Cardiovascular and Renal Drugs Advisory Committee Meeting

1
Cardiovascular and Renal Drugs Advisory Committee
Meeting
Avalide(irbesartan/hydrochlorothiazide)NDA
20-758S-037For Initial Treatment of Severe
Hypertension
18 April 2007
2

Meeting Background

• Reconsider the criteria for approval of
  combination products for first-line use in
  hypertension
• Review the data supporting first-line use of
  Avalide as a basis for developing this new
  paradigm
• Input regarding appropriate labeling combination
  products for initial use

3
Avalide

• Fixed-dose combination of irbesartan and
  hydrochlorothiazide
• Approved in 1997 for hypertension
• 10 million patient-years of exposure
• 150mg/12.5mg, 300mg/12.5mg, 300mg/25mg
• Current labeling precludes use of the combination
  until after titration with one component has not
  provided adequate BP control

4
Regulatory Practice and Implications

• Start with a single drug
• titrate full dose range
• avoid side effects from second drug unless needed
• Implications
• may delay BP control
• more effective initial therapies
• greater reductions are difficult to match
• differences persist

5
Approvals Allowing Initial Use ofCombination
Therapy

• Capozide (captopril / HCTZ) 1991
• more convenient dosing
• Ziac (bisoprolol / HCTZ) 1993
• better safety with similar efficacy
• Hyzaar (losartan / HCTZ) 2003
• large proportion very unlikely to be controlled
  on monotherapy

6
Proposed Indication

• Avalide is indicated as initial treatment of
  severe hypertension

7
JNC Guidelines Combination Therapy

• Severe Hypertension
• SBP 180 mmHg or DBP 110 mmHg
• Moderate Hypertension
• SBP 160180 mmHg or DBP 100110 mmHg
• Merged Moderate / Severe Stage 2 Hypertension
• start with a combination
• one drug should be a thiazide diuretic
• Initiation of therapy with more than one drug
  increases likelihood of achieving BP goal promptly

JNC VI
JNC 7
Chobanian et al. Hypertension 2003421221
8
Avalide Clinical Program

• Pivotal study compared Avalide to irbesartan
  monotherapy in severe hypertension
• Supportive study compared Avalide to irbesartan
  and HCTZ monotherapies in moderate hypertension
• Intent Determine the effect of Avalide in
  patients very unlikely to be controlled with
  irbesartan
• very unlikely 10 achieve DBP lt90 mmHg

9
Outcome of the Pivotal Study

• Irbesartan 33 achieved DBP lt 90 mmHg
• Avalide 47 achieved DBP lt 90 mmHg (p
  0.0005)
• Avalide 35 lt140/90 mmHg Irbesartan 19
• Favorable safety and tolerability profile with
  Avalide
• FDA issued approvable letter proposing an
  alternative criterion for approval

10
Considering Additional Criteria for Approval of
First-line Combination Therapies

• Current guidelines recommend first-line
  combination therapy for severe hypertension
• Criterion based on Hyzaar precedent has limited
  usefulness
• results dependent on study design, patient
  population, endpoint
• Alternative criteria
• establish a significant efficacy advantage with
  an acceptable tolerability profile

11
Presentation Overview
Unmet Need inSevere Hypertension William Weintraub, MD John H. Ammon Chair of Cardiologyand Director of the Christiana Care Center for Outcomes Research
Avalide Registrational Program Pablo Lapuerta, MD Executive Director, Global Medical AffairsBristol-Myers Squibb
Benefit / Risk Profile Michael Weber, MD Professor of Medicine, SUNY Downstate Medical Center College of MedicineBrooklyn, New York
Conclusion Anthony Waclawski, PhD Vice President, Global Regulatory SciencesBristol-Myers Squibb
12
Unmet Need In Severe Hypertension

• William Weintraub, MD
• John H. Ammon Chair of Cardiologyand Director of
  the Christiana Care Center for Outcomes Research

13
Severe Hypertension an Important Problem

• Defined as SBP  180 mmHg or DBP  110 mmHg
• 2.4 million people in the U.S.
• 40 untreated

NHANES 2003-2004 Sample, Data on File at
Bristol-Myers Squibb, 2007.
14
Morbidity and Mortality

• Hypertensive emergencies
• hypertensive retinopathy, nephropathy, heart
  failure, cerebral hemorrhage
• Cardiovascular events
• myocardial infarction, stroke, CV death
• Risks increase exponentially with increasing
  levels of blood pressure

15
Incidence of CV Events
CV Event rates in the Framingham study.1
6000
DBP
SBP
5000
4000
CV Events / 100,000 patient-years
3000
2000
1000
70
80
90
100
110
120
140
160
180
200
Blood Pressure (mmHg)
1 Anderson TW Re-examination of some of the
Framingham blood-pressure data. Lancet
197821139 1141.
16
Christiana Care Health System Study Cohort

• 16,719 patients seen from 1998-2007
• 2025 severe hypertension
• Primary care practice
• Electronic medical records
• HTN category index date based on maximum BP
• Outcomes included ER visits, hospitalizations
• ICD9 codes for CV events

