slide 1 ezt 2002-w-6022-ss ezetimibe co-administered with statins: efficacy and tolerability...

EZT 2002-W-6022-SS

Ezetimibe Co-administered with Statins: Efficacy and Tolerability

Copyright © 2003 MSP Singapore Company, LLC. All rights reserved.

EZT 2002-W-6022-SS

Ezetimibe Together with Statins Co-administration Studies

• Ezetimibe 10 mg co-administered with a statin in eight randomized phase III clinical trials

• Double-blind placebo-controlled studies– Co-administration at start of therapy (lovastatin, simvastatin,

pravastatin, atorvastatin)– Addition to current statin in patients with CHD or multiple

cardiovascular risk factors– Addition to therapy in patients not controlled by atorvastatin 10 mg or

simvastatin 20 mg• Double-blind study

– Addition to statin in patients with HoFH• Statins administered across the full range of recommended doses • Doses administered once daily

CHD = coronary heart disease; HoFH = homozygous familial hypercholesterolemia

EZT 2002-W-6022-SS

Initial Co-administration Study Design

*Only atorvastatin and simvastatin were given in an 80 mg dose.

Placebo

Ezetimibe 10 mg

Statin Statin Statin Statin Placebo 10 mg 20 mg 40 mg 80 mg*

• Statins: atorvastatin*, simvastatin*, lovastatin, and pravastatin• >2300 patients; 65 patients per group• Primary endpoint: % reduction from baseline in LDL-C

– Statin alone vs. ezetimibe + statin– Pairwise comparisons between treatment groups

EZT 2002-W-6022-SS

Ezetimibe Co-administered with Statins: LDL-C Efficacy

*p<0.01 ezetimibe + pooled statin doses vs. pooled statin doses alone

Ezetimibe 10 mg +

pooledatorvastatin

(n=255)

Pooled

atorvastatin

(n=248)

Ezetimibe 10 mg +

pooledsimvastatin

(n=274)

Pooled

simvastatin

(n=263)

Ezetimibe 10 mg +

pooledlovastatin

(n=192)

Pooled

lovastatin

(n=220)

Ezetimibe 10 mg +

pooledpravastatin

(n=204)

Pooled

pravastatin

(n=205)

–50

–40

–30

–20

–10

0

–60

–56.3

–44.2

12.1%*

14.8%*–51.3

–36.5 15.0%*–40.4

–25.4

13.4%*–38.6

–25.2

Mea

n %

ch

ang

e in

cal

cula

ted

L

DL

-C f

rom

bas

elin

e at

12

wee

ks

EZT 2002-W-6022-SS

Ezetimibe Co-administered with Simvastatin: LDL-C Efficacy

*p<0.01 combination therapy vs. statin alone

–46 –45

–27*

–36* –38*

Mea

n %

ch

ang

e in

cal

cula

ted

L

DL

-C f

rom

bas

elin

e at

12

wee

ks

10 mg

Ezetimibe 10 mg+

simvastatin 10 mg 80 mg40 mg20 mg

Simvastatin

–50

–40

–30

–20

–10

0

–60

EZT 2002-W-6022-SS

Ezetimibe Co-administered with Atorvastatin: LDL-C Efficacy

*p<0.01 combination therapy vs. statin alone

10 mg

Ezetimibe 10 mg+

atorvastatin 10 mg 80 mg40 mg20 mg

Atorvastatin

–50

–40

–30

–20

–10

0

–60

–54

–45*–42*

–37*

–53

Mea

n %

ch

ang

e in

cal

cula

ted

L

DL

-C f

rom

bas

elin

e at

12

wee

ks

EZT 2002-W-6022-SS

*p0.01 ezetimibe + pooled statin doses vs. pooled statin doses alone

Ezetimibe Co-administered with Statins: TG Efficacy

–30

–20

–10

0

–40

–33

–24

–29

–20

–25

–12

–21

–14

9%*

9%*

13%*7%*

Mea

n %

ch

ang

e in

TG

fro

m b

asel

ine

at 1

2 w

eeks

Ezetimibe 10 mg +

pooledatorvastatin

(n=255)

