CE-1

CRESTOR®

Clinical DevelopmentEfficacy

James W. Blasetto, MD, MPHSenior Director, Clinical Research

CE-2Evolution of Lipid Management Guidelines:The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP)

•Exclusive focus on LDL-C reduction

•Strong support for resins, niacin

•Statins, fibrates not first line

ATP I (1988)

•Risk assessment guides therapy

•Goal LDL-C for CHD set at ≤ 100 mg/dL

•Statins included in "major drugs"

ATP II (1993)

• Identifies optimal LDL-C level < 100 mg/dL

•High-risk patient group now includes patients with CHD risk equivalent, LDL-C goal < 100 mg/dL

• Increased focus on HDL-C; non-HDL-C as a secondary target of therapy

ATP III (2001)

CE-3Many Patients With CHD Fail to Achieve LDL-C and Non-HDL-C Goals Even With Dose TitrationACCESS

0

10

20

30

40

50

60

70

80

90

100

LDL-C Non-HDL-C

Pat

ien

ts,

% a

t g

oal

Atorvastatin 10 - 80 mg

Simvastatin 10 - 40 mg

Lovastatin 20 - 80 mg

Fluvastatin 20 - 80 mg

Pravastatin 10 - 40 mg

†Patients in CHD risk category. Ballantyne CM, et al. Am J Cardiol. 2001;88:265-269.

n = 2,543†

At Wk 54At Wk 54

CE-4

Provide an overall benefit-risk profile demonstrating

– Greater beneficial effects on key lipid parameters at both the start dose and across the dose range compared with marketed statins

– A similar safety profile compared with approved drugs in the statin class

– A low potential for significant drug-drug interactions

Objectives of the Rosuvastatin Clinical Development Program

CE-5

Efficacy in LDL-C Reduction

Dose-Range Effects

CE-6LDL-C: % Change From BaselineRosuvastatin vs PlaceboTrials 8 and 23 Pooled (Wk 6)

-33-40 -43

-50 -53-62

-65

-4

-80

-70

-60

-50

-40

-30

-20

-10

0

Rosuvastatin dose, mg

% c

han

ge

fro

m b

asel

ine

P < .001 vs placebo; data presented as LS mean ± SE.

1 2.5 5 10 20 40 80 Placebon = 14 15 18 17 17 34 31 31

Baseline characteristicsMean age: 56 yrMean LDL-C: 190 mg/dL

CE-7Lipids: % Change From BaselineRosuvastatin 5 mg and 10 mg Trials 24-28 Pooled (Wk 12)

-41

7.7

-16

-38-33

-47

9

-20

-43-37

-40-35

-60

-50

-40

-30

-20

-10

0

10

LDL-C HDL-C TG Non–HDL-C ApoB ApoB/ApoA-I

% c

ha

ng

e f

rom

ba

se

lin

e

Rosuvastatin 5 mg (n = 630) Rosuvastatin 10 mg (n = 615)

Data presented as means ± SE.

Baseline characteristicsMean age: 58 yrMean LDL-C: 187 mg/dL

CE-8LDL-C: % Change From Baseline Rosuvastatin 20 mg and 40 mgMultiple Trials

-55 -52 -50 -52-47

-63-59 -58 -55 -54

-70

-60

-50

-40

-30

-20

-10

0

8 25 33 65 30

% c

han

ge

fro

m b

asel

ine

Rosuvastatin 20 mg Rosuvastatin 40 mg

8

Trial

127 38 160 435 43544128 157N 17 18

Data presented as LS means.