17
Christiana Care Health System Population
Characteristics
Total N 16,719 Maximum BP Stage Maximum BP Stage Maximum BP Stage
Total N 16,719 Normal (lt 140/90) n 7472 Mild and Moderate (lt 180/110) n 7222 Severe ( 180/110) n 2025 p-value
Age, mean SD, (years) 36.7 14.8 50.3 16.6 58.0 15.9 lt 0.001
Gender, n () female 4870 (65.2) 3988 (55.2) 1312 (64.8) lt 0.001
Race, n () black 1671 (22.4) 2279 (31.6) 1037 (51.2) lt 0.001
Diabetes, n () 374 (5.0) 1260 (17.4) 654 (32.3) lt 0.001
BMI 26.3 5.9 31.0 7.6 32.4 8.9 lt 0.001
16,719 patients followed in primary care offices
with at least 2 blood pressure measurements
18
Severe Hypertension in Actual Practice
N 16,719
Events include ER Inpatient Admissions and
Deaths
19
Christiana Care Health System Outcomes
Unadjusted Disease-Specific Event Rates by
Hypertensive Stage for ER Inpatient Admissions
and Deaths
Event rate per 1000 patientsover a mean of 3.8 years Event rate per 1000 patientsover a mean of 3.8 years Event rate per 1000 patientsover a mean of 3.8 years
Event Normal Mild and Moderate Severe
All CV Events 45.9 160.7 388.9
HTN (ER and Inpatient Admissions) 1.7 14.3 95.7
Heart Failure 13.2 51.1 95.7
Cerebrovascular 5.9 25.1 68.9
Dysrhythmias 11.5 24.6 40.9
Ischemic HD (excluding AMI) 7.7 21.7 37.3
AMI 3.2 16.6 35.4
Hospital CV Mortality 6.7 10.9 21.9
Peripheral Vascular 2.7 7.2 14.9
N 16,719
20
Severe Hypertension Inadequate Titration
HTN Categoryat Visit Probability ofHTN Rx Increaseat Visit Median Days to Next Visit
Mild 20 66
Moderate 32 55
Severe 40 42
Personal communication Dan Berlowitz, MD, VA
Medical System Based on 59,207 patients seen in
VA Clinics
21
Treatment of Severe Hypertension Challenges

• Side effects of older medications
• Clonidine
• Nifedipine
• Limited data on newer medications
• dose titration
• side effects (hypotension, syncope)

22
Unmet Need Conclusions

• Severe hypertension is an important problem
• Leads to morbidity and mortality
• Current treatment is inadequate

23
Avalide Clinical Program for Initial Treatment of
Severe Hypertension

• Pablo Lapuerta, MD
• Executive DirectorGlobal Medical
  AffairsPharmaceutical Research
  InstituteBristol-Myers Squibb

24
Avalide Clinical Program

• Pivotal study in severe hypertension
• CV131-176
• Supportive study in moderate hypertension
• CV131-185
• Provides additional safety data

25
Pivotal Study (176)

• Avalide as initial therapy in severe hypertension
• Evaluate safety and efficacy
• N 695
• 21 randomization

2 additional patients were randomized to
monotherapy, but never received drug
26
Pivotal Study (176) Design
Forced titrationto 300/25 mg
Avalide
150/12.5 mg
Placebolead-in
R 21
Week 3
Week 5
Week 1
Week 7
150 mg
Forced titrationto 300 mg
Irbesartanmonotherapy
1 endpoint
27
176 Enrollment and Randomization Criteria

• Adults with severe hypertension
• untreated with DBP  110 mmHg or
• treated (monotherapy) with DBP  100 mmHg
• Subjects randomized if DBP  110 mmHg at two
  consecutive visits during placebo lead-in

28
176 Efficacy Endpoints

• Primary
• with DBP lt 90 mmHg at Week 5
• Secondary
• with DBP lt 90 mmHg at Weeks 1, 3, 7
• with BP control (lt 140/90 mmHg) at Weeks 1, 3,
  5, 7
• Change from baseline in SBP and DBP at Weeks 1,
  3, 5, 7

29
176 Safety Endpoints

• Overall frequency of Adverse Events (AEs)
• Frequency of discontinuations due to AEs
• AEs and laboratory abnormalities of special
  interest
• dizziness, hypotension, syncope, headache, and
  abnormalities of serum potassium

30
176 Baseline Characteristics
Avaliden 468 IrbesartanMonotherapyn 229
Age (years) 52.2 52.9
Gender
male () 59.2 54.1
Race
white () 84.4 83.8
black () 14.3 14.8
Diabetes () 11.1 13.1
BMI 30 () 47.0 54.6
Weight (kg) 89.7 91.8
Baseline BP (mmHg) 171/113 172/113
31
Efficacy Results Study 176 (Severe)
32
176 Primary Endpoint
Achievement of DBP lt 90 mmHg at Week 5

Subjects ()
Avalide
Irbesartan Monotherapy
Significant difference Week 5 P0.0005
33
176 Percent of Subjects with BP Control
BP lt 140/90 mmHg



Subjects ()

Significant difference Week 1 P0.023 Weeks
3, 5, 7 Plt0.0001
34
176 Change in DBP from Baseline
Mean Change from Baseline (mmHg)

