0
-23.2
-40
-35
-30
-25
-20
-15
-10
-5
0
-2.6**-2.6**
-3.0**-3.0**
-4.6**-4.6**
Stage IStage I(n = 4160)(n = 4160)
147147
Stage IIStage II(n = 3864)(n = 3864)
160160
Stage IIIStage III(n = 983)(n = 983)
178178
% o
f P
atie
nts
6
14
32
11
46
22
0
10
20
30
40
50
Stage IStage I Stage IIStage II Stage IIIStage III
Use of New Adjunctive Use of New Adjunctive Antihypertensive TherapyAntihypertensive Therapy
JNC-VIJNC-VI
Change in Systolic BP – JNC-VIChange in Systolic BP – JNC-VI
Baseline SBP Baseline SBP (mmHg)(mmHg)
** p** p 0.001 vs enalapril0.001 vs enalapril
OCTAVE (CV137-120)OCTAVE (CV137-120)Group 1Group 1
**
**
**
7/19-207/19-20
Control of BP (Control of BP (140/90 mmHg) in Multi-Drug Resistant 140/90 mmHg) in Multi-Drug Resistant Patients in Group 3 at Week 24Patients in Group 3 at Week 24
4442
35
28
0
10
20
30
40
50
60
% C
on
tro
lled
Omapatrilat
Enalapril
2 or More 2 or More Baseline Baseline
MedsMeds(n = 2309)(n = 2309)
OCTAVE (CV137-120)
3 or More 3 or More Baseline Baseline
MedsMeds(n = 703)(n = 703)
7/19-217/19-21
Difficult to Control Hypertension: Patients Difficult to Control Hypertension: Patients Uncontrolled with ACE-Inhibitor RegimenUncontrolled with ACE-Inhibitor Regimen
Maximal ACE-I Maximal ACE-I (alone or as (alone or as part of regimen)part of regimen)
SBP SBP 140 or 140 or DBP DBP 90 90
TitrationTitration2-4 Weeks2-4 Weeks
MaintenanceMaintenance4 Weeks4 Weeks
Enrollment / Lead-InEnrollment / Lead-In2+ weeks2+ weeks
RandomizationRandomizationD/C ACE-ID/C ACE-IContinue other antihypertensives (if any) at established doseContinue other antihypertensives (if any) at established dose
CV137-073
OmapatrilatOmapatrilat 20 40 8020 40 80
LisinoprilLisinopril 20 20 4020 20 40
7/19-227/19-22
AS
BP
(m
mH
g)
Hour Post-Dose
Changes in Ambulatory Systolic BP in Subjects Changes in Ambulatory Systolic BP in Subjects Uncontrolled with ACE-Inhibitor RegimenUncontrolled with ACE-Inhibitor Regimen
Week 4 Maintenance* *p 0.001 vs. lisinopril
110
115
120
125
130
135
140
145
150
155
160
1 3 5 7 9 11 13 15 17 19 21 23
Average ambulatory difference from Lisinopril = -8.8**Trough difference from Lisinopril = -7.0**
Omapatrilat 80 mg (n = 124)
Lisinopril 40 mg (n = 122)
CV137-073
7/19-237/19-23CV137-073
-10.7 -10.9
-3.1
0.6
-12
-10
-8
-6
-4
-2
0
2
AS
BP
Ch
ang
e (m
mH
g)
ACE-I Monotherapy
(n = 171)
ACE-ICombination
(n = 75)
Change in 24-Hour Average AmbulatoryChange in 24-Hour Average AmbulatorySystolic BP in Patients UncontrolledSystolic BP in Patients Uncontrolled
with ACE-Inhibitor Regimens at Baselinewith ACE-Inhibitor Regimens at Baseline
Omapatrilat 80 mg Lisinopril 40 mg
-7.6** -11.5**
Week 4 Maintenance* *p 0.001 vs. lisinopril
7/19-247/19-24
-15.4
-10.8-9.6
-11.9
-7.8
-3.7
-30
-25
-20
-15
-10
-5
0
ACE-I Monotherapy
(n = 2278)
ACE-I + 1Antihypertensive
Med (n = 1368)
SB
P C
han
ge
(mm
Hg
)
OmapatrilatEnalapril
Efficacy at Week 24: OCTAVE Patients Not at Efficacy at Week 24: OCTAVE Patients Not at Target with ACE-Inhibitor Regimens at BaselineTarget with ACE-Inhibitor Regimens at Baseline
ACE-I + 2 or More Antihypertensive
Meds (n = 546)
-3.5**-3.5**
-3.0**-3.0**-5.9**-5.9**
Group 2** p 0.001 vs. enalapril
7/19-257/19-25
-14.4-11.8
-9.3
-5.0
-9.7
-0.8
-30
-25
-20
-15
-10
-5
0
ACE-IMonotherapy
(n = 466)
ACE-I + 1 Antihypertensive
Med (n = 322)
SB
P C
han
ge
(mm
Hg
)
ACE-I + 2 or More Antihypertensive
Meds (n = 169)
