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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