Pooled

atorvastatin

(n=248)

Ezetimibe 10 mg +

pooledsimvastatin

(n=274)

Pooled

simvastatin

(n=263)

Ezetimibe 10 mg +

pooledlovastatin

(n=192)

Pooled

lovastatin

(n=220)

Ezetimibe 10 mg +

pooledpravastatin

(n=204)

Pooled

pravastatin

(n=205)

EZT 2002-W-6022-SS

*p0.05 ezetimibe + pooled statin doses vs. pooled statin doses alone

Ezetimibe Co-administered with Statins: HDL-C Efficacy

Mea

n %

ch

ang

e in

HD

L-C

fro

m b

asel

ine

at 1

2 w

eeks

2

4

6

8

10

0

7

9

7

9

4

8

7

4

3%*

2%*

5%*

1%

Ezetimibe 10 mg +

pooledatorvastatin

(n=255)

Pooled

atorvastatin

(n=248)

Ezetimibe 10 mg +

pooledsimvastatin

(n=274)

Pooled

simvastatin

(n=263)

Ezetimibe 10 mg +

pooledlovastatin

(n=192)

Pooled

lovastatin

(n=220)

Ezetimibe 10 mg +

pooledpravastatin

(n=204)

Pooled

pravastatin

(n=205)

EZT 2002-W-6022-SS

Ezetimibe Co-administered with Statins versus High-Dose Statins

Ezetimibe 10 mg once daily together with the lowest statin dose reduced plasma LDL-C as much as or more than the highest dose tested of statin alone.

Mea

n %

ch

ang

e in

LD

L-C

fr

om

bas

elin

e

–40

–20

0

–60

Atorvastatin80 mg(n=62)

–54

Ezetimibe 10 mg +

atorvastatin 10 mg (n=65)

–53

Simvastatin80 mg(n=66)

–45

Ezetimibe 10 mg +

simvastatin 10 mg(n=67)

–46

Lovastatin40 mg(n=73)

–30

Ezetimibe 10 mg +

lovastatin 10 mg(n=64)

–34

Pravastatin40 mg(n=69)

–31

Ezetimibe 10 mg +

pravastatin 10 mg(n=71)

–34

EZT 2002-W-6022-SS

Ezetimibe Co-administered with Statins: Easier Control of LDL-C

• One-step co-administration of ezetimibe equivalent to three-step statin titration

Adapted from Stein E Eur Heart J Suppl 2001;3(suppl E):E11-E16.

0 60

Three-step titration

One-step co-administrationStatin 10 mg

Statin 10 mg

+ Ezetimibe10 mg

5040302010

20mg

40mg

80mg

% reduction in LDL-C

EZT 2002-W-6022-SS

Ezetimibe Co-administration with Ongoing Statin Study Objectives

Adapted from Gagné C et al Am J Cardiol 2002;90:1084-1091.

Assess efficacy and safety profile of ezetimibe 10 mg/day co-administered with ongoing statin monotherapy in patientsneeding further LDL-C lowering

• Primary endpoint– LDL-C–lowering efficacy of co-administering ezetimibe

10 mg/day vs. placebo with a statin

• Secondary endpoints– TG-lowering and HDL-C–increasing efficacy– Patients achieving target LDL-C values with ezetimibe

vs. placebo– Tolerability

EZT 2002-W-6022-SS

Ezetimibe Co-administration with Ongoing Statin Study Design

*21 patients in the placebo group and 23 patients in the ezetimibe group were enrolled while taking nonmarketed doses of statins.


