1 COZAAR™ (losartan) in Type 2 Diabetes and Nephropathy Michael C. Elia, PhD Director, Regulatory Affairs Merck Research Laboratories

1

COZAAR™ (losartan) inType 2 Diabetes and Nephropathy

Michael C. Elia, PhD

Director, Regulatory AffairsMerck Research Laboratories

2

Reduction of Endpoints in NIDDM with the AII Antagonist Losartan

RENAAL

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

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

FDA Guidance - Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (1998)

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 Women’s 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 (cont’d)

– Peter Kowey, MD - Member, DSMCProfessor of Medicine, Jefferson Medical CollegeChief, Division of Cardiovascular DiseasesMain Line Hospitals, Philadelphia

– Marvin Konstam, MDProfessor of Medicine & Radiology, Chief of CardiologyTufts-New England Medical Center, Boston

Statistical Consultant

– Scott Zeger, PhDProfessor 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


RENAAL Demographics and Efficacy 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

Efferent ArterioleConstriction

Glomerulus

Increased Albuminuria

Afferent Arteriolar DilatationIncreasedGlomerularPressure

Angiotensin II

Theoretical Hemodynamic Role of Angiotensin II in Diabetic Glomerular Injury

Blood Flow

Blood Flow

16

Theoretical Non-Hemodynamic Role of Angiotensin II in Diabetic Glomerular Injury

Glomerulosclerosis

Angiotensin II

Increased filtering membrane permeability

Inflammation and fibrosis

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), N=409

– ESRD/death reduced (RR: 50%; 95% CI:18,70)

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

In patients with type 2 diabetes and nephropathy, does angiotensin II blockade

with losartan offer renal protection?

Primary Study Question in RENAAL

22

Reduction of Endpoints in NIDDM with the AII Antagonist Losartan

RENAAL

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

23250 centers from 28 countries worldwide

Merck Coordinating and Data Management Center

Data and Safety Monitoring Committee

(Unblinded)

Chairman:Carl Erik Mogensen, MD

Professor of Medicine,Aarhus Kommunehospital,

Denmark

Steering Committee (Blinded)

Chairman: Barry M. Brenner, MD

Professor of Medicine,Harvard Medical School

Director Emeritus, Renal Division

Brigham & Women’s Hospital, Boston

Endpoint AdjudicationCommittee

(Blinded)

Chairman: Steven M. Haffner, MD

Professor of MedicineUniversity of Texas Health

Science Center

RENAAL: Study Organization

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

Time

Death from any cause may occur at any time

ESRD or Death

100% Loss ofRenal Function

Doublingof sCr

~50% Loss ofRenal Function

NormalRenal Function

Progression of Renal Diseasein Type 2 Diabetes

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

Type 2 diabetes

Age 31-70 years

Proteinuria defined as:urine albumin/creatinine (UA/Cr) >300 mg/g or >500 mg protein/24hours

Serum creatinine:1.3-3.01 mg/dL

Known non-diabetic renal disease, e.g., renal artery stenosis

HbA1C >12%

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 >60 kg.2 Protocol amendment.

RENAAL: Key Inclusion/Exclusion Criteria

Inclusion CriteriaInclusion Criteria Exclusion Criteria

28

RENAAL: Study Design (I)

Double-blind

Randomized

Placebo-controlled

Multicenter (250 sites in 28 countries)

Stratified for baseline proteinuria (UA/Cr <2000, 2000 mg/g)

Clinic visits every 3 months

Planned one year enrollment, 5 year maximum follow-up

29

RENAAL: Study Design (II)

4 Wks

Losartan 100 mg

Losartan 100 mg + Titrate other antihypertensives

Goal: Titrate to achieve trough BP <140/90 mmHg

Losartan50 mg

Placebo

4 Wks6 Week Run-inPlanned 5 year maximum follow-up

Maintain other antihypertensives;

Discontinue ACEI or AIIA

Placebo

Baseline Stratificationand Randomization

Urine Protein Dipstick

Placebo + Titrate other antihypertensives

30

Patient Follow-upRENAAL: Study Design (III)

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

1Heart Outcomes Prevention Evaluation Study, NEJM 2000;342:145-53. 2Mann et al, Annals of Int Med, 2001;134:629-36.

