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CRESTOR®

(rosuvastatin calcium)Tablets

Endocrinologic and Metabolic DrugsAdvisory Committee

Bethesda, Maryland

July 9, 2003

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CRESTOR® Introduction and

Regulatory Overview

Mark S. Eliason, MSc

Director, Regulatory Affairs

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Objectives of the Rosuvastatin Clinical Development Program

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

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Rosuvastatin Is a Hydrophilic Statin Statin pharmacophore

OO

N

N

S

N

O H

OHO

O

C H3

C H3

CH3

F

CH3

Ca(3R, 5S)

Lipophilicity (log D at pH 7.4)

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

Rosuvastatin

CerivastatinSimvastatin

FluvastatinAtorvastatin

Pravastatin

McTaggart F, et al. Am J Cardiol. 2001;87:28B-32B.

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Rosuvastatin Human Pharmacokinetics

Absorption– Absolute bioavailability = 20.1%– Tmax = 3 to 5 hr

Distribution– Vss = 134.0 L– Plasma protein binding = 88%

Metabolism– Not extensively metabolized

Elimination– t½ = 16 to 20 hr– 90% in feces, 10% in urine

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The NDA Clinical Program

Large international clinical trial program 33 phase I trials 27 phase II/III trials– Doses of 5 to 80 mg studied in phase III– 12,569 patients in safety database

Phase III trial designs– Comparisons with placebo, atorvastatin,

simvastatin, pravastatin, niacin, fenofibrate– Combinations with niacin, fenofibrate, and

cholestyramine– Open-label extension trials

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Important Features of the Rosuvastatin Clinical Development Program

All clinical laboratory samples analyzed at 1 central laboratory in the phase III program

Trials were designed to be inclusive– No upper age limit for trials– For most trials, the upper limit for creatinine

was 2.5 mg/dL–Women of childbearing potential participated– Patients with comorbidities were included

provided they were stable

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US Regulatory History (1)

Initial NDA submission (June 2001)

– Proposed dose range of 10 to 80 mg

In March 2002 AstraZeneca and Division agreed to

– Suspend 80-mg development

– Back-titrate 80-mg dose to 40 mg

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US Regulatory History (2)

NDA Action Letter (May 2002)

– 10-mg, 20-mg, and 40-mg doses approvable

– Data requested on 600 patients for 20-mg and 40-mg doses each for 24 wk

– Additional information on renal effects

NDA amendment submitted (February 2003)

– 12,569 patients in final phase II/III integrated database

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Proposed Indications

Primary hypercholesterolemia and mixed dyslipidemia

Hypertriglyceridemia

Homozygous familial hypercholesterolemia

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Recommended Dosing of CRESTOR®

The recommended starting dose of CRESTOR is 10 mg once daily, with a maximum recommended daily dose of 40 mg

A 20-mg start dose is optional for patients with LDL-C > 190 mg/dL and aggressive lipid goals

For homozygous familial hypercholesterolemia, the recommended starting dose of CRESTOR is 20 mg once daily

A 5-mg dose will be made available for patients receiving cyclosporine

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Current Status of CRESTOR® Program

Market approvals currently in 24 countries

– EU, Asia, and the Americas

– 10- to 40-mg dose range

Ongoing trials program

– ~24,000 patients currently on rosuvastatin in ongoing trials in US and ROW

– Clinical outcomes trials (18,000 patients) initiated in May 2003

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Agenda for Presentation

Introduction and Regulatory Overview

Mark S. Eliason, MScDirector, Regulatory AffairsAstraZeneca

Clinical Development: Efficacy Overview

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

AstraZeneca

Clinical Development:Safety Overview

Howard G. Hutchinson, MDVice President, Clinical ResearchAstraZeneca

The Role of Rosuvastatin in Treatment of Hyperlipidemia

Daniel J. Rader, MDAssociate Professor of Medicine University of Pennsylvania

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Consultant Representatives

Daniel J. Rader, MDAssociate Professor of MedicineUniversity of Pennsylvania

Christie M. Ballantyne, MDProfessor of MedicineBaylor College of Medicine

Donald B. Hunninghake, MDProfessorDepartment of Pharmacology and Medicine (Cardiovascular)

University of Minnesota

Edmund J. Lewis, MDDirector, NephrologyProfessor of MedicineRush-Presbyterian-St. Luke’s Medical Center

Thomas Pearson, MD, PhD, MPHProfessor/Chair/Associate DeanUniversity of Rochester Medical Center

Evan Stein, MD, PhDPresident and CEOMedical Research Laboratories International