Efficacy at Week 24: OCTAVE Patients withEfficacy at Week 24: OCTAVE Patients withDiabetesDiabetes Not at Target with ACE-Inhibitor Not at Target with ACE-Inhibitor
Regimens at BaselineRegimens at Baseline
-4.8**-4.8**-6.9**-6.9**
-8.5*-8.5*
OmapatrilatEnalapril
* p 0.05** p 0.001 vs. enalapril
Group 2
7/19-267/19-26
Efficacy ConclusionsEfficacy Conclusions
Greater antihypertensive efficacy with Greater antihypertensive efficacy with regimen based on omapatrilatregimen based on omapatrilat
Greater efficacy apparent across patient Greater efficacy apparent across patient subgroups and continued over timesubgroups and continued over time
Greater efficacy maintained even when Greater efficacy maintained even when physicians encouraged to add adjunctphysicians encouraged to add adjunctto achieve BP goalto achieve BP goal
In patients with difficult to control In patients with difficult to control hypertension, omapatrilat provides hypertension, omapatrilat provides antihypertensive effect not achievedantihypertensive effect not achievedwith current drugswith current drugs
SafetySafety
7/19-287/19-28
Omapatrilat Safety DatabaseOmapatrilat Safety Database
Overall:Overall:
– 34,780 hypertensive patients34,780 hypertensive patients
– 18,723 exposed to omapatrilat 18,723 exposed to omapatrilat
Patients exposed by omapatrilat dose: Patients exposed by omapatrilat dose:
10 mg = 15,058 10 mg = 15,058
20 mg = 16,655 20 mg = 16,655
Patients exposed to omapatrilat by duration:Patients exposed to omapatrilat by duration:
3 months = 12,9953 months = 12,995
1 year = 1,4781 year = 1,478
Heart Failure (OVERTURE)Heart Failure (OVERTURE)
40 mg = 11,317 40 mg = 11,317
80 mg = 6,92280 mg = 6,922
7/19-297/19-29
Safety SummarySafety Summary
Safety well-characterized through extensiveSafety well-characterized through extensiveprogramprogram
Overall incidence of AE, SAE, D/C due to AE Overall incidence of AE, SAE, D/C due to AE comparable for omapatrilat and ACE-Icomparable for omapatrilat and ACE-I
Angioedema 3 times more common withAngioedema 3 times more common withomapatrilatomapatrilat
Angioedema: Clinical OverviewAngioedema: Clinical Overview
FDA Cardiovascular and Renal DrugsFDA Cardiovascular and Renal DrugsAdvisory Committee MeetingAdvisory Committee MeetingJuly 19, 2002July 19, 2002
Allen Kaplan, M.D.Medical University of South Carolina
Charleston, SC
7/19-317/19-31
Localized edema in a variety of anatomical sitesLocalized edema in a variety of anatomical sites
– Superficial (e.g., eyelids, lips, face)Superficial (e.g., eyelids, lips, face)
– Oropharyngeal (e.g., tongue, pharynx)Oropharyngeal (e.g., tongue, pharynx)
– Lower airway (e.g., larynx)Lower airway (e.g., larynx)
– Other (e.g., hands)Other (e.g., hands)
Most common etiologies are inherited and drug-inducedMost common etiologies are inherited and drug-induced
Bradykinin is the mediator of inherited and ACE-IBradykinin is the mediator of inherited and ACE-Iinduced angioedemainduced angioedema
ACE-I are the most common cause of drug-inducedACE-I are the most common cause of drug-inducedangioedemaangioedema
Anaphylaxis and angioedema are differentAnaphylaxis and angioedema are differentclinical syndromesclinical syndromes
Angioedema: Background InformationAngioedema: Background Information
7/19-327/19-32
Angioedema: Clinical InformationAngioedema: Clinical Information
Generally develops over several hours but may Generally develops over several hours but may progress over 1-2 hours in severe casesprogress over 1-2 hours in severe cases
