COZAAR losartan in Type 2 Diabetes and Nephropathy

1
COZAAR (losartan) inType 2 Diabetes and
Nephropathy

• Michael C. Elia, PhD
• Director, Regulatory AffairsMerck Research
  Laboratories

2
RENAAL
Reduction of Endpoints in NIDDM with the AII
Antagonist Losartan

• A multicenter, international, double-blind,
  randomized, placebo-controlled study designed to
  evaluate the long-term renal protective effects
  of losartan in patients with type 2 diabetes and
  nephropathy
• Prior to initiating RENAAL
• No conclusive, long-term renal outcomes data in
  patients with type 2 diabetes and nephropathy

3
RENAAL

• Primary endpoint - time to event analysis of the
  composite of
• Doubling of serum creatinine,
• End-stage renal disease (defined as the need for
  chronic dialysis or transplantation), or
• Death
• Key results
• Losartan delays progression of renal disease
• ESRD and death status known for all patients
• Safety and tolerability consistent with current
  labeling
• Renal protective benefit of losartan exceeds that
  attributable to reduction in blood pressure alone

4
COZAAR (losartan) Proposed New Indication

• Renal Protection in Type 2 Diabetic Patients with
  Proteinuria
• COZAAR is indicated to delay the progression of
  renal disease as measured by a reduction in the
  combined incidence of doubling of serum
  creatinine, end-stage renal disease (need for
  dialysis or renal transplantation) or death.

5
Evidentiary Standard for ApprovalsBased
Primarily on a Single Study

• In Jan-02, FDA Cardio-Renal Advisory Committee
  discussed the evidence needed to support a new
  claim for renal protection in patients with type
  2 diabetes and proteinuria
• Useful to review the evidentiary standard needed
  to support a new claim

6
Use of a Single Study to Support a New Claim
Points to Consider for COZAAR
FDA Guidance - Providing Clinical Evidence of
Effectiveness for Human Drug and Biological
Products (1998)

• Large multicenter study
• Treatment benefit on multiple endpoints involving
  different events
• Consistency among pre-defined subgroups
• Supportive data from separate (smaller) clinical
  and preclinical studies

7
COZAAR (losartan) Proposed New Indication

• Renal Protection in Type 2 Diabetic Patients with
  Proteinuria
• COZAAR is indicated to delay the progression of
  renal disease as measured by a reduction in the
  combined incidence of doubling of serum
  creatinine, end-stage renal disease (need for
  dialysis or renal transplantation) or death.

8
COZAAR (losartan) inType 2 Diabetes and
Nephropathy

• Agenda for Merck Presentation

Dr. S. Shahinfar,Senior DirectorCV Clinical
Research

• Background and Rationale
• RENAAL Demographicsand Efficacy Results
• RENAAL Safety Results
• Review of the Evidenceand Conclusions

Dr. W. Keane, Vice PresidentClinical Development
9
Merck Consultants

• Clinical Consultants
• Barry Brenner, MD - Chair, Steering Committee
  (P.I.)
• Professor of Medicine, Harvard Medical
  SchoolDirector Emeritus, Renal Division, Brigham
  and Womens Hospital, Boston
• Steven Haffner, MD - Chair, Adjudication
  Committee
• Professor of Medicine, University of Texas
  Health Science Center, San Antonio
• Carl Erik Mogensen, MD - Chair, DSMC
• Professor of Medicine, Aarhus Kommunehospital,
  Aarhus, Denmark

10
Merck Consultants

• Clinical Consultants (contd)
• Peter Kowey, MD - Member, DSMC
• Professor of Medicine, Jefferson Medical
  CollegeChief, Division of Cardiovascular
  DiseasesMain Line Hospitals, Philadelphia
• Marvin Konstam, MD
• Professor of Medicine Radiology, Chief of
  CardiologyTufts-New England Medical Center,
  Boston
• Statistical Consultant
• Scott Zeger, PhD
• Professor and Chair, Department of
  Biostatistics, Bloomberg School of Public Health,
  Johns Hopkins University

11
Losartan in Type 2 Diabetes and Nephropathy

• Shahnaz Shahinfar, MD
• Senior Director, Cardiovascular Clinical
  ResearchMerck Research Laboratories

12
Losartan in Type 2 Diabetes and NephropathyAgenda

• Background and Rationale
• RENAAL Demographics and Efficacy Results
• RENAAL Safety Results
• Review of Evidence and Conclusions