? 4.7 mmHg



Significant difference all Plt0.001
35
176 Change in SBP from Baseline
Mean Change from Baseline (mmHg)

? 9.7 mmHg



Significant difference all Plt0.0001
36
176 Blood Pressure Distributions at Week 5
42
Avalide

Irbesartan Monotherapy
37
36
30
P0.0003 Plt0.0001
Subjects ()
21

16
14

5
BP lt 140/90
SBP 140-159orDBP 90-99
SBP 160-179orDBP 100-110
SBP 180orDBP 110
Post-hoc analysis LOCF
37
176 Patients with DBP lt 90 mmHg at Week 5by Race
n 67 34 401 195
38
176 BP Control in Diabetic Subjects at Week 5
n 52 30 52 30
39
176 Influence of Baseline Blood Pressure

• Probability of Achieving SBP lt140 mmHg at Week 5

Probability of Achieving DBP lt90 mmHg at Week 5
Avalide
Avalide
IrbesartanMonotherapy
IrbesartanMonotherapy
of Patients
Baseline DBP (mmHg)
Baseline SBP (mmHg)
40
176 Efficacy Summary

• Avalide showed better efficacy than irbesartan
  monotherapy
• more patients achieved lt 90 mmHg (47 vs 33)
• more patients achieved lt 140/90 mmHg(35 vs 19)
• greater blood pressure reductions at each
  timepoint (? 9.7 / 4.7 mmHg at Week 5)
• fewer severe blood pressure elevations

41
176 Study Design Comparison with Hyzaar
Study 176 Hyzaar
Comparison Avalide 150/12.5 mg titrated to 300/25 mg vs Irbesartan 150 mg titrated to 300 mg Hyzaar 50/12.5 mgtitrated to 100/25 mg vs Losartan 50 mg titrated to 100 mg
Randomization criteria DBP gt 110 mmHg(twice) DBP gt 110 mmHg(twice)
Baseline DBP 113 mmHg 113 mmHg
Baseline SBP 172 mmHg 171 mmHg
titrated to highest dose of monotherapy 100 86
No. of previous anti-HTN medications allowed 1 3
Salerno. J Clin Hypertens. 20046614620.
42
176 Efficacy Differences Resulting fromStudy
Design
Study 176 Hyzaar
achieving DBP lt 90 mmHg Avalide 47 Irbesartan 33 Hyzaar 20 Losartan 10
Change from baseline DBP Avalide -24 mmHg Irbesartan -19 mmHg Hyzaar -14 mmHg Losartan -10 mmHg
Change from baseline SBP Avalide -31 mmHg Irbesartan -21 mmHg Hyzaar -18 mmHg Losartan -12 mmHg
Salerno. J Clin Hypertens. 20046614620.
43
Safety ResultsStudy 176 (Severe)
44
176 Overall Adverse Events
of Subjects of Subjects
Avaliden 468 IrbesartanMonotherapyn 227
Adverse Event 29.9 36.1
Treatment-related AE 11.3 10.1
Serious AEs 0.2 0.4
Discontinuationsdue to AE 1.9 2.2
Deaths 0 0
45
176 Adverse Events of Special Interest
of Subjects of Subjects
Avaliden 468 IrbesartanMonotherapyn 227
AEs of Special Interest 8.8 11.5
Dizziness 3.6 4.0
Headache 4.3 6.6
Hyperkalemia 0.2 0
Hypokalemia 0.6 0.4
Hypotension 0.6 0
Syncope 0 0
Investigator reported
46
176 Hypotension Adverse Events
PID Blood Pressure (mmHg) Blood Pressure (mmHg) Blood Pressure (mmHg) Blood Pressure (mmHg) Blood Pressure (mmHg) Reported AE (Verbatim text)
PID Pre-rand Week 1 Week 3 Week 5 Week 7 Reported AE (Verbatim text)
248-132/F 140/111 133/86 133/83 136/96 StBP 125/92 NA Hypotension (onset Day 30, mild intensity, resolved Day 36)
288-462/F 156/113 153/105 131/79 StBP 124/76 133/81 133/78 Dizziness, orthostatic hypotension (onset Day 19, moderate intensity, resolved Day 19)
293-238/F 190/125 145/109 133/97 StBP 136/104 142/103 134/96 Hypotension symptomatic (onset Day 16, mild intensity, resolved Day 24)
47
176 Most Common Treatment-related AEs
of Subjects of Subjects
Avaliden 468 IrbesartanMonotherapyn 227
Treatment-related AE 11.3 10.1
Dizziness 2.6 3.1
Headache 1.3 2.2
Erectile Dysfunction 1.1 0
Fatigue 1.1 0.4
Nausea 0.6 1.3
1.9 of males
48
176 Study Discontinuations
of Subjects of Subjects
Avaliden 468 IrbesartanMonotherapyn 229
Total Subjects Discontinued 10.3 12.2
Adverse Event 1.9 2.2
Lack of Efficacy 3.2 5.2
Other 5.2 4.8
2 subjects discontinued prior to receiving drug
49
176 Subjects with SBP lt 110 mmHg

• 9 subjects on Avalide (1.9)
• All lt 65 years of age
• No cases at Week 1
• 6 had BP lt 140/90 at Week 1
• 3 had dizziness (2 mild and 1 moderate)

