AT DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

ENDOCRINOLOGIC AND METABOLIC DRUGS

ADVISORY COMMITTEE

Wednesday, July 9, 2003

8:30 a.m.

Versailles Ballroom

Holiday Inn

8120 Wisconsin Avenue

Bethesda, Maryland

PARTICIPANTS

Glenn Braunstein, M.D., Chair

Dornette Spell-LeSane, M.H.A., NP-C, Executive

Secretary

Members

Dean Follman, Ph.D.

Lynne L. Levitsky, M.D.

Nelson Watts, M.D.

Paul Woolf, M.D.

Special Government Employee Consultants

Thomas O. Carpenter, M.D.

Jeffrey B. Kopp, M.D.

Charles Hennekens, M.D.

Margaret Wierman, M.D.

ACTING INDUSTRY REPRESENTATIVE

John F. Neylan, M.D.

FDA

Robert Temple, M.D.

Robert Meyer, M.D.

David Orloff, M.D.

Mary Parks, M.D.

C O N T E N T S

Call to Order and Introductions:

Glenn Braunstein, M.D. 4

Conflict of Interest Statement:

Dornette Spell-LeSane, M.H.A., NP-C 6

Announcement:

Dr. Catherine McComus 10

Welcome and Introductory Comments:

David Orloff, M.D. 12

NDA 21-366 Crestor (rosuvastatin calcium) tablets

AstraZeneca Pharmaceuticals

agent for iPR Pharmaceuticals, Inc.

Sponsor Presentation

Introduction and Regulatory Overview:

Mark S. Eliason, M.Sc. 19

Clinical Development, Efficacy Overview:

James W. Blasetto, M.D., M.P.H. 30

Clinical Development, Safety Overview:

Howard G. Hutchinson, M.D. 43

The Role of Rosuvastatin in the Treatment of

Hyperlipidemia:

Daniel J. Rader, M.D. 85

Questions from the Committee 100

FDA Presentation

Efficacy:

Joy Mele, M.S. 134

Safety and Dosing:

William Lubas, M.D., Ph.D. 143

Questions from the Committee 160

Open Public Hearing 194

Sidney M. Wolfe, M.D.

Sponsor Comments 206

Charge to the Committee:

David Orloff, M.D. 219

Committee Discussion/Questions 226

Summary: 279

Glenn Braunstein, M.D.

P R O C E E D I N G S

Call to Order and Introductions

DR. BRAUNSTEIN: Welcome to the Food and

Drug Administration, Center for Drug Evaluation and

Research, Meeting of the Endocrinologic and

Metabolic Drugs Advisory Committee for July 9,

2003\. Today we are going to discuss NDA 21-366,

Crestor, rosuvastatin, calcium tablets from

AstraZeneca Pharmaceuticals, agent for iPR

Pharmaceuticals.

We will start by going around the table

and introduce ourselves and tell where we are from

and what role we play on the committee. We will

start with Dr. Temple.

DR. TEMPLE: I\'m Bob Temple. I am

Director of the Office of Medical Policy at FDA and

I actually direct one of the review divisions, one

of the review offices, although it has nothing to

do with the one that is operating today.

DR. MEYER: I am Bob Meyer. I am Director

of the Office of Drug Evaluation II in CDER.

DR. ORLOFF: David Orloff, Director,

Division of Metabolic and Endocrine Drug Products,

CDER.

DR. PARKS: Mary Parks, Deputy Division

Director, Metabolic and Endocrine Drug Products,

CDER.

DR. CARPENTER: Tom Carpenter. I am a

pediatric endocrinologist at Yale University School

of Medicine in New Haven. This is my first meeting

with you all.

MS. SPEEL-LeSANE: Dornette Spell-LeSane,

Executive Secretary for the Committee.

DR. BRAUNSTEIN: Glenn Braunstein,

Chairman of Medicine, Cedars-Sinai Medical Center,

Chair of the Committee.

DR. WOOLF: Paul Woolf, Chairman of

Medicine, Crozer Chester Medical Center,

endocrinologist.

DR. HENNEKENS: Charlie Hennekens from

Medicine and Epidemiology at the University of

Miami. I am a consultant to the committee for this

review.

DR. FOLLMAN: I am Dean Follman, Assistant

Institute Director for Biostatistics at the

National Institute of Allergy and Infectious

Diseases.

DR. WATTS: Nelson Watts, an

endocrinologist from the University of Cincinnati.

DR. WIERMAN: I am Maggie Wierman, an

endocrinologist from the University of Colorado.

DR. LEVITSKY: I am Lynne Levitsky. I am

Chief of Pediatric Endocrinology at Mass General

Hospital in Boston.