13
End-Stage Renal Disease An Unmet Medical Need

• Type 2 diabetes is the most common type of
  diabetes
• Up to 40 of Type 2 diabetic patients develop
  nephropathy
• Incidence of end-stage renal disease (ESRD) is
  increasing worldwide
• Diabetic nephropathy is the leading cause of ESRD
  in the US
• ESRD is an irreversible condition requiring
  dialysis as life support
• Up to 40 of patients die within 2 years after
  initiating dialysis

14
Diabetic Nephropathy

• Diabetic nephropathy is primarily a glomerular
  disease
• Progression of renal disease is multifactorial
• Hemodynamic
• Non-hemodynamic
• Angiotensin II is hypothesized to play an
  important role in the progression of nephropathy

15
Theoretical Hemodynamic Role of Angiotensin II in
Diabetic Glomerular Injury
Increased Albuminuria
Afferent Arteriolar Dilatation
IncreasedGlomerularPressure
Blood Flow
Glomerulus
Angiotensin II
Efferent ArterioleConstriction
Blood Flow
16
Theoretical Non-Hemodynamic Role of Angiotensin
II in Diabetic Glomerular Injury
17
Preclinical Renal Data Blockade of Angiotensin
II System

• In experimental diabetic models, blockade of
  angiotensin II reduced glomerulosclerosis and
  proteinuria
• In experimental models of non-diabetic renal
  disease, blockade of angiotensin II, but not
  other antihypertensive therapy, reduced
  glomerulosclerosis and proteinuria

18
Clinical Renal Outcomes Data Renin-Angiotensin
System Blockade in Diabetic Nephropathy

• Type 1 Diabetes - Captopril Collaborative Study
  (1993), N409
• ESRD/death reduced (RR 50 95 CI18,70)
• Type 2 Diabetes - No conclusive evidence of a
  benefit on ESRD

19
Factors that Differentiate Type 2 from Type 1
Diabetic Patients

• Age
• Obesity
• Insulin resistance
• Advanced atherosclerosis
• Long standing hypertension

20
Current Clinical Approaches to Delay Progression
to ESRD in Type 2 Diabetes

• Metabolic control
• Blood pressure control

21
Primary Study Question in RENAAL

• In patients with type 2 diabetes and nephropathy,
  does angiotensin II blockade with losartan offer
  renal protection?

22
RENAAL
Reduction of Endpoints in NIDDM with the AII
Antagonist Losartan

• A multicenter, multinational, double-blind,
  randomized, placebo-controlled study to evaluate
  the renal protective effects of losartan in
  patients with type 2 diabetes and nephropathy

23
RENAAL Study Organization
Steering Committee (Blinded) Chairman
Barry M. Brenner, MD Professor of
Medicine,Harvard Medical School

Director Emeritus,
Renal DivisionBrigham Womens Hospital, Boston
Data and Safety Monitoring Committee
(Unblinded) ChairmanCarl Erik Mogensen,
MD Professor of Medicine,Aarhus
Kommunehospital,Denmark
Endpoint AdjudicationCommittee
(Blinded) Chairman Steven M. Haffner,
MD Professor of MedicineUniversity of Texas
Health Science Center
Merck Coordinating and Data Management Center
250 centers from 28 countries worldwide
24
RENAAL Primary Hypothesis

• In type 2 diabetic patients with nephropathy,
  losartan compared to placebo will increase the
  time to the first event of the composite endpoint
  of
• Doubling of serum creatinine (sCr)
• ESRD (need for chronic dialysis or
  transplantation)
• Death (all cause mortality)

25
Progression of Renal Diseasein Type 2 Diabetes
ESRD or Death
100 Loss ofRenal Function
NormalRenal Function
Time
Death from any cause may occur at any time
26
RENAAL Secondary Hypotheses

• In type 2 diabetic patients with nephropathy,
  losartan compared to placebo will
• Renal
• Reduce the rate of progression of renal disease,
  as measured by the slope of 1/sCr
• Reduce proteinuria during the course of the study
  
• Cardiovascular
• Increase the time to the first event of the
  composite endpoint of cardiovascular
  morbidity/mortality (cardiovascular death, MI,
  stroke, first hospitalization for heart failure,
  first hospitalization for unstable angina,
  peripheral and coronary revascularization)