50
176 Subjects with DBP lt 60 mmHg

• 1 subject on Avalide (0.2)
• lt 65 years of age
• Week 1 BP 121/73 mmHg
• BP 103/56 mmHg at Week 7
• No adverse events

51
176 Safety Results in Elderly

• Avalide was well tolerated in subjects  65
  years of age (n 92)
• No hypotension
• No syncope
• Dizziness in 1.9 of those  65 years of age vs
  3.9 in those lt 65
• Overall AEs 26.4 in those  65 years of age vs
  30.4 in those lt 65

52
176 Avalide Safety Conclusions

• Comparable safety to irbesartan
• No increase in dizziness
• Hypotension was uncommon
• occurred at a frequency consistent with the label
• No syncope
• Well tolerated in elderly

53
Efficacy Results Study 185 (Moderate)
54
185 Study Context

• Supportive Safety Data for Study 176 (Severe)
• hypotension
• syncope
• Examine efficacy of HCTZ and irbesartan
  monotherapy

55
185 Study Design
Forced titration to 300/25 mg
Avalide
150/12.5 mg
Placebolead-in
12.5 mg
Forced titration to 25 mg
HCTZ
R311
Irbesartanmonotherapy
150 mg
Forced titration to 300 mg
Week 4
Week 8
Week 2
Week 12
1 endpoint
56
185 Efficacy Endpoints

• Primary
• Compare the change from baseline in SBP between
  treatment arms at Week 8
• Secondary
• Change from baseline in DBP between treatment
  arms at Weeks 8, 12
• Change from baseline in SBP between treatment
  arms at Week 12
• with SBP lt 140 mmHg and DBP lt 90 mmHg between
  treatment arms at Weeks 8, 12

57
185 Safety Endpoints

• Overall frequency of AEs
• Frequency of discontinuations due to AEs
• AEs and laboratory abnormalities of special
  interest after 12 weeks of therapy
• hypotension, dizziness, syncope, headaches,
  hypokalemia, and hyperkalemia

58
185 Baseline Characteristics
Avaliden 328 IrbesartanMonotherapyn 106 HCTZn 104
Age (years) 55.1 55.3 56.0
Gender
male () 55.2 46.2 59.6
Race
white () 82.6 89.6 82.7
black () 15.2 8.5 14.4
Diabetes () 14.3 13.2 12.5
BMI 30 () 47.9 49.1 45.2
Weight (kg) 87.6 88.2 88.4
Baseline BP (mmHg) 162/98 161/98 162/98
59
185 Primary Endpoint
Change in SBP from Baseline to Week 8
Mean Change fromBaseline (mmHg)

Plt0.0001 vs HCTZ P0.0016 vs irbesartan
60
185 Change in SBP from Baseline
Mean Change fromBaseline (mmHg)




Plt0.0001 vs HCTZ P0.0044 vs irbesartan
61
185 Change in DBP from Baseline
Mean Change fromBaseline (mmHg)




Plt0.0001 vs HCTZ P0.0147 vs irbesartan
62
Safety Results Study 185 (Moderate)
63
185 Adverse Events
of Subjects of Subjects of Subjects
Avaliden 328 IrbesartanMonotherapyn 106 HCTZn 104
Adverse Event 47.0 45.3 39.4
Treatment-Related AE 14.3 11.3 7.7
Serious AEs 1.8 0 2.9
Discontinuationsdue to AE 6.7 3.8 4.8
Deaths 0 0 0
64
185 SAE of Symptomatic Hypokalemia

• 50-year-old woman with chest pain
• On Avalide
• Ruled out for myocardial infarction
• K 3.2 mEq/L on one occasion
• Cardiac catheterization results normal
• Investigator felt probable relation to study
  drug

65
185 AEs of Special Interest
of Subjects of Subjects of Subjects
Avaliden 328 IrbesartanMonotherapyn 106 HCTZn 104
AEs of Special Interest 10.7 6.6 6.7
Dizziness 3.0 3.8 1.0
Headache 5.5 3.8 4.8
Hyperkalemia 1.2 0 1.0
Hypokalemia 0.9 0 0
Hypotension 0.9 0 0
Syncope 0 0 1.0
66
185 Study Discontinuations
of Subjects of Subjects of Subjects
Avaliden 328 Irbesartan Monotherapyn 106 HCTZn 104
Total Subjects Discontinued 12.5 11.3 12.5
Adverse Event 6.7 3.8 4.8
Lack of Efficacy 0.3 0.9 1.0
Other 5.4 6.6 6.7

• 2.1 of patients discontinued Avalide due to
  dizziness or hypotension

67
185 Safety Results in Elderly

• Avalide was well tolerated in subjects  65
  years of age (n 68)
• No hypotension
• No syncope
• Dizziness in 2.9 of those  65 years of age vs
  3.1 of those lt 65
• Overall AEs 47.1 in those  65 years of age vs
  46.9 of those lt 65

68
185 Avalide Conclusions

• Avalide showed better efficacy than irbesartan
  monotherapy and HCTZ monotherapy
• Safety comparable to monotherapy
• Dizziness and hypotension were consistent with
  the current label
• 2.1 of patients discontinued due to dizziness or
  hypotension
• Well tolerated in elderly