CE-9

Across the Dose-RangeComparative Efficacy

CE-10

6-wk 6-wk dietary lead-indietary lead-in

6-wk6-wkactive treatmentactive treatment

RandomizationRosuvastatin (643 patients)

10 mg20 mg40 mg

10 mg20 mg40 mg80 mg10 mg20 mg40 mg

10 mg20 mg40 mg

Simvastatin (655 patients)

Atorvastatin (641 patients)

Pravastatin (492 patients)

80 mg

80 mg

Across the Dose-Range ComparisonTrial Design Trial 65 – STELLAR

Baseline characteristicsMean age: 57 yrMean LDL-C: 189 mg/dL

CE-11LDL-C: % Change From Baseline Rosuvastatin 10 to 40 mg vs ComparatorsTrial 65 – STELLAR (Wk 6)

-70

-60

-50

-40

-30

-20

-10

010 20 40 80

Dose, mg

% c

ha

ng

e f

rom

ba

se

lin

e

Rosuvastatin (n = 156 - 160)Atorvastatin (n = 158 - 165)Pravastatin (n = 158 - 165)Simvastatin (n = 161 - 164)

P < .001 vs comparators on a mg-to-mg basis.Data presented as means.

CE-12

-100

-75

-50

-25

0

25

Rosuva, mg

% c

han

ge

fro

m b

asel

ine

LDL-C: % Change From BaselineRosuvastatin 10 to 40 mg vs ComparatorsTrial 65 – STELLAR (Wk 6)

10 20 40 10 20 40 80Atorva, mg

N = 156 160 157 158 155 156 165

10 20 40 80Simva, mg

165 162 158 163

10 20 40Prava, mg

160 164 161

33

CE-13HDL-C: % Change From BaselineRosuvastatin 10 to 40 mg vs Comparators Trial 65 – STELLAR (Wk 6)

9.69.5

7.7

2.1

4.44.85.7 5.6

4.53.2

6.8

5.26.0

5.3

0

2

4

6

8

10

12

10 20 40 10 20 40 80 10 20 40 10 20 40 80

Treatment, mg

% c

ha

ng

e f

rom

ba

se

lin

e

Rosuvastatin Atorvastatin

Pravastatin Simvastatin

P < .002 RSV 10 mg vs PRA 10 mg. P < .002 RSV 20 mg vs ATV 20 mg, 40 mg, 80 mg; PRA 20 mg, 40 mg; SIM 40 mg.P < .002 RSV 40 mg vs ATV 40 mg, 80 mg; PRA 40 mg; SIM 40 mg.Data presented as LS means ± SE.

N = 156 160 157 158 155 156 165 160 164 161 165 162 158 163

CE-14Non HDL-C: % Change From BaselineRosuvastatin 10 to 40 mg vs Comparators Trial 65 – STELLAR (Wk 6)

-42-48

-51

-34-40

-45-48

-19-22

-27 -26

-33 -35

-42

-60

-50

-40

-30

-20

-10

0

10 20 40 10 20 40 80 10 20 40 10 20 40 80

Treatment, mg

% c

han

ge

fro

m b

asel

ine

Rosuvastatin AtorvastatinPravastatin Simvastatin

P < .002 RSV 10 mg vs ATV 10 mg; PRA 10 to 40 mg; SIM 10 to 40 mg.P < .002 RSV 20 mg vs ATV 20 mg; PRA 20 mg, 40 mg; SIM 20 to 80 mg.P < .002 RSV 40 mg vs ATV 40 mg; PRA 40 mg; SIM 40 mg, 80 mg.Data presented as LS means ± SE.

N= 156 160 157 158 155 156 165 160 164 161 165 162 158 163

CE-15

Efficacy in Achievement of NCEP Targets

Trial 26

Titration to Goal Comparison to Atorvastatin

CE-16

Rosuva 5 mg

Rosuva 10 mg

10 mg

20 mg

20 mg40 mg

80 mg

40 mg80 mg

20 mg40 mg

80 mg

Atorva 10 mg

Titration to Goal Comparison With Atorvastatin: Titration Scheme Trial 26

Baseline characteristicsMean age: 57 yrMean LDL-C: 187 mg/dL

6-wk 6-wk dietary lead-indietary lead-in

52-wk active treatment52-wk active treatmentTitrated to goals if needed after wk 12Titrated to goals if needed after wk 12

Randomization Titration phase

n = 138

n = 134

n = 140

CE-17% Achieving ATP II LDL-C GoalRosuvastatin 10 to 40 mg vs Atorvastatin 10 to 80 mgTrial 26 (Wk 52)

010

2030

4050

6070

8090

100

Rosuvastatinn = 106

Atorvastatinn = 116

Pat

ien

ts,

%

*P < .05 vs atorvastatin.