27
RENAAL Key Inclusion/Exclusion Criteria
Inclusion Criteria
Exclusion Criteria

• Type 2 diabetes
• Age 31-70 years
• Proteinuria defined asurine albumin/creatinine
  (UA/Cr) gt300 mg/g or gt500 mg protein/24hours
• Serum creatinine1.3-3.01 mg/dL

• Known non-diabetic renal disease, e.g., renal
  artery stenosis
• HbA1C gt12
• History of
• MI or CABG (within 1 month)
• Stroke or PTCA (within 6 months)
• TIA (within 1 year)
• Heart failure2

1 Lower limit 1.5 mg/dL in male patients gt60
kg. 2 Protocol amendment.
28
RENAAL Study Design (I)

• Double-blind
• Randomized
• Placebo-controlled
• Multicenter (250 sites in 28 countries)
• Stratified for baseline proteinuria
  (UA/Cr lt2000, ?2000 mg/g)
• Clinic visits every 3 months
• Planned one year enrollment, 5 year maximum
  follow-up

29
RENAAL Study Design (II)
Losartan 100 mg Titrate other antihypertensives
Losartan 100 mg
Losartan 50 mg
Urine Protein Dipstick
Goal Titrate to achieve trough BP lt140/90 mmHg
Placebo
Maintain other antihypertensives Discontinue
ACEI or AIIA
Placebo
Placebo Titrate other antihypertensives
4 Wks
4 Wks
6 Week Run-in
Planned 5 year maximum follow-up
Baseline Stratificationand Randomization
30
RENAAL Study Design (III)
Patient Follow-up

• Patients were to remain on study therapy, with
  clinic visits every three months, regardless of a
  non-fatal event, until study completion
• For patients who discontinued study therapy
• Clinic visits for renal and CV endpoints were to
  be conducted every three months
• Telephone contact for ESRD and death information
  was conducted if clinic visits were not feasible,
  therefore doubling of serum creatinine and CV
  morbidity were not collected
• ESRD and death information was collected on all
  patients

31
RENAAL Early Study Termination

• On February 10, 2001, the Steering Committee,
  while blinded to the study results, voted
  unanimously to end RENAAL prior to its planned
  termination date of March 2002 because of
  concerns of continuing the placebo group without
  blockade of the renin-angiotensin system
• This decision was based on increasing evidence
  that ACE inhibitors may be effective in reducing
  cardiovascular events in patients with
  cardiovascular risk factors1,2

1Heart Outcomes Prevention Evaluation Study, NEJM
2000342145-53. 2Mann et al, Annals of Int Med,
2001134629-36.
32
Agenda

• Background and Rationale
• RENAAL Demographics and Efficacy Results
• Renal (Primary and Secondary)
• Cardiovascular (Secondary)
• RENAAL Safety Results
• Review of Evidence and Conclusions

33
RENAAL Patient Disposition
3893 Screened
2380 Ineligible
1513 Randomized
751 Losartan
762 Placebo
407 Completed onstudy drug 142 D/C study drug
after aprimary event 202 D/C study drug prior
toa primary event
359 Completed onstudy drug 162 D/C study
drug after aprimary event 241 D/C study drug
prior toa primary event
34
RENAAL Baseline Demographics (I)
Placebo
Losartan
N Age (yrs) Male () SBP/DBP (mmHg) BMI (kg/m2)
751 60 62 152/82 30
762 60 65 153/82 29
35
RENAAL Baseline Demographics (II)
Race Asian Black Caucasian Hispanic Region
Asia Europe Latin America North America
36
RENAAL Medical History at Baseline
Treatment for hypertension Angina
pectoris Myocardial infarction Stroke Anemia Amput
ation Neuropathy Retinopathy Laser
therapy/photocoagulation Smoking (current)
37
RENAAL Selected Mean Baseline Laboratory Values
Losartan(n751)
Placebo(n762)
Urine albumin/creatinine (mg/g)1 Serum creatinine
(mg/dL) Serum potassium (mEq/L) Hemoglobin
(g/dL) Hemoglobin A1c ()
1873 1.9 4.6 12.5 8.5
1743 1.9 4.6 12.5 8.4
1UA/Cr 1873 mg/g approximately 3.4 grams per 24
hours (calculated). 1743 mg/g
approximately 3.2 grams per 24 hours (calculated).
38
RENAAL Primary Hypothesis

