CRESTORCRESTOR®® (ZD4522, rosuvastatin calcium)(ZD4522, rosuvastatin calcium) TABLETSTABLETS

Comments on Efficacy Comments on Efficacy

CRESTORCRESTOR®® (ZD4522, rosuvastatin calcium)(ZD4522, rosuvastatin calcium) TABLETSTABLETS

Comments on Efficacy Comments on Efficacy

Joy MeleJoy MeleFDA Statistical ReviewerFDA Statistical ReviewerDivision of Biometrics 2Division of Biometrics 2

Joy MeleJoy MeleFDA Statistical ReviewerFDA Statistical ReviewerDivision of Biometrics 2Division of Biometrics 2

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

2

Comments on EfficacyComments on Efficacy

• Rosuvastatin Effect on LDL–Studies 8, 33 and 65

• Comparison of Rosuvastatin and Atorvastatin –Studies 33 and 65

• Rosuvastatin Effect on HDL

• Rosuvastatin Effect on LDL–Studies 8, 33 and 65

• Comparison of Rosuvastatin and Atorvastatin –Studies 33 and 65

• Rosuvastatin Effect on HDL

3

Three Dose Response StudiesThree Dose Response StudiesType IIa/IIb PatientsType IIa/IIb Patients

Three Dose Response StudiesThree Dose Response StudiesType IIa/IIb PatientsType IIa/IIb Patients

Study Doses Sample Size Baseline LDL per arm

8 ROSU 1-40 14-18 ~190 33 ROSU 5-80 38-45 ~191

ATOR 10-80

65 ROSU 10-80 158-163 ~189 ATOR 10-80

Study Doses Sample Size Baseline LDL per arm

8 ROSU 1-40 14-18 ~190 33 ROSU 5-80 38-45 ~191

ATOR 10-80

65 ROSU 10-80 158-163 ~189 ATOR 10-80

4

LDL Mean % Change from Baseline LDL Mean % Change from Baseline for the Dose Range of Rosuvastatinfor the Dose Range of RosuvastatinLDL Mean % Change from Baseline LDL Mean % Change from Baseline for the Dose Range of Rosuvastatinfor the Dose Range of Rosuvastatin

1 2.5 5 10 20 40 80

-70

-60

-50

-40

-30

-20

-10

0

Rosuvastatin Dose (mg)

Study 8

Study 33

Study 65

5

Comparability of Rosuvastatin Comparability of Rosuvastatin and Atorvastatinand Atorvastatin

Comparability of Rosuvastatin Comparability of Rosuvastatin and Atorvastatinand Atorvastatin

• Rosuvastatin is significantly more potent on mg per mg basis

• What doses are comparable?– 2x? 4x?

• Treatment difference and 95% CI

• Rosuvastatin is significantly more potent on mg per mg basis

• What doses are comparable?– 2x? 4x?

• Treatment difference and 95% CI

6

Rosuvastatin vs. 2x AtorvastatinRosuvastatin vs. 2x AtorvastatinStudies 33 + 65 - LDL % change from baselineStudies 33 + 65 - LDL % change from baseline

Treatment Differences and 95% CITreatment Differences and 95% CI

Rosuvastatin vs. 2x AtorvastatinRosuvastatin vs. 2x AtorvastatinStudies 33 + 65 - LDL % change from baselineStudies 33 + 65 - LDL % change from baseline

Treatment Differences and 95% CITreatment Differences and 95% CI

BB

BB

BB

B

S 65S 33

40 vs 80

S 65S 33

20 vs 40

S 65S 33

10 vs 20

S 335 vs 10

-12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12

Rosuvastatin minus Atorvastatin

ROSU Better ATOR Better

7

Rosuvastatin 40 vs. Atorvastatin 80Rosuvastatin 40 vs. Atorvastatin 80Study 65 - LDL % Change from Baseline LOCFStudy 65 - LDL % Change from Baseline LOCF

Rosuvastatin 40 vs. Atorvastatin 80Rosuvastatin 40 vs. Atorvastatin 80Study 65 - LDL % Change from Baseline LOCFStudy 65 - LDL % Change from Baseline LOCF

Rosu40 Ator80

-80-70-60-50-40-30-20-10

010

-80 -60 -40 -20 00

23

42

60

80

100

Cum

ulat

ive

Pct

.

Trt:Rosu40Ator80

8

Rosuvastatin vs. 4x AtorvastatinRosuvastatin vs. 4x Atorvastatin Studies 33 + 65 - LDL % change from baseline Studies 33 + 65 - LDL % change from baseline

Mean Treatment Differences and 95% CI Mean Treatment Differences and 95% CI

Rosuvastatin vs. 4x AtorvastatinRosuvastatin vs. 4x Atorvastatin Studies 33 + 65 - LDL % change from baseline Studies 33 + 65 - LDL % change from baseline

Mean Treatment Differences and 95% CI Mean Treatment Differences and 95% CI

B

B

B

B

B

S 65

S 33

20 vs 80

S 65

S 33

10 vs 40

S 33

5 vs 20

-12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12

Rosuvastatin minus Atorvastatin

ROSU Better ATOR Better

9

HDL % Change from Baseline HDL % Change from Baseline Rosuvastatin Compared to PlaceboRosuvastatin Compared to PlaceboHDL % Change from Baseline HDL % Change from Baseline

Rosuvastatin Compared to PlaceboRosuvastatin Compared to PlaceboStudy BSL 0 5 10 20 40 80

8 ~50 +3% +13% +14% +8% +9%

23 ~55 +3% +11% +15%

24 ~49 +4% +12% +12%

35 ~35 -2% +4% +6% +18% +15% +10%

Treatment group n<30 in Studies 8, 23 and 35; ~128 in Study 24

Study BSL 0 5 10 20 40 80

8 ~50 +3% +13% +14% +8% +9%

23 ~55 +3% +11% +15%

24 ~49 +4% +12% +12%

35 ~35 -2% +4% +6% +18% +15% +10%

Treatment group n<30 in Studies 8, 23 and 35; ~128 in Study 24

10

HDL % Change from Baseline HDL % Change from Baseline for Atorvastatin and Rosuvastatinfor Atorvastatin and Rosuvastatin

Study 65 Type IIa/IIb Study 65 Type IIa/IIb

HDL % Change from Baseline HDL % Change from Baseline for Atorvastatin and Rosuvastatinfor Atorvastatin and Rosuvastatin

Study 65 Type IIa/IIb Study 65 Type IIa/IIb

n= 156 n= 160 n= 157 n= 161 n= 158 n= 154 n= 156 n= 165

R10 R20 R40 R80 A10 A20 A40 A80

-30

-20

-10

0

10

20

30

HD

L %

Ch

an

ge

11

SummarySummarySummarySummary

• Rosuvastatin achieves about 4% more mean LDL-lowering than 2 times the dose of atorvastatin

• The HDL effects are variable– No dose response relationship

• Small increase for 20 mg over 10 mg– Consistent with the statin class

• Rosuvastatin achieves about 4% more mean LDL-lowering than 2 times the dose of atorvastatin

• The HDL effects are variable– No dose response relationship

• Small increase for 20 mg over 10 mg– Consistent with the statin class