Patients are aware of the swelling of angioedemaPatients are aware of the swelling of angioedema
In contrast to antihistamines, treatmentIn contrast to antihistamines, treatmentwith epinephrine can halt furtherwith epinephrine can halt furtherprogression of episodeprogression of episode
Laryngeal edema without other symptoms Laryngeal edema without other symptoms is very rareis very rare
7/19-337/19-33
Anaphylaxis Compared with AngioedemaAnaphylaxis Compared with Angioedema
Time CourseTime Course
SymptomsSymptoms
MediatorsMediators
TreatmentTreatment
Rapid evolution; typically occursRapid evolution; typically occursover several minutes afterover several minutes afterantigen exposureantigen exposure
Mucocutaneous - swelling, Mucocutaneous - swelling, erythema, urticariaerythema, urticaria
Cardiovascular - hypotension, Cardiovascular - hypotension, shockshock
Respiratory - laryngeal edema, Respiratory - laryngeal edema, bronchial constrictionbronchial constriction
Multiple inflammatory mediators Multiple inflammatory mediators including histamineincluding histamine
Epinephrine, steroids,Epinephrine, steroids,anti-histamineanti-histamine
Evolves over hoursEvolves over hours
Mucocutaneous - localized Mucocutaneous - localized edema of face, oropharynxedema of face, oropharynx
Cardiovascular - noneCardiovascular - none
Respiratory - laryngeal Respiratory - laryngeal edemaedema
BradykininBradykinin
Epinephrine; observationEpinephrine; observation
Drug-Induced or Inherited AngioedemaAnaphylaxis
Safety of OmapatrilatSafety of Omapatrilat
7/19-357/19-35
Angioedema reported as adverse eventAngioedema reported as adverse event
Precise incidence of angioedema difficultPrecise incidence of angioedema difficultto determineto determine
– ICD-9 based coding system assignedICD-9 based coding system assignedpotential angioedema events to severalpotential angioedema events to severalterms (angioedema, head/neck edema)terms (angioedema, head/neck edema)
– AE reports generally did not provideAE reports generally did not providesufficient detail to further assess casessufficient detail to further assess cases
Angioedema with Omapatrilat:Angioedema with Omapatrilat:Findings Prior to OCTAVEFindings Prior to OCTAVE
7/19-367/19-36
Adverse Event
Frequency of Angioedema andFrequency of Angioedema andHead and Neck Edema with OmapatrilatHead and Neck Edema with Omapatrilat
(Prior to OCTAVE*)(Prior to OCTAVE*)
Head and Neck Edema,n (%)
Airway Compromise,n (%)
Angioedema,n (%)
20 mg(N = 1544)
20 mg(N = 2740)
11 (0.71) 29 (1.06)
0 (0) 4 (0.15)
7 (0.45) 37 (1.35)
Total(N = 4284)
40 (0.93)
4 (0.09)
44 (1.03)
*Randomized controlled HTN studies
7/19-377/19-37
Description of Airway Compromise Cases Description of Airway Compromise Cases (Prior to OCTAVE)(Prior to OCTAVE)
4 patients required airway protection in previous NDA submission
Patient 1(CV137-024;020-001)
Patient 2(CV137-037;034-029)
Patient 3(CV137-037;089-017)
Race White Black Black
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
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,tracheostomy
Epi, steroids,diphenhydramine,diltiazem, intubation
Epi, steroids,diphenhydramine,albuterol nebulizer tx, intubated
CurrentSmoker
Yes No Yes
Patient 4(CV137-042;094-009)
White
6 days sincerandomization(20 mg) hospitalizedfor LOC with head injury. While underobservation developed subsequent glottis and laryngeal edema,tongue swelling anddifficulty speaking.