• Losartan compared to placebo will increase the
  time to the first event of the composite endpoint
  of
• Doubling of serum creatinine (DsCr)
• ESRD (need for chronic dialysis or
  transplantation)
• Death (all cause mortality)

39
RENAAL Analysis of Primary Composite Endpoint
Endpoint Captured
Patient
DsCr
ESRD
Death
A B C D E
? ? ?
? ?
? ? ? ?
40
RENAAL Analysis of Primary Composite Endpoint
Endpoint Captured
Patient
DsCr
ESRD
Death
A B C D E
? ? ?
? ?
? ? ? ?
41
RENAAL Primary Composite Endpoint
Doubling of Serum Creatinine/ESRD/Death
Risk Reduction 16.1 (2.3, 27.9)
p0.022
Patients with an Event
0
12
24
36
48
Months
n at Risk
Pbo
762
689
554
296
37
751
692
583
330
51
Los
42
RENAAL Analysis of Irreversible
Clinical Endpoints (Pre-specified)

• Irreversible clinical endpoints
• ESRD, death, composite of ESRD or death
• Key principles
• Patient counted as having endpoint in all
  relevant analyses
• Patient counted only once in any analysis

43
RENAAL Analysis of Irreversible
Clinical Endpoints (Pre-specified)

• ESRD Time to ESRD, regardless of whether
  doubling of serum creatinine occurred first
• Death Time to death regardless of whether
  doubling of serum creatinine or ESRD occurred
  first
• ESRD or death Time to first event of ESRD or
  death, regardless of whether doubling of serum
  creatinine occurred first

44
RENAAL Analysis of IrreversibleClinical
Endpoints (Pre-specified)
Endpoint Captured
Patient
DsCr
ESRD
Death
A B C D E
? ? ?
? ?
? ? ? ?
45
RENAAL Analysis of IrreversibleClinical
Endpoints (Pre-specified)
Endpoint Captured
Patient
DsCr
ESRD
Death
A B C D E
? ? ?
? ?
? ? ? ?
46
RENAAL Irreversible Clinical Endpoints (I)
ESRD
60
Risk Reduction 28.6 (11.5, 42.4)
p0.002
40
Patients with an Event
20
0
0
12
24
36
48
Months
n at Risk
Pbo
762
715
610
348
43
43
43
43
43
43
751
714
625
375
68
68
68
68
68
68
Los
47
RENAAL Irreversible Clinical Endpoints (II)
All Cause Mortality
60
Risk Reduction -1.7 (-26.9, 18.6)
p0.884
40
Patients with an Event
20
0
Months
n at Risk
762
732
690
439
65
Pbo
751
730
680
430
84
Los
48
RENAAL Irreversible Clinical Endpoints (III)
ESRD or Death
60
Risk Reduction 19.9 (5.3, 32.3)
p0.009
40
Patients with an Event
20
0
0
12
24
36
48
Months
n at Risk
Pbo
762
715
610
348
43
43
43
43
43
43
Los
751
714
625
375
68
68
68
68
68
68
49
RENAAL Summary of Primary Compositeand Clinical
Endpoints
Percent Risk Reduction (95 CI)
DsCr/ESRD/Death
ESRD
Death
ESRD or death
-50
50
0
Favors Losartan Favors Placebo
50
RENAAL Imbalance in Baseline Risk

• Patients were stratified for baseline level of
  proteinuria, lt2000 and ?2000 mg/g UA/Cr
• Equal numbers of patients were randomized to
  losartan and placebo within the low and high
  strata
• However, within the high stratum of ?2000 mg/g,
  an imbalance in the distribution of patients was
  observed
• There were more losartan patients in the highest
  level of proteinuria that led to the imbalance in
  risk

51
RENAAL Distribution of Baseline Proteinuria by
Stratum
511
70
501
Losartan
60
Placebo
50
40
of Patients
251
250
30
20
10
0
lt2000 mg/g
³2000 mg/g
Baseline Proteinuria (UA/Cr, mg/g)
52
RENAAL Distribution of Baseline Proteinuria
within Strata
lt2000 mg/g Stratum
?2000 mg/g Stratum
50
Losartan
326
330
Placebo
40
p 0.012
30
of Patients
181
175
20
115
97
92
71
65
61
10
0
lt1000
1000-1999
2000-2999
3000-3999
³4000