Reached on 10 mg

82%

59%

Reached on 80 mg

Reached on 40 mg

Reached on 20 mg

*96%

87%

CE-18

Efficacy in Patients With Severe Hypercholesterolemia:

Comparison With Atorvastatin

Trial 30

Patients With Heterozygous Familial Hypercholesterolemia (FH)

CE-19Heterozygous Familial Hypercholesterolemia Rosuvastatin vs Atorvastatin—Trial DesignTrial 30

Forced-titration

Baseline characteristicsMean age: 48 yrMean LDL-C: 291 mg/dL

RSV 20 mgn = 435

ATV 20 mgn = 187

40 mg 80 mg

40 mg 80 mg

6-wk 6-wk dietary lead-indietary lead-in

18-wk active treatment18-wk active treatmentTitrated at Wk 6, 12, and 18Titrated at Wk 6, 12, and 18

CE-20LDL-C: % Change From BaselineRosuvastatin vs Atorvastatin: Heterozygous FH

Trial 30 (Wk 6 - 18)

-47-54

-58

-38-46

-50

-70

-60

-50

-40

-30

-20

-10

0

Wk 6 Wk 12 Wk 18

% c

han

ge

fro

m b

asel

ine

Rosuvastatin (n = 435)

Atorvastatin (n = 187)

**

*P < .05 vs atorvastatin; data presented as LS means ± SE.

*

20 mg 40 mg 80 mg

CE-21HDL-C: % Change From BaselineRosuvastatin vs Atorvastatin: Heterozygous FHTrial 30 (Wk 6 - 18)

*P < .05 vs atorvastatin; data presented as LS means ± SE.

12

10

12

2.92.7

5.3

0

2

4

6

8

10

12

14

Wk 6 Wk 12 Wk 18

% c

han

ge

fro

m b

asel

ine

Rosuvastatin (n = 435)

Atorvastatin (n = 187)

*

*

*

20 mg 40 mg 80 mg

CE-22% Achieving ATP III LDL-C Goal—All Categories Rosuvastatin vs Atorvastatin: Heterozygous FHTrial 30 (Wk 6 - 18)

*P < .05 vs atorvastatin.

37

49

58

25

33

44

0

10

20

30

40

50

60

70

Wk 6 Wk 12 Wk 18

Pat

ien

ts,

%

Rosuvastatin (n = 435)

Atorvastatin (n = 187)

*

**

20 mg 40 mg 80 mg

CE-23

6.5

17

24

1.53

4.5

0

5

10

15

20

25

30

Wk 6 Wk 12 Wk 18

Pat

ien

ts,

%

Rosuvastatin (n = 155)

Atorvastatin (n = 67)

% Achieving ATP III LDL-C Goal—High RiskRosuvastatin vs Atorvastatin: Heterozygous FHTrial 30 (Wk 6 - 18)

*P < .05 vs atorvastatin; high-risk patients with atherosclerosis/diabetes.

*

LDL-C goal < 100 mg/dL

*

20 mg 40 mg 80 mg

CE-24

Summary of Efficacy

Rosuvastatin 10 mg to 40 mg reduced LDL-C 50% to 62%

Rosuvastatin lowered LDL-C and non-HDL-C more than atorvastatin, simvastatin, and pravastastin across the dose range– Greater increases in HDL-C observed

More patients achieved NCEP goals with a rosuvastatin regimen (10 to 40 mg), than with atorvastatin (10 to 80 mg), simvastatin (20 to 80 mg), or pravastatin (20 to 40 mg)