ScreeningScreeningCo-administration phaseCo-administration phase

(ezetimibe or placebo with statin)*(ezetimibe or placebo with statin)*

SimvastatinSimvastatin(n=240)(n=240)

AtorvastatinAtorvastatin(n=308)(n=308)

Other statinsOther statins(n=221)(n=221)

RandomizeRandomize

Ezetimibe 10 mgEzetimibe 10 mg(n=114)(n=114)

Placebo (n=112)Placebo (n=112)

Patients taking statin who require further LDL-C lowering





EZT 2002-W-6022-SS

Ezetimibe Co-administered with Ongoing Statin Therapy: Effect on Lipid Levels

*p<0.001 vs. statin + placebo **p<0.05 vs. statin + placebo***median % change


–25*

–14*

–4 –3

1 3**

–30

–25

–20

–15

–10

–5

0

5

Mea

n %

ch

ang

e fr

om

M

ean

% c

han

ge

fro

m

bas

elin

e at

8 w

eeks

bas

elin

e at

8 w

eeks

–11%

–21%

Statin and placebo (n=390)

Statin and ezetimibe (n=379)

LDL-C

HDL-C

TG***

EZT 2002-W-6022-SS

Ezetimibe Co-administered with Ongoing Statin Therapy: Better LDL-C Goal Attainment

*p<0.001 vs. statin monotherapy **p<0.01 vs. statin monotherapy

NCEP ATP = National Cholesterol Education Program Adult Treatment Panel


Statin monotherapy (n=388)

Ezetimibe + statin (n=375)

% o

f p

atie

nts

at

LD

L-C

g

oal

at

8 w

eeks

All patients Patients not above goal at baseline

20

40

60

0

80

100

76*

27

72*

19

NCEP ATP II Goal Attainment

EZT 2002-W-6022-SS

Ezetimibe Co-administered with Ongoing Statin Therapy: Consistent LDL-C Reductions Across Patient Subgroups

BMI = body mass index


Placebo + statinPlacebo + statin

Ezetimibe 10 mg + statinEzetimibe 10 mg + statin

Difference between treatmentsDifference between treatments

Mean difference in % LDL-C Mean difference in % LDL-C reduction between treatmentsreduction between treatments

% LDL-C reduction by treatment group% LDL-C reduction by treatment group

Non-CaucasianNon-Caucasian

CaucasianCaucasian

65 years65 years

<65 years<65 years

WomenWomen

MenMen

2 4 6 8 10 12 14 16 18 20 22 24 26 28 302 4 6 8 10 12 14 16 18 20 22 24 26 28 30 10 15 20 25 3010 15 20 25 30

• Similar consistency observed for NCEP ATP II risk grades and BMI subcategories

EZT 2002-W-6022-SS

Ezetimibe Co-administered with Statins: Consistency of Study Results

Ezetimibe plus statin resulted in 20 to 22% lower LDL-C than statin alone

Mea

n L

DL

-C (

mm

ol/

L)

at s

tud

y en

d

0.5

1.5

2.5

3.0

3.5

0

1.0

2.0

Statin alone

Statin + ezetimibe

Atorvastatin

2.1

2.7 22%

Simvastatin

2.3

2.9 21%

Pravastatin

2.8

3.5 20%

Lovastatin

2.8

3.5 20%

Ongoing statins

2.7

3.421%

0.5

1.5

2.5

3.0

3.5

0

1.0

2.0

EZT 2002-W-6022-SS

Ezetimibe Co-administration with a Statin for Treatment of HoFH

*p=0.007 vs. statin alone**p=0.0001 vs. statin alone

Adapted from Gagné C et al Circulation 2002;105:2469-2475.