DR. NEYLAN: John Neylan. I am a

nephrologist by training and am Vice President of

Clinical Research and Development at Wyeth

Research. I serve on this committee as the Acting

Industry Representative.

DR. BRAUNSTEIN: Thank you.

We will now have the conflict-of-interest

statement read.

Conflict of Interest Statement

MS. SPELL-LeSANE: The following

announcement addresses the issue of conflict of

interest with regard to this meeting and is made a

part of the record to preclude even the appearance

of such at this meeting.

Based on the submitted agenda for the

meeting and all financial interests reported by the

committee participants, it has been determined that

all interests in firms regulated by the Center for

Drug Evaluation and Research which have been

reported by the participants present no potential

for an appearance of a conflict of interest at this

meeting with the following exceptions.

Dr. Glenn Braunstein has been granted a

waiver under 21 U.S.C. 355(n)(4), an amendment of

Section 505 of the Food and Drug Administration

Modernization Act for ownership in stock in a

competitor valued between \$5,001 to \$25,000.

Because this stock interest falls below the de

minimis exemption allowed under 5 C.F.R

2640.202(a)(2), a waiver under 18 U.S.C. 208 is not

required.

Dr. Thomas Carpenter has been granted a

waiver under 18 U.S.C. 208(b)(3) for his membership

on a competitor\'s data safety monitoring board on

unrelated matters. He receives less than \$10,001

per year.

Dr. Charles Hennekens has been granted

waivers under 18 U.S.C. 208(b)(3) and under 21

U.S.C. 355(n)(4), an amendment of Section 505 of

the Food and Drug Administration Modernization Act

for ownership of stock in one of Crestor\'s

competitors valued between \$5,001 to \$25,000 for

ownership of a bond in one of Crestor\'s competitors

valued between \$25,001 to \$50,000 and for ownership

of stock in another of Crestor\'s competitors valued

between \$5,001 to \$25,000. These investments were

made independent of Dr. Hennekens by Sun Trust Bank

which has sole discretionary authority in these

matters.

In addition, the 18 U.S.C. 208(b)(3)

waiver is also for Dr. Hennekens\' membership on two

data safety monitoring boards for a competitor of

Crestor. He receives less than \$10,001 per year

for membership on a competitor\'s advisory board

where he receives less than \$10,001 per year and

for membership on a competitor\'s data safety

monitoring board. He receives less than \$10,000

per year.

Finally, the waiver includes consulting

for two of Crestor\'s competitors. He receives less

than \$10,001 per year from each firm.

Dr. Jeffrey Kopp has been granted a waiver

under 18 U.S.C. 208(b)(3) for his consulting for a

competitor on unrelated matters. The less than

\$10,001 per year is donated to charity.

Dr. Nelson Watts has been granted a waiver

under 18 U.S.C. 208(b)(3) for his consulting for

two competing firms on unrelated matters. He

receives between \$10,001 to \$50,000 per year from

each firm.

Dr. Margaret Wierman has been granted a

waiver under 18 U.S.C. 208(b)(3) for her membership

on a competitor\'s speakers bureau. She receives

between \$10,001 to \$50,000 a year annually, also

for her membership on another competitor\'s speakers

bureau. Less than \$5,000 is paid directly to Dr.

Wierman\'s employer for her research accounts.

Dr. Paul Woolf has been granted waivers

under 18 U.S.C. 208(b)(3) and under 21 U.S.C.

355(n)(4), an amendment of Section 505 of the Food

and Drug Administration Act for ownership of stock

in one of Crestor\'s competitors valued between

\$25,001 and \$50,000.

A copy of these waiver statements may be

obtained by submitting a written request to the

agency\'s Freedom of Information Office, Room 12A30

of the Parklawn Building.

In addition, we would like to disclose

that Dr. John Neylan is participating in this

meeting as an acting industry representative acting

on behalf of regulated industry. In the event that

the discussions involved any other products or

firms not already on the agenda for which an FDA

participant has a financial interest, the

participants are aware of the need to exclude

themselves from such involvement and their

exclusion will be noted for the record.

With respect to all other participants, we

ask, in the interest of fairness, that they address

any current or previous financial involvement with

any firm whose products they wish to comment upon.

DR. BRAUNSTEIN: Thank you.

Dr. Kopp, perhaps you will tell the

audience who you are and what you do.

DR. KOPP: My name is Jeffrey Kopp. I am

a nephrologist with the NIDDK Intramural Research

Program.

DR. BRAUNSTEIN: Thank you.

Dr. Catherine McComus has a brief

announcement.

Announcement

DR. McCOMUS: Good morning. My name is

Catherine McComus. I am a faculty member at the

University of Maryland. I am here today to ask for

your help on a study that I am conducting with the

FDA on what the public knows and understands about

the conflict-of-interest procedures that the FDA

uses to monitor and manage real or potential

conflicts of interest of its advisory-committee

members.