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

32

Agenda


RENAAL Demographics and Efficacy Results – Renal (Primary and Secondary)– Cardiovascular (Secondary)



33

1513 Randomized

2380 Ineligible 3893 Screened

751 Losartan 762 Placebo

RENAAL: Patient Disposition

407 Completed onstudy drug

142 D/C study drug after a

primary event

202 D/C study drug prior to

a primary event

359 Completed onstudy drug

162 D/C study drug after a

primary event

241 D/C study drug prior to

a primary event

34

N

Age (yrs)

Male (%)

SBP/DBP (mmHg)

BMI (kg/m2)

751

60

62

152/82

30

762

60

65

153/82

29

Losartan Placebo

RENAAL: Baseline Demographics (I)

35

Race Asian Black Caucasian Hispanic

Region Asia Europe Latin America North America

16174819

17201845

Losartan(n=751)

%

18145018

17191846

Placebo(n=762)

%

RENAAL: Baseline Demographics (II)

36

Treatment for hypertension

Angina pectoris

Myocardial infarction

Stroke

Anemia

Amputation

Neuropathy

Retinopathy

Laser therapy/photocoagulation

Smoking (current)

RENAAL: Medical History at BaselineLosartan(n=751)

%

92

9

12

0

21

9

50

66

7

20

Placebo(n=762)

%

95

10

14

0.1

22

9

49

62

7

17

37

Urine albumin/creatinine (mg/g)1

Serum creatinine (mg/dL)

Serum potassium (mEq/L)

Hemoglobin (g/dL)

Hemoglobin A1c (%)

Losartan(n=751)

Placebo(n=762)

1UA/Cr 1873 mg/g = approximately 3.4 grams per 24 hours (calculated). 1743 mg/g = approximately 3.2 grams per 24 hours (calculated).

1873

1.9

4.6

12.5

8.5

1743

1.9

4.6

12.5

8.4

RENAAL: Selected Mean Baseline Laboratory Values

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

A

B

C

D

E

Patient

Endpoint Captured

–

–

DsCr ESRD

–

–

–

Death

–

40

RENAAL: Analysis of Primary Composite Endpoint

A

B

C

D

E

Patient

Endpoint Captured

–

–

DsCr ESRD

–

–

–

Death

–

41Los147 AC PrimComp DsCr Stripped Mar. 26, 2002

Doubling of Serum Creatinine/ESRD/Death RENAAL: Primary Composite Endpoint

0 12 24 36 48Months

0

20

40

60%

Pat

ient

s w

ith a

n E

vent

p=0.022Risk Reduction: 16.1% (2.3, 27.9)

PboLos 751 692 583 330 51

762 689 554 296 37

PlaceboLosartan

n at Risk

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)

A

B

C

D

E

Patient

Endpoint Captured

–

–

DsCr ESRD

–

–

–

Death

–

45

RENAAL: Analysis of IrreversibleClinical Endpoints (Pre-specified)

A

B

C

D

E

Patient

Endpoint Captured

–

–

DsCr ESRD

–

–

–

Death

–

ClinicalEndpoint Analysis

ESRD

X

X

–

–

–

Death

X

X

X

X

–

ESRD/Death

X

X

X

X

–

46

ESRD strippedjan02 Mar. 26, 2002

ESRD RENAAL: Irreversible Clinical Endpoints (I)

0 12 24 36 48Months

0

20

40

60%

Pat

ient

s w

ith a

n E

vent

762 715 610 348 434343434343751 714 625 375 686868686868

PboLos

p=0.002Risk Reduction: 28.6% (11.5, 42.4)

n at Risk

PlaceboLosartan

47Los147 AC Death1 stripped Mar. 26, 2002

RENAAL: Irreversible Clinical Endpoints (II)

0 12 24 36 48Months

0

20

40

60

% P

atie

nts

with

an

Eve

nt

p=0.884Risk Reduction: -1.7% (-26.9, 18.6)