69
Original NDA Matrix Study Dose-Dependent SBP
Lowering
Mean change from baseline at Week 8 (mm Hg)
Irbesartan dose
HCTZ dose
Kochar M et al. Am J Hypertens. 199912797-805.
70
Matrix Study Serum Potassium Changes
Adjusted Mean Change from Baseline (mEq/L)
Irbesartan dose
HCTZ dose
Kochar M et al. Am J Hypertens. 199912797-805.
71
Original NDA Comparison of Avalide vs. Control
AEs
Avalide Compared to Adjusted RR Approximate 95 CI for Adjusted RR
Irbesartan Monotherapy 1.02 (0.91, 1.15)
HCTZ 1.04 (0.94, 1.16)
Placebo 1.03 (0.90, 1.18)
Subjects reporting at least one AE Includes
protocols CV131-037, -038, -039, -040
72
Post-marketing Spontaneous ReportsAvalide vs.
Irbesartan

• Over 10 million patient-years of data
• Thorough review of events
• Rates of events were low
• No safety concerns

Detail BMS Briefing Book Table 4, p. 42
73
Overall Safety of Avalide

• Low incidence of dose-dependent side effects
• Pivotal Study 176
• Supportive Study 185
• No signal of dose-independent side effects
• Original NDA
• Post-marketing surveillance

74
Benefit / Risk

• Michael Weber, MD
• Professor of MedicineSUNY Downstate Medical
  Center College of MedicineBrooklyn, New York

75
Benefit / Risk Profile of Initial Combination
Therapy

• Overall rationale
• Risks
• Benefits
• avoiding severe blood pressure elevations
• long-term blood pressure advantages
• preventing cardiovascular events

76
Rationale for Initial Combination Therapy

• Why consider an ARB/Thiazide combination as
  initial treatment?
• Combination vs. ARB alone
• equal safety
• greater efficacy
• Combination vs. HCTZ alone
• greater safety
• greater efficacy

77
Effects of Low-Dose Combination Therapy
MetaAnalysis of 50 Studies (Treatment vs.
Placebo)
Mean decrease in BP vs placebo (mm Hg)
Law et al. BMJ 2003 3261-8.
78
Meta-analysis Value of Combination Therapy

• Benefit/Risk Analysis of Law and Colleagues
• Minimal metabolic effects of low-dose diuretics
  in combinations did not compromise safety
• Incremental benefits projected to prevent CVD

Law et al. BMJ 2003 3261-8.
79
ARB/Thiazide Potential Risk Hypotension

• Is there a serious risk of hypotension with
  1st-line combination therapy?
• Study 176 (severe)
• hypotension 0.6 on Avalide
• 3/3 on maximum dose
• Study 185 (moderate)
• hypotension 0.9 on Avalide
• 2/3 on maximum dose

80
Why Is Starting Treatment with HCTZ Possibly a
Greater Risk than Starting with Combination
Treatment?

• HCTZ in monotherapy doses that are efficacious
  causes metabolic changes
• After HCTZ is established, adding an ARB can
  produce hypotension

81
Risk of Hypotension with Diuretic Monotherapy
From Avapro Package Insert(Similar to all other
ARBs, ACE inhibitors and renin inhibitors)

• WARNING
• Initiation of antihypertensive therapy may cause
  symptomatic hypotension in patients with
  intravascular volume or sodium depletionsuch
  volume depletion should be corrected prior to
  administration of Avapro

82
Benefits of Initial Avalide

• Avoiding severe blood pressure elevations
• Study 176 (severe)
• Sustained blood pressure reduction with potential
  cardiovascular protection
• Study 176 (severe)
• Study 185 (moderate)

83
176 Reducing Severe Blood Pressure Levels
(Baseline BP 172/113 mmHg)
of Patients of Patients
BP category at Week 5 Avalide Irbesartan Monotherapy p-value
Severe(SBP 180 or DBP 110) 5 14 0.0003
Moderate(SBP 160-179 or DBP 100-110) 16 30 lt0.0001
JNC 7 Stage 2 (moderate severe) 21 44
Mean BP difference 10/5 mmHg
84
Risk of HTN Emergencies inSevere Hypertension
Study Number on Placebo Follow-Up Time (Years) Excess Events on Placebo Excess Riskof Events(per patient-yr)
VA Study I 1967 70 1.3 25 27
VA Study II 1972 110 3.3 37 11
NHLBI, 1966 42 2 13 14

• Active treatment yielded immediate benefits

Compared with active treatment
VA Cooperative Study Group. JAMA.
19672021028-1034. VA Cooperative Study Group.
Circulation 1972 45991-1004. Wolff and
Lindeman. J Chronic Dis. 196619227-240.
85
Sustained BP Reduction

• Initial Avalide provides additional BP reduction
• Study 176 (severe) 10/5 vs irbesartan
• Study 185 (moderate) 5/3 vs irbesartan 11/7 vs
  HCTZ
• Clinical trials
• BP reduction persists long-term
• Epidemiology studies
• lower BP associated with lower CV risk