This is a study that is being conducted

across multiple centers at the FDA. This, I

believe, is the tenth meeting where I have

collected data. I have distributed questionnaires

for members in the audience. I have also

distributed a separate questionnaire for the

advisory-committee members. If you have a chance

to complete it today, there is a box outside this

room where you can deposit it. Otherwise, there is

a business-reply envelope that you can drop it in

and mail it back at your convenience.

I do hope that you will take a few moments

to complete this survey. They are anonymous and

the more responses we get, that better we are able

to represent how people feel about the

conflict-of-interest procedures and to provide

recommendations to the FDA on how we might improve

satisfaction with the procedures.

I will be around today if you have any

questions. There is also my contact information

and a letter that is in the survey research and

please feel free to contact me if you have any

questions.

Thank you very much for allowing me to

address the group.

DR. BRAUNSTEIN: Thank you.

Dr. David Orloff will give his

introductory comments.

Welcome and Introductory Comments

DR. ORLOFF: Good morning. First, I want

to thank the members of the committee and the

invited consultants for their review of the

materials beforehand, obviously, and for their

agreement to participate in today\'s meeting.

I don\'t know if Dr. Braunstein noted it,

but Dr. Kreisberg, Robert Kreisberg, who was

supposed to be attending today as a consultant for

the FDA, was unable to attend due to a last-minute

conflict.

I also want to thank the FDA reviewers,

primarily Dr. William Lubas and Joy Mele, for their

work not only in reviewing the NDA but in preparing

for today\'s meeting.

I have some brief introductory remarks

that I will just read, if that is okay with

everyone. Crestor is the seventh HMG CoA-reductase

inhibitor, or statin, to come before the FDA for

review of data addressing safety and efficacy going

back to lovastatin, approved in 1987. Since the

approval of lovastatin, as most in the room

understand, much has been learned about the risks

and benefits of this class of drugs and of

individual members, some, perhaps, more than

others.

With regard to efficacy, HMG CoA-reductase

inhibition, as a pharmacologic approach to lipid

altering, favorably impacts the course of

atherosclerotic cardiovascular disease in a broad

range of populations across ages, genders,

concomitant risk factors, those with diabetes or

without diabetes, in patients with high or low LDL

cholesterol and in those with normal or low HDL

cholesterol.

The controlled clinical-trials experience

with this class includes nearly 30,000

statin-treated patients followed in five-year

placebo-controlled trials examining hard

cardiovascular outcomes as well as

noncardiovascular serious morbidity and mortality.

Suffice it to say that lowering LDL

cholesterol with HMG CoA-reductase inhibitors in

at-risk individuals is, I think, irrefutably proven

to reduce all the manifestations of atherosclerotic

cardiovascular disease including cardiovascular

mortality with no evidence from those trials of a

countervailing excess of noncardiovascular deaths.

This, then, is a remarkably effective class of

drugs.

With regard to specific aspects of the

safety profile of the statins, it has long been

known that statin use is associated with a

dose-related increase incidence of mild to moderate

asymptomatic, often transient and resolving on

therapy, elevations in hepatic transaminases. Rare

cases of serious liver injury have been reported in

association with statin use although causality has

been difficult to establish. I would say that, by

and large, these drugs are safe with regard to the

liver.

Also long known, although not well

understood, is a potentially much more serious side

effect of statins, myopathy. This adverse effect

presents across a broad clinical spectrum from

asymptomatic creatine-kinase elevations to marked

creatine-kinase elevations with symptoms to

full-blown rhabdomyolysis.

From clinical trials, we know that marked

creatine-kinase elevations with or without

clinically evident myopathy, which we consider

surrogates for rhabdomyolysis risk, occur with

increasing frequency at increasing doses of drug.

The risk of myopathy in rhabdo appears further

related to a number of different factors, some

better understood than others; for example,

systemic bioavailability of drug, pharmacokinetic

interactions leading to augmented drug exposure,

the \"affinity,\" in quotes, if you will, of drug for

muscle, the potency of the drug as an inhibitor of

HMG CoA-reductase and predisposing factors such as

diabetes, renal failure, hypothyroidism, surgery,

severe acute illness or injury.

Rhabdomyolysis, or fulminant myopathy with

frank necrosis, myoglobinemia and myoglobinuria and

acute pigment-induced renal failure occurs very

rarely in the clinic in, at least retrospectively,

uniquely susceptible individuals in whom it

appears, after the fact, that some threshold muscle

exposure to drug has been exceeded. As above, as I

stated earlier, this is the most serious side

effect of statins, potentially fatal, and the

dose-limiting toxicity.

