IDNT Irbesartan Diabetic Nephropathy Trial

1
NDA 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
2
Efficacy
3
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
4
Order 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

5
Dose-Related Mean Reductionfrom Baseline in
Trough Blood Pressure
Weeks 6-9CV137-006, -022, -024 and -045
6
Changes 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
7
Changes 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
8
Effects 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
9
OCTAVE 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

10
OCTAVE 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
11
OCTAVE 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
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OCTAVE 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

13
OCTAVE 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
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OCTAVE 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
15
Demographic SubgroupsChange in Systolic BP at
Week 24
OCTAVE (CV137-120)
16
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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OCTAVE 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

18
Role 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

19
Efficacy 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
20
Control 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)
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Difficult 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
22
Changes 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
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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
Omapatrilat 80 mg
Lisinopril 40 mg
CV137-073
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Efficacy 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
25
Efficacy 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
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Efficacy 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

27
Safety
28
Omapatrilat 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
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Safety 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

30
Angioedema Clinical Overview
Allen Kaplan, M.D.Medical University of South
CarolinaCharleston, SC
FDA Cardiovascular and Renal DrugsAdvisory
Committee Meeting July 19, 2002
31
Angioedema 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

32
Angioedema 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

33
Anaphylaxis 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
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Safety of Omapatrilat
35
Angioedema 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

36
Frequency 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
37
Description 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
38
OCTAVE 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

39
OCTAVE 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)
40
OCTAVE 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
41
OCTAVE 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
42
Risk 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
43
OCTAVE 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
44
Angioedema 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
45
Patient 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

46
Patients 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

47
OCTAVE Incidence of Angioedema by Time Period
OCTAVE (CV137-120)
48
OCTAVE 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.
49
Angioedema 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

50
Risk 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

51
Risk 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

52
Projected 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