86
Coronary Heart Disease Rates bySBP, DBP, and Age
Diastolic Blood Pressure
Systolic Blood Pressure
Age at risk
Age at risk
80-89 years
256
256
128
128
70-79 years
64
64
60-69 years
CHD mortality(floating absolute risk and 95
CI)
32
32
50-59 years
16
16
40-49 years
8
8
4
4
2
2
1
1
70
80
90
100
110
120
140
160
180
Usual SBP (mm Hg)
Usual DBP (mm Hg)
CI, confidence interval IHD, ischemic heart
disease
Lewington S et al. Lancet. 2002360(9349)1903-191
3
87
Initial Efficacy Is Related to Long-term Outcomes

• Early, inadequate blood pressure responses are
  never fully corrected (ASCOT, VALUE, ALLHAT)
• 1st-line combination therapy associated with the
  best BP control ever reported in a large
  hypertension outcomes study (ACCOMPLISH)
• 73 patients lt140/90 by 6 months

Jamerson K et al, ASH Abstract, 2007
88
Patients on Monotherapy Do Not Catch Up with
Those Starting on a Combination

• Follow-up visits are inadequate
• can be costly and inconvenient for patients
• some health plans encourage prescription refills,
  but do not incentivize doctor visits
• practitioners renewing prescriptions in
  multi-doctor settings may not be aware of the
  original treatment goal
• simple regimens preferred by patients and doctors
• BP varies between visits
• physicians wait before taking action
• physicians intensify treatment at only 40 of
  visits even when hypertension severe

Berlowitz et al, NEJM 1998 3391957, and
personal communication
89
ALLHAT Early BP Differences Persisted
Systolic Blood Pressure
ALLHAT Collaborative Research Group. JAMA. 2000
283 1967-75
90
Early BP Differences Associated with Outcomes

• ALLHAT1 15 ? stroke (p0.02)
• chlorthalidone vs lisinopril
• Syst-Eur2 28 ? stroke (p0.01)
• early vs late treatment with CCB
• SCOPE3 28 ? stroke (p0.04)
• candesartan vs control
• ASCOT4 23 ? stroke (p0.0003)
• amlodipine-based regimen

1. ALLHAT Collaborative Research Group. JAMA. 2000
   283 1967-75.
2. Staessen et al. Lancet. 1997350(9080)757-64.
3. Lithell et al.  J Hypertens. 200321875-886.
4. Dahlöf et al. Lancet. 2005366895906.

91
VALUE Early Difference in BP Persisted
Difference in SBP Between Valsartan and Amlodipine
5.0
4.0
3.0
mmHg
2.0
1.0
0
1
24
48
2
3
4
6
12
18
30
36
42
54
60
66
(or final visit)
1.0
Months
Julius S et al. Lancet. June 2004363.
92
VALUE Outcome and SBP Differencesat Specific
Time Periods Stroke
STROKE
Time Interval
? SBP
Odds Ratios and 95 CIs
(months)
(mmHg)
Overall study
2.2
03
3.8
36
2.3
612
2.0
1224
1.8
2436
1.6
3648
1.4
Study end
1.7
1.0
2.0
0.5
0.25
4.0
Favors valsartan Favors amlodipine
Julius S et al. Lancet. June 2004363.
93
Summarizing Overall Risks Benefits
94
Overall Risk

• Avalide safety adequately demonstrated
• Study 176, Study 185, Original NDA,Post-marketing
  surveillance
• Meta-analyses have shown low-dose combinations do
  not compromise safety
• Initial Avalide safety may be better than with
  HCTZ monotherapy
• fewer metabolic effects (lower HCTZ doses,
  compensating effects of ARB)
• lower risk of hypotension than if ARB added to
  therapeutic dose of diuretic

95
Overall Benefit

• Initial Avalide provides additional BP reduction
• Study 176 (severe) 10/5 vs irbesartan
• Study 185 (moderate) 5/3 vs irbesartan 11/7 vs
  HCTZ
• Short-term 23 mmHg additional BP lowering
  considered clinically meaningful
• Early advantages in BP reduction persist and are
  associated with better long-term outcomes

96
Benefit / Risk Conclusion

• Initial use of Avalide can provide greater
  efficacy without compromising safety
• Patients with severe hypertension
• Patients 20/10 away from goal
• Patients at increased CV risk (diabetes, CKD, CHD)

97
Conclusions

• Anthony Waclawski, PhD
• Vice PresidentGlobal Regulatory
  SciencesResearch and Development Bristol-Myers
  Squibb

98
Safety and Efficacy Conclusions

• Avalide, compared to irbesartan monotherapy
• Lowered blood pressure
• further
• more rapidly
• in a higher proportion of patients
• with a similar safety and tolerability profile
• Hypotension was infrequent and not severe
• Risk of HCTZ-related hypokalemia is decreased by
  irbesartan
• Dose-independent side effects are very rare in
  post-marketing data, published meta-analysis

99
Proposed Labeling Revision

• Add an indication Initial use in severe
  hypertension
• Remove restriction requiring titration with a
  component before using Avalide
• Provide guidance to physicians

Probability of Achieving SBP lt140 mmHg at Week 5
Probability of Achieving DBP lt90 mmHg at Week 5
Avalide
Avalide
IrbesartanMonotherapy
IrbesartanMonotherapy
of Patients
of Patients
Baseline DBP (mmHg)
Baseline SBP (mmHg)
100
Overall Conclusions