Finally, in the Crestor Development

Program, a heretofore undescribed renal side effect

of an HMG CoA-reductase inhibitor has been

observed.

The original New Drug Application for

Crestor was submitted on June 26, 2001. An

approvable action was taken by the agency on May

31, 2002, based on safety concerns arising out of

the initial review regarding muscle and kidney.

More specifically, several cases of severe myopathy

or rhabdomyolysis occurred in patients treated with

80 milligrams daily, the highest dose initially

proposed.

There were no cases seen at 40 milligrams,

although patient exposures at 40 milligrams were

far fewer. Based on this primary safety concern

and the marginal incremental LDL lowering seen with

the step from 40 to 80 milligrams, the agency

concluded that 80 milligrams should not be

approved.

Because the clinical-trial exposures had

been skewed toward the low and high ends of the

proposed dosage range, further data were deemed

necessary before a decision could be reached on the

20 and 40 milligram doses. The FDA requested that

the sponsor conduct additional trials to augment

the patient exposure at 40 milligrams specifically

as 40 milligram starts, patients de novo treated

with Crestor at a dose of 40 milligrams, in order

to answer this important question, is Crestor more

prone to cause myopathy than currently marketed

statins, or, alternatively, was 80 milligrams

simply too high a dose to be, overall, safe for

use.

This question was particularly important

in light of the experience with Baycol,

cerivastatin, which, as was observed post-approval,

conferred substantial risk of myopathy relative to

other members of the class, a doses effecting

little LDL-cholesterol lowering.

In response to the FDA request, the

sponsor has studied the myopathic risk associated

with Crestor use in a very large premarketing

patient exposure, indeed, by far the largest of any

statin brought before the FDA. The sponsor and the

FDA medical officer, Dr. Lubas, will present data

today that suggests that the risk of myopathy with

Crestor relative to LDL-lowering efficacy is, at

the very least, no greater than that with the other

marketed members of the class. I emphasize the

critical importance of this issue in the evaluation

of the safety of this drug.

In addition, the sponsor was asked to

investigate further the finding of new-onset mild

proteinuria observed mostly in patients taking

Crestor 80 milligrams. Specifically, the sponsor

was charged with investigating the \"nature,

magnitude and frequency\" of renal adverse events

observed in patients treated with rosuvastatin and

to explore whether these effects were \"reversible,

chronic or progressive.\"

As you will hear presented, the renal

effects occur with very low frequency at doses

below 80 milligrams although in up to 10 percent of

patients taking 80 milligrams. This is not a

finding noted in other statin-development programs

or in long-term trials of statins.

The clinical picture of Crestor-associated

renal effects seems to include variably the

combination of low-grade proteinuria, minor

elevations in creatinine and microscopic hematuria.

This will be discussed by Dr. Lubas and by the

sponsor.

The sponsor, furthermore, will present

information supporting the possibility that these

renal effects represent a mechanism of

action-related class effect of statins on the

proximal statins on the proximal renal tubule.

This requires close attention and discussion in the

evaluation of the safety of this drug.

In addition, the FDA clinical and

statistical reviewers will make further comments on

specific efficacy and safety issues.

I will end my comments there and have a

few more remarks at the time that I charge the

committee later during the proceedings. Thank you

very much.

DR. BRAUNSTEIN: Thank you Dr. Orloff.

We will now move on to the sponsor\'s

presentation.

NDA 21-366 Crestor (rosuvastatin calcium) tablets

AstraZeneca Pharmaceuticals

Agent for iPR Pharmaceuticals Incidence.

\*\*\*

Sponsor Presentation

Introductory and Regulatory Overview

MR. ELIASON: Good morning everyone. My

name is Mark Eliason and I am the US Regulatory

Director for CRESTOR at AstraZeneca.

\[Slide.\]

Mr. Chairman, distinguished members of

this committee, AstraZeneca is pleased to present

information regarding the safety and efficacy of

CRESTOR Tablets, as currently contained in our NDA.

We hope that you will find our presentations this

morning to be helpful in your deliberations later

in the day.

On behalf of AstraZeneca, I wish

acknowledge at this time the multitude of

physicians, and other healthcare professionals who

participated in the very large CRESTOR drug

development program.

To begin my presentation, Iþd like to

discuss the development objectives established by

AstraZeneca for a new statin candidate.

\[Slide.\]

From the early information derived from

the molecule, we focused on the development of

rosuvastatin to provide an overall benefit risk

profile demonstrating:

greater beneficial effects on key lipid parameters,

at both the start dose and across the dose range,

when compared to approved drugs in this class; a

similar safety profile in relation to muscle,

liver, and other effects, when compared to approved

drugs in the statin class; and, lastly, a low

potential for significant drug-drug interactions,

especially through the Cytochrome P450 and

P-glycoprotein systems, as plasma levels of other

drugs in this class had been shown to be driven

higher due to drug-drug interactions.

\[Slide.\]

Rosuvastatin is a novel synthetic

inhibitor of HMG-CoA reductase that was discovered

by the Shionogi Company of Japan. In terms of its

structure, at first glance rosuvastatin is a

conventional statin as it resembles other statins

in having the common pharmacophore group, the

group that resembles the HMG substrate.