Steroids, Amoxicillincricothyrotomy withsubsequenttracheostomy
No
7/19-387/19-38
OCTAVE: Assessment of AngioedemaOCTAVE: Assessment of Angioedema
Compare incidence of angioedema withCompare incidence of angioedema withomapatrilat (10-80 mg) and enalapril (5-40 mg)omapatrilat (10-80 mg) and enalapril (5-40 mg)
Incidence of angioedema with a starting doseIncidence of angioedema with a starting doseof 10 mg vs. 20 mg omapatrilat was not testedof 10 mg vs. 20 mg omapatrilat was not tested
Special process created for evaluationSpecial process created for evaluationof angioedemaof angioedema
– Active collection of all potential eventsActive collection of all potential events
– Detailed follow-up information collectedDetailed follow-up information collectedon structured questionnaireon structured questionnaire
– Potential angioedema cases adjudicatedPotential angioedema cases adjudicatedby expert committee without knowledgeby expert committee without knowledgeof treatment assignmentof treatment assignment
7/19-397/19-39
OCTAVE: Incidence of AngioedemaOCTAVE: Incidence of Angioedema
Omapatrilat (N = 12,609)
Enalapril (N = 12,557)
Patients withAngioedema, n (%)
274 (2.17%) 86 (0.68%)
Risk Ratio (95% CI) 3.17 (2.52, 4.12)
7/19-407/19-40
OCTAVE: Pre-specified Severity ScaleOCTAVE: Pre-specified Severity Scale
Severity
I No treatment administered or antihistaminesonly
Treated with catecholamines or steroids
Hospitalized but no mechanical airwayprotection
IIIa No airway compromise
IIIb With airway compromise
IV Mechanical airway protection or death fromairway compromise*
III
II
7/19-417/19-41
OCTAVE: Pre-specified Severity ScaleOCTAVE: Pre-specified Severity Scale
Number (%) of Patients
Severity Omapatrilat(N = 12,609)
Enalapril(N = 12,557)
I No treatment administered or antihistaminesonly
Treated with catecholamines or steroids
Hospitalized but no mechanical airwayprotection
IIIa No airway compromise
IIIb With airway compromise
IV Mechanical airway protection or death fromairway compromise*
161 (1.28%)
94 (0.75%)
18 (0.14%)
17
1
1 (0.01%)
65 (0.52%)
19 (0.15%)
2 (0.02%)
2
0
0 (0.00%)
274 (2.17%)
* No deaths occurred from angioedema
Total 86 (0.68%)
III
II
7/19-427/19-42
Risk of Angioedema withRisk of Angioedema withAirway CompromiseAirway Compromise
N
Number of
events (%)
Rate of AngioedemaEvents with Airway
Compromise per 10,000 treated
(95% CI)Treatment
12,557OCTAVE 0 0 (0.0, 2.9)Enalapril
12,609OCTAVE 2 1.6 (0.2, 5.7)Omapatrilat
Duration(weeks)
24
24
18,723Combined OCTAVE/Pre-OCTAVE Studies
6 3.2 (1.2, 7.0)Omapatrilat8 - 24
7/19-437/19-43
OCTAVE: Angioedema with Airway CompromiseOCTAVE: Angioedema with Airway Compromise
Did Not Require Did Not Require Airway Protection Airway Protection
(n = 1)(n = 1)
Race
ClinicalPresentation
Treatment
White Black
RequiredRequired Airway Protection Airway Protection
(n = 1)(n = 1)
Current Smoker Yes No
• Edema of the – Eyelid(s)– Lip(s)– Neck
• Difficulty speaking• Difficulty swallowing• Dyspnea• Hoarseness• Hypotensive• Cyanotic
Epinephrine
• Edema of the – Eyelid(s)– Face– Lip(s)– Mucous Membranes– Neck– Pharynx– Tongue
• Difficulty speaking• Difficulty swallowing
Epinephrine, Steroids, Tracheostomy
7/19-447/19-44
Omapatrilat (n = 17)
Enalapril (n = 2)