• Appropriate labeling of Avalide will result in
• Reduced exposure to severe hypertension
• potential for fewer hypertensive emergencies
• Lower overall BP
• potential for fewer CV events

101
ADDITIONAL SLIDES
102
Risk of First CV Event Christiana Care
Adjusted Risk of Cardiovascular Eventsby
Severity of Hypertension
Severe (n 2025)
Mild and Moderate
Normal
Cumulative Hazard for CV Event
Total N 16,719
Time to CV Event (months)
63 - 1
Personal communication Bill Weintraub, MD
103
Awareness, Treatment, and Control of Hypertension
in the US
Hypertension, Awareness, Treatment, and Control
US 1976 to 2002
Hypertensive Adults ()
Cheung et al. J Clin Hypertens. 200689398.
63 - 14
104
176 BP Medications Prior to Double-blind
Treatment
of Subjects of Subjects
Drug Class Avalide n 468 Irbesartan monotherapy n 229
Alpha1 blocking agent 0.2 0.4
Alpha2 agonist 1.7 0.9
Angiotensin Converting Enzyme Inhibitor 17.4 22.6
Angiotensin Receptor Blocker 14.8 12.2
Beta Blocker 6.5 9.6
Calcium Channel Blocker 8.5 12.5
Diuretic 4.5 3.0
Other 1.4 1.6
33 - 11
105
185 Percent of Subjects with BP Control
BP lt 140/90 mmHg



Subjects ()
Plt0.0001 vs HCTZ Plt0.05 vs irbesartan.
Plt0.0001 vs HCTZ and vs Irbesartan.
25 - 104
106
Results from 176 and 185 by Baseline SBP
Combined Target
Probability of Achieving BP lt140/90 mmHg
Study 176Results at Week 5
Study 185Results at Week 8
of Patients
of Patients
Baseline SBP (mmHg)
Baseline SBP (mmHg)
Avalide Irbesartan Monotherapy
51 - 101
107
176 Model for 130/80
Probability of Achieving BP lt130/80at Week 5
Probability of Achieving BP lt130/80at Week 5
of Patients
of Patients
Baseline SBP (mmHg)
Baseline DBP (mmHg)
Avalide Irbesartan Monotherapy
Using subjects with baseline DBP between 110
and 130 mmHg and SBP lt 220 mmHg
51 - 24
108
185 Model for BP 130/80
Probability of Achieving BP lt130/80at Week 8
Probability of Achieving BP lt130/80at Week 8
of Patients
of Patients
Baseline SBP (mmHg)
Baseline DBP (mmHg)
Avalide Irbesartan Monotherapy
51 - 87
109
176 Model Variability
Probability of Achieving DBP lt90at Week 5
Probability of Achieving SBP lt140at Week 5
of Patients
Baseline SBP (mmHg)
Baseline DBP (mmHg)
Avalide Avalide CI Irbesartan Monotherapy Irbesar
tan Monotherapy CI
Using subjects with baseline DBP between 110
and 130 mmHg and SBP lt 220 mmHg
51 - 32
110
Mean BP Change at Week 8by Race
Study 185
Diastolic
Systolic
n 46 7 257 88 46 7 257 88
Change in Blood Pressure (mmHg)
25 - 59
111
Mean BP Change at Week 8by Race
Study 185
Diastolic
Systolic
n 46 7 12 257 88 83 46 7 12 257 88 83
Change in Blood Pressure (mmHg)
25 - 136
112
176 Mean BP Change at Week 5 by Stage of
Renal Function
Diastolic
Systolic
Stage 1 Stage 2 Stage 3 Stage 1 Stage 2 Stage 3
GFR 90 GFR 60-89 GFR 30-59 GFR 90 GFR 60-89 GFR 30-59
n 171 73 225 118 24 15
171 73 225 118 24 15
Change in Blood Pressure (mmHg)
25 - 207
113
Mean BP Change at Week 8 by Diabetes Status
Study 185
Diastolic
Systolic
n 41 14 10 262 81 85 41 14 10 262 81 85
Change in Blood Pressure (mmHg)
25 - 132
114
176 Proportion of Subjects withOrthostatic
Changes
Avalide IrbesartanMonotherapy
Baseline 3.3 3.1
Week 1 3.1 3.2
Week 3 2.0 2.7
Week 5 1.4 1.0
Week 7 0.9 2.5
Either the (SeSBP-StSBP) ? 20 mmHg or
(SeDBP-StDBP) ? 10 mmHg
35 - 175
115
Mean BP Change at Week 18 with Avalide by Race
INCLUSIVE Study
Diastolic
Systolic
n 454 157 454 157
Change in Blood Pressure (mmHg)
After 2 weeks HCTZ, 8 weeks Avalide 150/12.5 mg,
and 8 weeks Avalide 300/25 mgBaseline BP
White 154 / 91 Black 156 / 94
25 - 182
116
Risks of Initial Use of Avalide vs. Irbesartan
Pharmetrics Observational Study, 1997-2006
Lower Risk with Irbesartan Monotherapy
Lower Risk with Avalide
Adverse Event
Risk Ratio (95 CI)
31 - 60
Patients with a history of diabetes were
excluded from this analysis
117
Baseline Characteristics of Subjects in the
Pharmetrics Study
Baseline Characteristics Avalide Irbesartan HCTZ
Mean Age (SD) 51.7 (8.6) 52.3 (8.8) 51.3 (9.4)
Gender ( Male) 49.5 51.9 44.2
History of diabetes () 21.6 30.9 14.8
History of congestive heart failure () 2.8 6.2 2.6
History of cardiovascular disease () 1.1 2.7 1.0
Concomitant use of HCTZ () 5.65 8.83
Concomitant use of other antihypertensives () 54.9 62.2 58.2
31 - 79
118
Improved Adherence with Combination Therapy
Amlodipine/Atorvastatin
Retrospective analysis of claims in elderly
insured population, n2,098Adherence defined as
days covered 80
Plt0.0001
Adherent
Patel et al. Circ 2006 Suppl A
63 - 53
119
Improved Adherence with Combination Therapy
Metformin/Glyburide
Retrospective analysis of claims in managed care
population, n6,502Adherence defined as days
covered 80
Plt0.001
Adherent
Melikian et al. Clin Ther 2002 Mar24(3)460-7.
63 - 54
120
Improved Persistence with Combination Therapy
ACE/Diuretic
Retrospective analysis of claims in managed care
population, n3,942Persistent defined as
refilling medication within 3x days prescribed