% L

DL

-C r

edu

ctio

n

at 1

2 w

eeks

–20

–10

0

–30

Statin80 mg(n=17)

Ezetimibe + statin

40 or 80 mg(n=33)

–20.7%*

–6.7%

–27.5%**

–7.0%

Statin80 mg(n=17)

Ezetimibe + statin 80 mg(n=17)

EZT 2002-W-6022-SS

Data from Controlled Clinical Trials:Ezetimibe Tolerability and Safety Profile in Co-administration

• Tolerability profile of ezetimibe + statin similar to that of statin alone• Tolerability profile of ezetimibe monotherapy similar to that of placebo

• No increased risk of hematologic or blood chemistry abnormalities over statin alone

• No clinically significant ezetimibe–statin pharmacokinetic interactions

Ezetimibe Placebo Ezetimibe Statin + statin(n=259) (n=262) (n=936) (n=925)

Treatment-related AE (%) 18.1 15.6 16.9 19.5

Discontinuation due to 3.9 2.7 2.5 3.7treatment-related AE (%)

Serious treatment-related AE (%) 0 0.4 0.1 1.1

EZT 2002-W-6022-SS

Ezetimibe Initial Co-administration with Statin Studies: Pooled Safety Data

*From placebo-controlled monotherapy studies**All asymptomatic and reversible with drug continuation or discontinuationGI = gastrointestinal; ULN = upper limit of normal; ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma-glutanyl transpepsidase; CK = creatine kinase

Adapted from Melani L et al. Presented at American Diabetes Association Meeting, San Francisco, CA, July 14–18, 2002 .

Ezetimibe Ezetimibe Statin + statin

Placebo* 10 mg (pooled) (pooled) (n=259) (n=262) (n=936) (n=925)

Adverse events, no. (%) 166 (64.1) 177 (67.6) 606 (64.7) 593 (64.1)

GI disorders, no. (%) 47 (18.1) 54 (20.6) 171 (18.3) 155 (16.8)

Liver function tests (3 ULN)**ALT, no. (%)—total 0 (0) 0 (0) 4 (0.4) 12 (1.3)AST, no. (%) 0 (0) 0 (0) 3 (0.3) 5 (0.5)GGT, no. (%) 3 (1.2) 9 (3.5) 26 (2.8) 33 (3.6)

CK (10 ULN), no. (%) 0 (0) 0 (0) 4 (0.4) 1 (0.1)Myalgia, no. (%) 12 (4.6) 13 (5.0) 38 (4.1) 42 (4.5)

EZT 2002-W-6022-SS

Initial Co-administration of Ezetimibe with Statins: Summary

• Phase III trials of ezetimibe + statin show– Additive effects of ezetimibe + atorvastatin, simvastatin,

pravastatin, or lovastatin on LDL-C reduction– LDL-C–lowering efficacy of ezetimibe + lowest-dose

statin comparable to maximum dose of every statin tested

– Beneficial effects on HDL-C and TG– Good tolerability

EZT 2002-W-6022-SS

Ezetimibe Co-administration with Ongoing Statin Therapy: Summary

• Significant additional efficacy – LDL-C lowered 21% more than placebo (p<0.001)– HDL-C raised 2% more than placebo (p<0.05)– TG lowered 11% more than placebo (p<0.001)

• Significantly better NCEP ATP II goal attainment among patients not at goal when randomized (p<0.001)– 72% (vs. 19%, statin + placebo)


EZT 2002-W-6022-SS

Ezetimibe: Dosage and Administration

• Recommended dose of ezetimibe is 10 mg once daily, co-administered with a statin or alone, to be used as per approved product information

• Ezetimibe may be taken at any time of day, with or without food

• Ezetimibe is not recommended for patients with moderate or severe hepatic insufficiency

• Ezetimibe co-administration with fibrates has not been studied and is not recommended

• No important interactions with commonly used drugs (cholestyramine lowered mean AUC of ezetimibe by 55%)

AUC = area under the plasma concentration-time curve

EZT 2002-W-6022-SS

Before prescribing, please consult full

manufacturer’s prescribing information.

slide 1 ezt 2002-w-6022-ss ezetimibe co-administered with statins: efficacy and tolerability...

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