Airway compromise None None
Signs/Symptoms 8 tongue swelling9 lip swelling
1 tongue swelling2 lip swelling
Other Indicationsfor observation
7 late hour3 social factors2 comorbid conditions
1 comorbid conditions
Progression inHospital
None None
Treatment Epi (5) / steroids (16) Epi (1) / steroids (2)
Time to Discharge 14 next day3 after 2 days
1 next day1 after 6 days
Angioedema Hospitalizations withoutAngioedema Hospitalizations withoutAirway CompromiseAirway Compromise
7/19-457/19-45
Patient Response to SymptomsPatient Response to Symptomsof Angioedemaof Angioedema
Most (80.5%) angioedema events occurred Most (80.5%) angioedema events occurred outside the physician’s officeoutside the physician’s office
–Most (63.7%) patients with angioedema Most (63.7%) patients with angioedema occurring outside of physician’s officeoccurring outside of physician’s officepresented to medical facilities more than presented to medical facilities more than one hour after onset of symptomsone hour after onset of symptoms
–Many (28.6%) patients presented to medical Many (28.6%) patients presented to medical facilities more than 6 hours after onset of facilities more than 6 hours after onset of symptomssymptoms
OCTAVE: Class II-IV PatientsOCTAVE: Class II-IV Patients
7/19-467/19-46
Patient’s AbilityPatient’s Abilityto Recognize Angioedemato Recognize Angioedema
Patients with airway compromise were Patients with airway compromise were highly symptomatic with a constellation highly symptomatic with a constellation of symptomsof symptoms
Patients without airway compromise alsoPatients without airway compromise alsohad clinically overt presentation with visible had clinically overt presentation with visible swelling +/- functional complaintsswelling +/- functional complaints
No patients with angioedema had non-specific No patients with angioedema had non-specific lower airway complaints (stridor, dyspnea, lower airway complaints (stridor, dyspnea, hoarseness) alonehoarseness) alone
7/19-477/19-47
OCTAVE: Incidence of Angioedema OCTAVE: Incidence of Angioedema by Time Periodby Time Period
OCTAVE (CV137-120)
Time Period
Omapatrilat Enalapril
Day 1 88 (0.70 %) 3 (0.02%)
Day 2 – Week 4 83 (0.66 %) 43 (0.34%)
Week 5 – Week 8 44 (0.38%) 22 (0.19%)
Week 9 – Week 12 25 (0.23%) 3 (0.03%)
Week 13 – Week 16 14 (0.13%) 7 (0.06%)
Week 17 – Week 20 10 (0.09%) 4 (0.04%)
Week 21 – Week 24 10 (0.10%) 4 (0.04%)
(N = 12,609) (N = 12,557)
Total 274 (2.17%) 86 (0.68%)
7/19-487/19-48
OCTAVE: Summary of Angioedema RiskOCTAVE: Summary of Angioedema Riskwith Omapatrilat in Subgroups*with Omapatrilat in Subgroups*
2.962.96
1.511.51
1.171.17
Relative RiskRelative Risk
2.582.58
Black raceBlack raceCurrent smoker**Current smoker**Renal diseaseRenal diseaseSeasonal allergiesSeasonal allergiesFemale genderFemale genderFormer smoker**Former smoker**Age Age 65 years 65 yearsACE-I useACE-I useDiabetesDiabetesAtherosclerotic diseaseAtherosclerotic disease
0.580.58
0.550.55
1.551.55
0.970.97
1.481.48
Decreased RiskDecreased Risk Increased RiskIncreased Risk
* Multivariate logistic regression model with angioedema as the dependent variable and all other listed variables as independent variables. ** vs those who never smoked.