Persistent
Plt0.05
Dezii CM. Manag Care 2000 Sep9(9 Suppl)2-6.
63 - 55
121
Purpose
Label Research

• Research designed to determine the utility of 2-D
  figures compared to 3-D figures to
• Interpret the relationship between baseline blood
  pressure and the proportion of patients reaching
  BP goal
• What is the best way to show the magnitude of the
  BP reduction data

47 - 2
122
Methods
Label Research

• Online survey
• 985 US physicians
• gt20 hypertensive patients per week
• Exposure to
• product description
• one of four displays (two 2-D graphs two 3-D
  graphs)
• Asked to
• identify patients attaining goal based on SBP
  and/or DBP baseline levels
• assess understandability and helpfulness

47 - 3
123
Graph 1
Label Research
Example The probability of a patient with a
baseline BP of 180/115 mmHg achieving a goal BP
of lt140/90 mmHg would be 14 with monotherapy,
and 23 with combination therapy.
Using subjects with baseline DBP between 110
and 130 mmHg and SBP lt 220 mmHg
47 - 4
124
Graph 2
Label Research
Example The probability of a patient with a
baseline SBP of 180 mm Hg achieving a goal BP of
lt140/90 mmHg would be 13 with monotherapy, and
26 with combination therapy.
Example The probability of a patient with a
baseline DBP of 115 mm Hg achieving a goal BP of
lt140/90 mmHg would be 14 with monotherapy, and
29 with combination therapy.
47 - 5
125
Graph 3
Label Research
Example The probability of a patient with a
baseline SPB of 180 mm Hg achieving a goal SBP of
lt140 mmHg would be 16 with monotherapy, and 34
with combination therapy.
Example The probability of a patient with a
baseline DPB of 115 mm Hg achieving a goal DBP of
lt90 mmHg would be 28 with monotherapy, and 42
with combination therapy.
47 - 6
126
Graph 4
Label Research
Example The probability of a patient with a
baseline BP of 180/115 mmHg achieving a goal BP
of lt140/90 mmHg would be 14 with monotherapy,
and 23 with combination therapy.
47 - 7
127
Results
Label Research
3-D 3-D 2-D 2-D
Graph 1 (n 245) Graph 4 (n 243) Graph 2 (n 253) Graph 3 (n 244)
Unable to Respond 22 29 11 11
Comprehension 2 - 13 3 - 13 1 - 7 2 - 8
Easy to Understand 6 5 45 45
Helpful 38 29 63 69
of physicians responding Dont know/Cant
tell Represents the range of the mean
percent difference from correct answer of those
responding to each of the four baseline sample
BPs given When choosing fixed combination vs
monotherapy as initial therapy Statistically
significant difference from Graphs 1 and 4
47 - 8
128
Mean BP Change at Week 5 by Race
Study 176
Diastolic
Systolic
n 59 29 364 177 59 29 364 177
Change in Blood Pressure (mmHg)
25 - 54
129
Current Avalide Labeling Race

• Irbesartan monotherapy was effective in reducing
  blood pressure regardless of race
• the effect was somewhat less in blacks (usually a
  low-renin population)
• Black patients show an improved response with the
  addition of a low dose diuretic (e.g., 12.5 mg
  hydrochlorothiazide) as in Avalide

41 - 31
130
176 Magnitude of Response at Week 5
Baseline SBP (mmHg)
lt150 150-159 160-169 170-179 180-189 190-199 200
n 33 16 63 33 112 53 92 46 74 34 23 12 26 12
SBP Change from Baseline (mmHg)
Post-hoc analysis
51 - 30
131
176 Magnitude of Response at Week 5
Baseline SBP (mmHg)
lt180 180
n 300 148 123 58
SBP Change from Baseline (mmHg)
Post-hoc analysis
51 - 31