However, rosuvastatin is distinctive in

its structure as it contains a relatively polar

methane sulfonamide group. This helps to place

rosuvastatin low on the scale of lipophilicity,

near pravastatin, when plotted against the other

statins as shown on the scale on the right of this

slide.

This has two consequences for

pharmacology: first, compounds with low

lipophilicity have the potential of being highly

selective for entry into liver cells as compared to

non-hepatic cells. Secondly, compounds low on this

scale are relatively water soluble and therefore

would not require extensive metabolism by the

hepatic CYP P450 system to render them sufficiently

water soluble for excretion.

In essence, preclinically, rosuvastatin

has some of the favorable properties of

pravastatin, namely a high degree of cell

selectivity and a low degree of metabolism by the

cytochrome P450 system.

\[Slide.\]

On this slide, I would now like to briefly

summarize the key pharmacokinetics and disposition

characteristics of rosuvastatin. The absolute

bioavailability of rosuvastatin is approximately 20

percent. The molecule is only moderately bound to

plasma proteins, principally albumin.

Rosuvastatin does not undergo extensive

metabolism in man. Finally, the terminal half-life

of rosuvastatin is approximately 16 to 20 hours.

\[Slide.\]

Moving to our clinical program, our NDA is

supported by a large international clinical

development program. The results of the studies

outlined on this slide will be discussed later in

our presentations. The program included

thirty-three Phase I studies, and twenty-seven

Phase II/III trials. During Phase III, we

evaluated doses from 5 to 80 milligrams.

The safety database from this set of Phase

II/III trials now contains over 12,500 patients

taking rosuvastatin having a total of over 14,000

patient years. As Dr. Orloff had stated earlier

today, this is by far the largest initial approval

NDA database submitted for a statin to date.

The design of the Phase III program trials

included comparative trials to both placebo and key

statin therapies, which included atorvastatin,

simvastatin and pravastatin, as well as to

non-statin therapies, such as niacin and

fenofibrate in hypertriglyceridemic patients. In

addition, we studied rosuvastatin in combination

with niacin and with fenofibrate, as well as

cholestyramine.

At the completion of the controlled

portion of our Phase III trials, the enrolled

patients were allowed to continue into long-term

rosuvastatin open-labeled extension trials. These

open label extensions are all still active and

continue to add valuable long-term rosuvastatin

safety information to the clinical database.

\[Slide.\]

There were a number of important trial

features in the clinical development program for

rosuvastatin, some of which are presented here on

this slide. For our Phase III program, all

clinical laboratory samples were analyzed at one

central laboratory. This reduced the potential for

inter-lab variability.

As you will see later in our

presentations, we also tried to be as inclusive as

possible in the range of patients enrolled in our

Phase II/III trials. The purpose of this was to

recruit a diverse population of patients, in

various states of health, that would be considered

representative of the general population requiring

statin therapy.

To be specific, we had no upper age limit

for our trials so that approximately a third of the

patients participating in our trials were over 65

years of age.

For most of our trials, we allowed patients with

creatinines of up to two and a half milligrams per

deciliter. From this, over 50 percent of the

patients enrolled in our trials had some degree of

renal insufficiency.

Women of childbearing potential were

permitted to enter into most trials, provided that

they were not pregnant and used appropriate

contraception. Finally, we allowed patients into

trials with existing co-morbidities, such as

hypertension, diabetes, and cardiovascular disease,

provided that the patient\'s condition was stable

prior to randomization.

\[Slide.\]

Now I would like to turn to the Crestor

NDA itself. As Dr. Orloff had previous stated, our

original new drug application for CRESTOR Tablets

was submitted to the FDA in June of 2001. The

initial NDA submission proposed a dose range of 10

to 80 milligrams once daily for rosuvastatin.

As further clinical data became available,

it was evident that the 80-milligram dose provided

additional lipid effects that would be of potential

benefit to those patients with difficult-to-control

dyslipidemias.

However, the emergent profile for the

80-milligram dose did not meet our objectives for

the favorable benefit-risk profile for the general

populations. So, in March of 2002, AstraZeneca and

the Review Division agreed to suspend further

development of the rosuvastatin 80-milligram dose

for the general population, and all patients who

were receiving the 80-milligram daily dose had

their dose reduced to 40-milligram daily.

\[Slide.\]

The NDA action letter was issued in May

2002, noting that the proposed 10, 20 and 40

-milligram doses of rosuvastatin were approvable.