Baseline Proteinuria (UA/Cr, mg/g)
53
RENAAL Risk for Primary Composite Endpoint Rises
with Increasing Baseline Proteinuria
Pooled Analysis
Hazard Ratio
1
300
2000
4000
6000
Baseline Proteinuria (UA/Cr, mg/g)
54
RENAAL Risk for Primary Composite Endpoint Rises
with Increasing Baseline Proteinuria
Pooled Analysis
Hazard Ratio
1
300
2000
4000
6000
Baseline Proteinuria (UA/Cr, mg/g)
55
RENAAL Primary Composite Endpoint Adjusted by
Baseline Proteinuria (post hoc)
60
Risk Reduction 22.2 (9.4, 33.2)
p0.001
40
Patients with an Event
20
0
0
12
24
36
48
Month
n at Risk
762
689
554
296
37
Pbo
751
692
583
330
51
Los
56
RENAAL Endpoints Adjusted for Baseline
Proteinuria as a Continuous Covariate (post hoc)
Percent Risk Reduction (95 CI)
50
0
-50
Favors Losartan Favors Placebo
57
RENAAL Pre-defined Sensitivity Analyses

• HbA1c
• Mean arterial pressure (MAP)
• Baseline subgroups

58
RENAAL Blood Pressure Control
Goal Trough lt140/90 mmHg

• Study therapy
• Titrate losartan or placebo from 50 to 100 mg at
  Month 1 if BP gt140/90 mmHg
• Increase other open-label antihypertensives if BP
  gt140/90 mmHg at Month 2 or at any subsequent
  clinic visit (ACEI and AIIA excluded)
• Clinic visits
• Additional visits performed to adjust study
  therapy and open-label antihypertensives if BP
  gt140/90 mmHg

59
RENAAL Concurrent Antihypertensive Medications
100
Losartan
85
85
83
Placebo
81
80
60
47
of Patients
42
38
36
40
20
0
Diuretic
CCB
AlphaBlocker
BetaBlocker
60
RENAAL Comparable Blood Pressure (Trough)
Control Between Treatment Groups
Systolic
Blood Pressure (mmHg)
Diastolic
Pbo (n)
762
641
491
247
30
751
662
529
295
44
Los (n)
61
RENAAL Mean Arterial Pressure
MAP (mmHg)
Losartan
Placebo
Months
n
Pbo
762
758
621
469
189
Los
751
749
632
510
228
Distribution at 5, 25, 50, 75, and 95 percentiles
at each timepoint
62
RENAAL Endpoints Adjusted for Mean Arterial
Blood Pressure
Percent Risk Reduction (95 CI)
50
0
-50
FavorsLosartan
FavorsPlacebo
63
RENAAL Baseline Subgroups
Overall Primary Composite
Overall Primary Composite
Overall Primary Composite
lt65 years
lt2000 mg/g
Age
Proteinuria
?65 years
Yes
?2000 mg/g
Insulin
No
Female
lt2 mg/dL
Gender
Ser. Creatinine
Male
?2 mg/dL
Yes
Dihydropyridine CCB
Asian
lt3.6 g/dL
No
Ser. Albumin
Black
?3.6 g/dL
Race
White
Hispanic
lt240 mg/dL
Yes
Ser. Cholesterol
Prev. ACEI/AIIA
?240 mg/dL
lt30 kg/m2
No
BMI
?30 kg/m2
lt7 mg/dL
Ser. Uric Acid
?7 mg/dL
Asia
Yes
Smoking
Latin America
Region
No
lt12 g/dL
Europe
Hemoglobin
?12 g/dL
North America
Duration of
lt10 yr
lt140 mmHg
lt10
Hypertension
SiSBP
HbA
?10 yr
1c
?140 mmHg
?10
50
0
-50
50
0
-50
50
0
-50
Favors Favors Los Pbo
Percent Risk Reduction (95 CI)
64
RENAAL Baseline Subgroups
Overall Primary Composite
Overall Primary Composite
Overall Primary Composite
lt65 years
lt2000 mg/g
Age
Proteinuria
?65 years
Yes
?2000 mg/g
Insulin
No
Female
lt2 mg/dL
Gender
Ser. Creatinine
Male
?2 mg/dL
Yes
Dihydropyridine CCB
Asian
lt3.6 g/dL
No
Ser. Albumin
Black
?3.6 g/dL
Race
White
Hispanic
lt240 mg/dL
Yes
Ser. Cholesterol
Prev. ACEI/AIIA
?240 mg/dL
lt30 kg/m2
No
BMI
?30 kg/m2
lt7 mg/dL
Ser. Uric Acid
?7 mg/dL
Asia
Yes
Smoking
Latin America
Region
No
lt12 g/dL
Europe
Hemoglobin
?12 g/dL
North America
lt10 yr
Duration of
lt140 mmHg
lt10
Hypertension
SiSBP
HbA
?10 yr
1c
?140 mmHg
?10
50
0
-50
50
0
-50
50
0
-50
Favors Favors Los Pbo
Percent Risk Reduction (95 CI)
65
RENAAL Secondary Hypotheses (Renal)