751 730 680 430 84762 732 690 439 65Pbo

Los

n at Risk

PlaceboLosartan

All Cause Mortality

48

PlaceboLosartan

Hard stripped Jan02 Mar. 26, 2002

ESRD or Death RENAAL: Irreversible Clinical Endpoints (III)

PboLos

0 12 24 36 48Months

0

20

40

60%

Pat

ient

s w

ith a

n E

vent

p=0.009Risk Reduction: 19.9% (5.3, 32.3)

751 714 625 375 686868686868762 715 610 348 434343434343

n at Risk

49

DsCr/ESRD/Death

ESRD

Death

ESRD or death

+50 0 -50

Percent Risk Reduction (95% CI)

Favors Losartan Favors Placebo

RENAAL: Summary of Primary Compositeand Clinical Endpoints

50

RENAAL: Imbalance in Baseline Risk

Patients were stratified for baseline level of proteinuria, <2000 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

0

10

20

30

40

50

60

70

% o

f Pa

tien

ts

LosartanPlacebo

501 511

250 251

<2000 mg/g 2000 mg/g

Baseline Proteinuria (UA/Cr, mg/g)

RENAAL: Distribution of Baseline Proteinuria by Stratum

52

RENAAL: Distribution of Baseline Proteinuria within Strata

<1000 1000-1999

2000-2999

3000-3999

4000


0

10

20

30

40

50

% o

f P

atie

nts

326

175

9761

92

330

181

11565 71

LosartanPlacebo

<2000 mg/g Stratum 2000 mg/g Stratum

p = 0.012

53

0

5

10

15

Haz

ard

Rat

io

300 2000 4000 6000

1


Pooled Analysis

RENAAL: Risk for Primary Composite Endpoint Rises with Increasing Baseline Proteinuria

54Baseline Proteinuria (UA/Cr, mg/g)

Haz

ard

Rat

io

300 2000 4000 60000

5

10

15

1

RENAAL: Risk for Primary Composite Endpoint Rises with Increasing Baseline Proteinuria

Pooled Analysis

55

PlaceboLosartan

Los147 AC Prim-uacr adjE stripped Apr. 4, 2002

0 12 24 36 48Month

0

20

40

60%

Pat

ient

s w

ith a

n E

vent

751 692 583 330 51762 689 554 296 37

n at RiskPboLos

Risk Reduction: 22.2% (9.4, 33.2)p=0.001

RENAAL: Primary Composite Endpoint Adjusted by Baseline Proteinuria (post hoc)

56

+50 0 -50



RENAAL: Endpoints Adjusted for Baseline Proteinuria as a Continuous Covariate (post hoc)

ESRD or death

Death

ESRD

DsCr/ESRD/Death Pre-specified

Adjusted

57

RENAAL: Pre-defined Sensitivity Analyses

HbA1c

Mean arterial pressure (MAP)

Baseline subgroups

58

RENAAL: Blood Pressure Control

Study therapy– Titrate losartan or placebo from 50 to 100 mg at Month 1

if BP >140/90 mmHg– Increase other open-label antihypertensives if BP >140/90

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 >140/90 mmHg

Goal: Trough <140/90 mmHg

59

RENAAL: Concurrent Antihypertensive Medications

LosartanPlacebo

0

20

40

60

80

100

% o

f Pat

ient

s

Diuretic CCB AlphaBlocker

BetaBlocker

85% 81%

42%36%

85% 83%

47%38%

60

Los147 AC BP stacked 1 stripped Apr. 8, 2002

RENAAL: Comparable Blood Pressure (Trough) Control Between Treatment Groups

0 12 24 36 48Months

80

100

120

140

160B

lood

Pre

ssur

e (m

mH

g)

751 662 529 295 44762 641 491 247 30

Systolic

Diastolic

Pbo (n)Los (n)

PlaceboLosartan

61

Baseline 12 24 36 >36Months

70

80

90

100

110

120

130M

AP

(m

mH

g)