The NDA action letter centered on the request for

additional safety data for patients receiving the

20 and 40-milligram, in order to fully assess the

therapeutic index of rosuvastatin. In addition,

the Division requested additional information

regarding the renal effects observed in the

program.

AstraZeneca and Division representatives

met in July 2002 to outline the data package for

responding to the action letter. At this meeting,

the Review Division requested that a minimum of 600

patients treated with rosuvastatin at the 20

milligram and at the 40-milligram for six months be

included in the response.

From that, an NDA amendment was submitted

in February of this year supporting a proposed 10

to 40-milligram dose range for the general

population. The NDA amendment provided the

requested additional safety information for the 20

and 40-milligram doses, and with the submission of

an interim safety update in June of this year, the

final NDA safety database contains over 12,500

patients treated with rosuvastatin.

\[Slide.\]

The Rosuvastatin Clinical Development

Program supports the proposed CRESTOR Tablet NDA

indications which are fully presented in Section

1.1 of our briefing document. I will, just for

time\'s sake, go through them here very quickly.

Our first indication involves primary

hypercholesterolemia and mixed dyslipidemia.

A second indication involves patients with

hypertriglyceridemia. Finally, a third indication

involves the genetic familial homozygous

hypercholesterolemic patient population.

\[Slide.\]

The dosing recommendations proposed in the

CRESTOR NDA are outlined on this slide. For

primary hypercholesterolemia, mixed dyslipidemia

and hypertriglyceridemia, the recommended start

dose of CRESTOR is 10 milligrams, once daily, with

a maximum recommended daily dose of 40 milligrams.

A 20-milligram start dose is optional for

patients with LDL-C levels of greater than 190

milligrams per deciliter and aggressive lipid

targets. For the homozygous familial

hypercholesterolemia indication, the recommended

starting dose for CRESTOR is 20 milligrams once

daily.

Finally, a 5-milligram dose will be made available

for patients taking cyclosporine.

The rationale regarding these dosing

recommendations will be discussed in our

presentations

\[Slide.\]

Regarding the status of the CRESTOR, we

have approval in 24 countries in Europe, Asia and

the Americas, all incorporating the 10-milligram to

40-milligram dose range. In addition to the

described NDA activity, we continue to study

rosuvastatin. Our ongoing trials program,

investigating rosuvastatin in cardiovascular risk

reduction, currently includes approximately 24,000

patients in the U.S. and the rest of the world all

who are taking rosuvastatin.

Also, as part of this program, we have

initiated two clinical-outcomes trials in May of

this year, which will enroll a total of 18,000

patients between them.

\[Slide.\]

With this background in mind, here is the

agenda for remainder of our presentation. Next,

Dr. James Blasetto will present a brief overview of

the key efficacy results from our NDA clinical

development program.

After Dr. Blasetto, Dr. Howard Hutchinson

will discuss the safety profile of rosuvastatin

from our NDA clinical program, with a focus on key

safety issues from the statin drug class.

Finally, AstraZeneca has invited Dr.

Daniel Rader, from the University of Pennsylvania,

to present his thoughts as a practicing physician

on the potential role of rosuvastatin in treating

hypercholesterolemia.

\[Slide.\]

AstraZeneca has also asked the following

individuals to assist in responding to any points

that the advisory committee members may wish to

have addressed during this meeting. In addition to

Dr. Rader, we have Dr. Christie Ballantyne from

Baylor College, Dr. Donald Hunninghake from the

University of Minnesota, Dr. Edmund J. Lewis from

Rush Presbyterian St. Luke\'s Medical Center, Dr.

Thomas Pearson from the University of Rochester

Medical Center and Dr. Evan Stein from Medical

Research Laboratories International.

Now I would like to introduce Dr. James

Blasetto, Senior Director at AstraZeneca, who will

present the efficacy portion of our presentation.

Dr. Blasetto?

Clinical Development

Efficacy Overview

DR. BLASETTO: Good morning.

\[Slide.\]

I am Dr. James Blasetto, Senior Director,

Clinical Research at AstraZeneca.

\[Slide.\]

Hypercholesterolemia represents a

significant, persistent yet potentially treatable

medical program in the United States. If we look

at the evolution of the Cholesterol Management

Guidelines as proposed by the National Cholesterol

Education Program, we see an ever-increasing need

for more lipid-modifying efficacy.

If we focus in on the most recent

guidelines, the ATP-3 Guidelines launched in 2001,

we see a number of new and important features.

Firstly, identifies the optimal LDL-C level at less

than 100 milligrams per deciliter.