• In type 2 diabetic patients with nephropathy,
  losartan compared to placebo will
• Reduce the rate of progression of renal disease,
  as measured by the slope of 1/sCr
• Reduce proteinuria during the course of the study

66
RENAAL Reduction in the Rate of Loss of Renal
Function (On-treatment Approach)
Median 1/sCr Slope
Losartan
Placebo
0
-.02
Median Changein 1/sCr(dL/mg/yr)
-.04
-.06
-.08
18 Reductionp0.01
67
RENAAL Losartan Reduces Proteinuria(On-treatment
Approach)
Change in Mean UA/Cr ()1
34 OverallReductionplt0.001
Placebo
Losartan
0
3
12
24
36
gt36
Months
762
632
529
389
120
Pbo (n)
Los (n)
751
661
558
432
163
1Based on geometric mean (95 CI).
68
RENAAL Efficacy Summary (Renal)

• In type 2 diabetic patients with proteinuria,
  losartan
• Is renal protective by delaying the onset of the
  primary composite endpoint of doubling of serum
  creatinine, ESRD (need for chronic dialysis or
  transplantation), or death
• Reduces the risk of ESRD by 28.6
• Reduces the rate of decline in renal function as
  measured by the slope of 1/sCr
• Reduces proteinuria
• Has a beneficial effect on the primary composite
  endpoint and proteinuria beyond its beneficial
  effect on blood pressure

69
Agenda

• Background and Rationale
• RENAAL Demographics and Efficacy Results
• Renal (Primary and Secondary)
• Cardiovascular (Secondary)
• RENAAL Safety Results
• Review of Evidence and Conclusions

70
RENAAL Secondary Hypotheses (Cardiovascular)

• In type 2 diabetic patients with nephropathy,
  losartan compared to placebo will increase the
  time to the first event of the composite of
  cardiovascular morbidity/mortality
• Cardiovascular death
• Myocardial infarction
• Stroke
• First hospitalization for heart failure
• First hospitalization for angina
• Revascularization (coronary and peripheral)

71
RENAAL Secondary Cardiovascular Composite
Endpoint
60
Risk Reduction 9.6 (-7.5, 24.0)
p0.253
40
Patients with an Event
20
0
0
12
24
36
48
Months
n at Risk
762
646
551
328
48
Pbo
Los
751
658
569
329
61
72
RENAAL Secondary Cardiovascular Composite
Endpoint and Components
Percent Risk Reduction (95 CI)
50
0
-50
Favors Losartan Favors Placebo
73
RENAAL Composite of ESRD/MI/Stroke/Death (post
hoc)
60
Risk Reduction 21.2 (7.8, 32.6)
p0.003
40
Patients with an Event
20
0
0
12
24
36
48
Months
n at Risk
762
685
565
314
39
Pbo
751
684
585
350
62
Los
74
RENAAL Summary of Cardiovascular Data

• There was no statistically significant difference
  in cardiovascular morbidity and mortality between
  losartan and placebo
• The renal protective effects of losartan are not
  at the expense of increased risk of
  cardiovascular outcomes and support the overall
  benefits of therapy in this population
• Post hoc analysis of ESRD/MI/Stroke/Death
  demonstrated the beneficial effect of losartan in
  diabetic patients with proteinuria

75
Agenda

• Background and Rationale
• RENAAL Demographics and Efficacy Results
• RENAAL Safety Results
• Review of Evidence and Conclusions