LosartanPlacebo

Distribution at 5, 25, 50, 75, and 95 percentiles at each timepoint

Pbo 762 758 621 469 189Los 751 749 632 510 228

RENAAL: Mean Arterial Pressure

n

62

+50 0 -50Favors

Losartan


RENAAL: Endpoints Adjusted for Mean Arterial Blood Pressure

FavorsPlacebo

DsCr/ESRD/Death

ESRD

UnadjustedAdjusted

Death

ESRD/Death

63


Age

Gender

Race

BMI

Region

SiSBP

<65 years65 years

FemaleMale

AsianBlackWhiteHispanic

<30 kg/m2

30 kg/m2

AsiaLatin AmericaEuropeNorth America

<140 mmHg140 mmHg

Overall Primary Composite

+50 0 -50

Insulin

DihydropyridineCCB

Prev. ACEI/AIIA

Smoking

Duration of Hypertension

Yes

No

Yes

No

Yes

No

Yes

No

<10 yr

10 yr


+50 0 -50

Proteinuria

Ser. Creatinine

Ser. Albumin

Ser. Cholesterol

Ser. Uric Acid

Hemoglobin

HbA1c

<2000 mg/g2000 mg/g

<2 mg/dL2 mg/dL

<3.6 g/dL3.6 g/dL

<240 mg/dL240 mg/dL

<7 mg/dL7 mg/dL

<12 g/dL12 g/dL

<10%10%


+50 0 -50Favors Favors

Los PboFavors Favors

Los Pbo Favors Favors

Los Pbo

RENAAL: Baseline Subgroups

64

Age

Gender

Race

BMI

Region

SiSBP

<65 years65 years

FemaleMale

AsianBlackWhiteHispanic

<30 kg/m2

30 kg/m2

AsiaLatin AmericaEuropeNorth America

<140 mmHg140 mmHg


+50 0 -50

Yes

No

Yes

No

Yes

No

Yes

No

<10 yr

10 yr


+50 0 -50

Proteinuria

Ser. Creatinine

Ser. Albumin

Ser. Cholesterol

Ser. Uric Acid

Hemoglobin

HbA1c

<2000 mg/g2000 mg/g

<2 mg/dL2 mg/dL

<3.6 g/dL3.6 g/dL

<240 mg/dL240 mg/dL

<7 mg/dL7 mg/dL

<12 g/dL12 g/dL

<10%10%


+50 0 -50Favors Favors

Los PboFavors Favors

Los Pbo Favors Favors

Los Pbo

RENAAL: Baseline Subgroups


Insulin

DihydropyridineCCB

Prev. ACEI/AIIA

Smoking

Duration of Hypertension

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

Median 1/sCr Slope

-.08

-.06

-.04

-.02

0

Med

ian

Cha

nge

in 1

/sC

r(d

L/m

g/yr

)

Losartan Placebo

18% Reductionp=0.01

RENAAL: Reduction in the Rate of Loss of Renal Function (On-treatment Approach)

67

0 3 12 24 36 >36Months

Cha

nge

in M

ean

UA

/Cr

(%)1

-60

-40

-20

0

20

1Based on geometric mean (95% CI).

34% OverallReductionp<0.001

Losartan

751 661 558 432 163762 632 529 389 120Pbo (n)

Los (n)

Placebo

RENAAL: Losartan Reduces Proteinuria(On-treatment Approach)

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


RENAAL Demographics and Efficacy Results – Renal (Primary and Secondary)– Cardiovascular (Secondary)



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

0 12 24 36 48Months

0

20

40

60%

Pat

ient

s w

ith a

n E

vent

p=0.253Risk Reduction: 9.6% (-7.5, 24.0)

751 658 569 329 61762 646 551 328 48

n at RiskPboLos

PlaceboLosartan

Los147 AC SecCom stripped Mar. 26, 2002

72

Favors Losartan Favors Placebo+50 0 -50


RENAAL: Secondary Cardiovascular Composite Endpoint and Components

CV composite

CV death

Myocardial infarction

Stroke

Hosp. for heart failure

Hosp. for angina

Revascularization

73

Los147 AC SecKM ITT stripped Mar. 26, 2002

PlaceboLosartan

0 12 24 36 48Months

0

20

40

60

% P

atie

nts

with

an

Eve

nt

p=0.003Risk Reduction: 21.2% (7.8, 32.6)

751 684 585 350 62762 685 565 314 39Pbo

Los

n at Risk

RENAAL: Composite of ESRD/MI/Stroke/Death (post hoc)