Secondly, the target goal for patients in

the high-risk group has been made more aggressive,

less than 100 milligrams per deciliter, and a

number of patients that qualify for the high-risk

group has been expanded with the introduction of

the CHD risk-equivalent patients.

Thirdly, there is an increased focus on

HDL-C with a secondary target for therapy, the

non-HDL-C goal, for patients with persistent

elevated triglycerides. Thus, with the current

guidelines, it is estimated that over 36 million

patients will require lipid-lowering therapy and

approximately 60 percent of those, or approximately

21 million, will require a treatment LDL-C goal of

less than 100 milligrams per deciliter.

\[Slide.\]

Yet, if we look at recent clinical data,

we see that a treatment gap still exists between

what current therapies can obtain and what is

needed. This is data that was presented by Dr.

Christie Ballantyne in 2001 from the ACCESS Trial,

the Atorvastatin Comparative Cholesterol Efficacy

and Safety Study.

This is a cohort of patients in the CHD

risk category. Patients were treated and titrated

up to achievement of the ATP-2 goal, an LDL-C of

less than or equal to 100 milligrams per deciliter.

If we focus in on the patients that were

treated with up to maximum doses of atorvastatin,

80 milligrams, we see that 28 percent of the

patients did not achieve their LDL-C target goal

and approximately 40 percent of the patients did

not achieve an established non-HDL-C goal.

If we look at the percent of patients that

did not achieve their LDL or non-HDL-C goals with

the other statins at the doses studied, we see the

numbers were even greater. Thus, with the current

guidelines, more patients require more aggressive

treatments yet, with current therapies, a treatment

deficit still exists.

\[Slide.\]

Now, as you heard in the opening remarks,

there were three key objectives that were core to

our Clinical Development Program. My presentation

will focus on efficacy data to support the first

key objective which was to demonstrate greater

beneficial effects on key lipid parameters over

currently marketed statins. In addition, I will

discuss data that addresses efficacy questions

raised to this advisory committee.

\[Slide.\]

Our first LDL efficacy data came from two

Phase II dose-ranging studies. These studies were

prospectively designed to be pooled. The patient

population evaluated were patients with Type IIa

and IIb hypercholesterolemia.

This is the response seen in percent

change from baseline in LDL-C at each of the doses

evaluated. The mean age in the population studied

was 56 years and the mean baseline LDL-C, 190

milligrams per deciliter. Statistically

significant differences compared to placebo at each

of the doses evaluated were seen, a 33 percent

reduction up to a 65 percent reduction in LDL-C.

Now, based on the efficacy that we saw in

these dose-ranging studies, we initially chose to

evaluate two potential starting doses, rosuvastatin

5 milligrams and rosuvastatin 10 milligrams.

\[Slide.\]

Our Phase III data has confirmed the added

benefits on key lipid parameters with the

10-milligram dose compared to the 5-milligram dose

with an indistinguishable safety profile.

This is data from five clinical trials in

our Phase III program which was prospectively

designed to be pooled. The patient populations

studied were patients with Type IIa and IIb

hypercholesterolemia. The mean age in the

population was 58 with a mean baseline LDL-C of 187

milligrams per deciliter.

After twelve weeks of treatment, this is

the response seen in key lipid parameters with

rosuvastatin 10-milligrams and rosuvastatin 5

milligrams. The 10-milligram dose added benefit on

all lipid parameters compared to the 5-milligram

dose, in particular, a 6 percent further LDL-C

reduction and an approximate 5 percent further

non-HDL-C reduction.

Thus, the risk-benefit profile of the

10-milligram dose is better than the 5-milligram

dose and offers a better treatment option as a

starting dose for patients. Thus, our proposed

starting dose for the general population is

rosuvastatin 10 milligrams.

Alternatively, we initially evaluated

doses up to and including the 80-milligram dose.

As you heard in the opening remarks, after an

assessment of the benefit-risk profile of the

80-milligram dose, we elected to back-titrate

patients from 80 milligrams to 40 milligrams and

not to pursue at this time further development of

the 80-milligram dose. Thus, the maximum proposed

dose is rosuvastatin 40 milligrams.

Rosuvastatin 40 milligrams offers benefit

in key lipid parameters compared to the

20-milligram dose for patients requiring more

reductions to achieve their NCEP targets.

\[Slide.\]

This is data from five individual clinical

trials in our development program which looks at

the effects on LDL-C with rosuvastatin 40

milligrams and rosuvastatin 20 milligrams. In each

of these trials, the patient populations studies

were patients with Type IIa and IIb

hypercholesterolemia with a cohort of patients with

heterozygous familiar hypercholesterolemia

evaluated in Trial 30.