72 (5.5%)72 (5.5%) 89 (3.9%)89 (3.9%) 11 (3.6%)11 (3.6%) 55 (3.3%)55 (3.3%)153 (2.5%)153 (2.5%) 78 (2.1%)78 (2.1%) 70 (2.0%)70 (2.0%) 90 (2.0%)90 (2.0%) 23 (1.3%)23 (1.3%) 14 (1.2%)14 (1.2%)
IncidenceIncidence
(vs. those without characteristics)(vs. those without characteristics)
SubgroupSubgroup
1.911.91
0.50.5 1.01.0 2.02.0 4.04.0
7/19-497/19-49
Angioedema Safety SummaryAngioedema Safety Summary
Incremental risk of angioedema relative to ACE-I Incremental risk of angioedema relative to ACE-I treatmenttreatment
Angioedema has wide spectrum of severityAngioedema has wide spectrum of severity
Current smokers and black patients have a higher Current smokers and black patients have a higher incidence of angioedemaincidence of angioedema
Life-threatening in 1.6/10,000 (95% CI 0.2-5.7)Life-threatening in 1.6/10,000 (95% CI 0.2-5.7)
Symptomatic event with characteristic presentationSymptomatic event with characteristic presentation
Onset rapid but not fulminantOnset rapid but not fulminant
Effective treatment exists for angioedemaEffective treatment exists for angioedema
7/19-507/19-50
Risk ManagementRisk Management
Angioedema has clinical features which facilitateAngioedema has clinical features which facilitateits management through patient education:its management through patient education:
Symptomatic, recognizable clinical presentationSymptomatic, recognizable clinical presentation
Rapid but not fulminant progressionRapid but not fulminant progression
Effective therapy exists which can preventEffective therapy exists which can preventpoor outcomespoor outcomes
7/19-517/19-51
Risk ManagementRisk Management
Labeling and packagingLabeling and packaging Indication, warning, risk factors, etc.Indication, warning, risk factors, etc. Unit of use packagingUnit of use packaging
Comprehensive educational programComprehensive educational program Includes mandatory patient counselingIncludes mandatory patient counseling Multiple points of contact (physicians,Multiple points of contact (physicians,
patients, pharmacists)patients, pharmacists)
Post-marketing surveillancePost-marketing surveillance Includes prospective observational cohort studyIncludes prospective observational cohort study
Ongoing assessment of program effectivenessOngoing assessment of program effectiveness Expert panelExpert panel
7/19-527/19-52
Projected Reduction in CV EventsProjected Reduction in CV Events Per annum per 10,000 TreatedPer annum per 10,000 Treated
CV Risk CategoryCV Risk Category
Projected ReductionProjected Reductionin CV Eventsin CV Events
BPBPReductionReduction3/2 mmHg3/2 mmHg
BPBPReductionReduction5/3 mmHg5/3 mmHg
ProjectedProjectedCV EventsCV Events
Low (1.5% per annum) 15 23 150
Medium (1.5-2% per annum) 15 - 20 23 - 30150 - 200
High (2-3% per annum) 20 - 30 30 - 45200 - 300
Very High ( 3% per annum) 30 45300
Observed incidence of angioedema with airway compromise Observed incidence of angioedema with airway compromise over 24 weeks in OCTAVE: 1.6 (95% CI 0.2 -- 5.7) per 10,000over 24 weeks in OCTAVE: 1.6 (95% CI 0.2 -- 5.7) per 10,000
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