76
RENAAL Clinical Adverse Experience Summary
100
95.7
95.3
Losartan
Placebo
80
64.0
63.9
60
of Patients
40
24.0
19.0
17.2
20
13.9
9.1
9.2
3.2
2.6
0
With Oneor MoreAEs
WithSeriousAEs
With Drug-RelatedAEs
With SeriousDrug-RelatedAEs
DeathDue to AE
Discon.Due to AE
77
RENAAL Laboratory Adverse Experience Summary
100
Losartan
Placebo
80
60
49.5
of Patients
42.4
40
20
14.8
7.5
2.7
2.6
2.1
1.1
0.8
0.4
0
0
0
With Oneor MoreAEs
WithSeriousAEs
With Drug-RelatedAEs
With SeriousDrug-RelatedAEs
DeathDue to AE
Discon.Due to AE
78
RENAAL Pre-specified Analysis of Adverse
Experiences
79
RENAAL Distribution of Serum Potassium Values at
Each Time Point
Serum Potassium (mEq/L)
Losartan
Placebo
Baseline
12
24
36
gt36
Months
Distribution at 5, 25, 50, 75 and 95 percentile
at each time point
80
RENAAL Serum Potassium at Any Time During the
Study
Patients Who Had at Least One Measurement of
?3.5 and/or ?6.0 mEq/L
Losartann/N ()
Placebon/N ()
Potassium ? 3.5 mEq/L Potassium ? 6.0
mEq/L
32/751 (4.2) 73/751 (10.0)
43/762 (5.6) 40/762 (5.0)
81
RENAAL Hyperkalemia
Adverse Experiences
20
Losartan
Placebo
15
of Patients
10
5
2.6
1.3
1.3
0.7
0
0
0
WithSerious AEs
Discon.Due to AE
DeathDue to AE
82
RENAAL Summary of Safety

• In type 2 diabetic patients with proteinuria
• There were no unusual or unexpected adverse
  experiences beyond those already noted in the US
  prescribing information for losartan
• Losartan had a higher incidence of hyperkalemia
  and lower incidence of hypokalemia compared to
  placebo
• Losartan was generally well tolerated

83
RENAALReview of Evidence and Conclusions

• William F. Keane, MD
• Vice President, Clinical DevelopmentMerck US
  Human Health

84
RENAAL Strength of the Evidence

• Robust design features
• Results are clinically important and
  statistically significant
• Internal consistency across multiple endpoints
  and multiple subgroups

85
RENAAL Robust Study Design

• Large multinational study conducted in 28
  countries at 250 clinical sites
• Diverse study population consistent with disease
  demographics
• No patients lost to follow-up for ESRD and death
• Renal and cardiovascular endpoints adjudicated
• For the primary composite endpoint, no patients
  missing from ITT analysis

86
RENAAL Clinically Important and Statistically
Significant Results

• Primary composite endpoint
• Doubling sCr/ESRD/death
• Clinical endpoints
• ESRD
• Death
• ESRD or death

87
RENAAL Imbalance in Baseline Risk

• Patients were stratified for baseline level of
  proteinuria, lt2000 and ?2000 mg/g UA/Cr
• However, within the high stratum of ?2000 mg/g,
  an imbalance in the distribution of patients was
  observed

88
RENAAL Clinically Important and Statistically
Significant Results
Adjusted forBaselineProteinuria
RR ()
p-Value

• Primary composite endpoint
• Doubling sCr/ESRD/death
• Clinical endpoints
• ESRD
• Death
• ESRD or death

22.2 36.7 1.3 25.7
0.001 lt0.001 0.907 lt0.001
89
RENAAL Renal Protective Effects and Blood
Pressure Control

• Effective blood pressure control is critically
  important in treatment of type 2 diabetic
  patients with proteinuria
• In RENAAL
• Blood pressure was aggressively treated and
  comparable BP control was achieved in both
  treatment groups
• Small differences in MAP were not sufficient to
  account for the renal protective effects of
  losartan

90
RENAAL Clinically Important and Statistically
Significant Results
p-Value
Reduction

• Secondary renal endpoints
• Rate of progression of renal disease (1/sCr)
• Reduction in proteinuria

0.01 lt0.001
18 34
91
RENAAL Secondary Cardiovascular Composite
Endpoint and Components
Percent Risk
Reduction (95 CI)
p-Value
0.253
CV composite
Composite of ESRD/MI/stroke/death (post hoc)
0.003
50
0
-50
Favors Losartan Favors Placebo
92
Conclusions

• As demonstrated in RENAAL, in patients with type
  2 diabetes and proteinuria
• The beneficial treatment effects of losartan
  across multiple renal endpoints provide robust,
  reliable and clinically relevant evidence for
  renal protection
• The safety profile of losartan in this population
  is consistent with the current US prescribing
  information for losartan