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


RENAAL Demographics and Efficacy Results



76

RENAAL: Clinical Adverse Experience Summary

LosartanPlacebo

With Oneor More

AEs

WithSerious

AEs

WithDrug-

RelatedAEs

With SeriousDrug-Related

AEs

DeathDue to

AE

Discon.Due to

AE

95.3

17.2

64.0

3.2

19.0

9.1

95.7

13.9

63.9

2.6

24.0

9.2

0

20

40

60

80

100

% o

f P

atie

nts

77

RENAAL: Laboratory Adverse Experience Summary

0

20

40

60

80

100

49.5

0.8 02.7

42.4

1.1 02.1

% o

f P

atie

nts

14.87.5

0.4 2.6

LosartanPlacebo

With Oneor More

AEs

WithSerious

AEs

WithDrug-

RelatedAEs

With SeriousDrug-Related

AEs

DeathDue to

AE

Discon.Due to

AE

78

RENAAL: Pre-specified Analysis of Adverse Experiences

Adverse Experience

Acute renal failure

Hyperkalemia

Hypokalemia

Anemia

Hyperglycemia

Hypoglycemia

Losartan(n=751)

%

1.7

24.2

2.5

14.1

13.0

14.9

Placebo(n=762)

%

1.6

12.3

4.7

10.8

15.0

11.8

Losartan vs. PlaceboHazard Ratio (95% CI)

1.01 (0.46, 2.21)

2.00 (1.56, 2.57)

0.50 (0.28, 0.86)

1.25 (0.94, 1.67)

0.82 (0.63, 1.08)

1.21 (0.92, 1.60)

p-Value

0.981

<0.001

0.013

0.126

0.156

0.174

79

Baseline 12 24 36 >36Months

3

4

5

6

Ser

um P

otas

sium

(m

Eq/

L)

LosartanPlacebo

Distribution at 5, 25, 50, 75 and 95 percentile at each time point

RENAAL: Distribution of Serum Potassium Values at Each Time Point

80

Potassium 3.5 mEq/L

Potassium 6.0 mEq/L

RENAAL: Serum Potassium at Any Time During the Study

32/751 (4.2)

73/751 (10.0)

Losartann/N (%)

43/762 (5.6)

40/762 (5.0)

Placebon/N (%)

Patients Who Had at Least One Measurement of 3.5 and/or 6.0 mEq/L

81

RENAAL: Hyperkalemia

0

5

10

15

20

% o

f P

atie

nts

WithSerious AEs

Discon.Due to AE

DeathDue to AE

2.61.3

01.3 0.7 0

Adverse Experiences

LosartanPlacebo

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

RENAAL:Review 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

RR (%)

16.1

28.6

-1.7

19.9

p-Value

0.022

0.002

0.884

0.009

Unadjusted

87

RENAAL: Imbalance in Baseline Risk

Patients were stratified for baseline level of proteinuria, <2000 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


Primary composite endpoint:

– Doubling sCr/ESRD/death

Clinical endpoints:

– ESRD

– Death

– ESRD or death

RR (%)

16.1

28.6

-1.7

19.9

p-Value

0.022

0.002

0.884

0.009

Unadjusted

RR (%)

22.2

36.7

1.3

25.7

p-Value

0.001

<0.001

0.907

<0.001

Adjusted forBaseline

Proteinuria

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


Secondary renal endpoints

– Rate of progression of renal disease (1/sCr)

– Reduction in proteinuria

0.01

<0.001

p-Value

18%

34%

Reduction

91

RENAAL: Secondary Cardiovascular Composite Endpoint and Components

+50 0 -50

Percent Risk


0.003

Reduction (95% CI) p-Value

Composite of ESRD/MI/stroke/death (post hoc)

0.253CV composite0.453CV death0.079Myocardial infarction0.783Stroke0.006Hosp. for heart failure0.888Hosp. for angina0.337Revascularization

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

Documents

1 COZAAR™ (losartan) in Type 2 Diabetes and Nephropathy Michael C. Elia, PhD Director, Regulatory Affairs Merck Research Laboratories