In each of these clinical trials, the

40-milligram dose added greater reductions in LDL-C

compared to the 20-milligram dose. In four or five

of the clinical trials, there was a 7 percent or

greater LDL-C reduction seen with the 40-milligram

dose compared to the 20-milligram dose. Thus, for

patients requiring more reductions in LDL-C or

non-HDL-C to achieve their NCEP target goals, the

40-milligram dose offers benefits over the

20-milligram dose.

Thus our proposed dose range is

rosuvastatin 10 to 40 milligrams and, for the

remainder of my presentation, I will focus on the

10 to 40-milligram dose range.

\[Slide.\]

We studied the effects comparatively of

rosuvastatin in several clinical trials.

\[Slide.\]

The largest clinical trial comparatively

done was the STELLAR Trial, Trial 65, as presented

here. This trial included over 2,000 patients.

After a six-week dietary lead-in, patients were

randomized in an open-label fashion to one of the

treatment arms with rosuvastatin, atorvastatin,

simvastatin or pravastatin, as shown, for six weeks

of treatment.

Baseline characteristics in all treatment

arms were well-matched. The mean age in the

population was 57 and the mean baseline LDL-C 189

milligrams per deciliter.

\[Slide.\]

After six weeks of treatment, this is the

response seen in percent change from baseline in

LDL-C. Rosuvastatin, 10 to 40 milligrams on a

milligram-to-milligram basis demonstrated greater

reductions than atorvastatin, simvastatin and

pravastatin.

Doubling of the dose of statin therapy

yielded an approximate 4.5 to 5 percent further

LDL-C reduction. If we assess the effects of

patients treated with rosuvastatin 40 milligrams to

those treated with atorvastatin 80 milligrams, we

saw an approximate 4 percent further LDL-C

reduction with rosuvastatin therapy.

\[Slide.\]

If we look at the distribution of LDL-C at

each of the treatment arms, we see that the

distribution of LDL-C was similar in each treatment

arm, the number of outliers was similar and the

median reduction in LDL-C seen with rosuvastatin 40

milligrams was greater than that seen with the

other statin comparators.

\[Slide.\]

The STELLAR Trial was designed to perform

multiple pairwise and dose-to-dose comparisons on

other key lipid parameters. This is the response

in HDL-C after six weeks of treatment in each of

the treatment arms evaluated. Rosuvastatin 20 and

40 milligrams raised the HDL-C approximately 10

percent.

Comparatively, the 10-milligram-response

rosuvastatin was statistically greater than the

10-milligram response of pravastatin. The

20-milligram-response rosuvastatin was

statistically greater than the 20 to 80-milligram

response of atorvastatin, the 20 and 40-milligram

response of pravastatin and the 40-milligram

response of simvastatin. The 40-milligram response

of rosuvastatin was greater than the 40 and

80-milligram response of atorvastatin and the

40-milligram response of both simvastatin and

pravastatin.

\[Slide.\]

We assessed the results on the important

parameter non-HDL-C goal. Rosuvastatin, at the

40-milligram dose, reduced non-HDL-C by greater

than 50 percent. Comparatively, compared to

similar doses of atorvastatin and similar doses, or

higher doses, of simvastatin and pravastatin,

rosuvastatin reduced non-HDL-C by a greater

percent.

\[Slide.\]

Now, to assess the effects on achievement

on NCEP targets at higher doses, we evaluated

rosuvastatin comparative to atorvastatin in a

titration-to-goal study, Study 26.

\[Slide.\]

This is the design of that trial. After a

six-week dietary lead-in, patients were randomized

in a double-blind fashion to one of the treatment

arms with rosuvastatin or a common starting dose,

atorvastatin 10 milligrams, for twelve weeks of

active treatment.

After twelve weeks, patients were then

subsequently titrated to the next highest dose if

they did not achieve their ATP-2 LDL-C targets.

Baseline characteristics in each of the treatment

arms were well matched. In this population of

patients with Type IIa and IIb

hypercholesterolemia, the mean age was 57 and the

mean baseline LDL-C 187 milligrams per deciliter.

\[Slide.\]

After 52 weeks of treatment, this is the

response seen in the percent of patients achieving

target goal. 82 percent of the patients on

rosuvastatin 10 milligrams achieved their target

goal without need for titration compared to 59

percent of the patients on atorvastatin 10

milligrams.

Overall, 96 percent of the patients

achieved target goal with a regimen of rosuvastatin

10 to 40 milligrams compared to 87 percent of the

patients with a regimen of atorvastatin 10 to 80

milligrams. Thus, overall, more patients achieved

their target goal but, in particular, a greater

percentage achieved target goal at the starting

dose without need for titration.

\[Slide.\]

I would like to conclude with an

assessment of rosuvastatin in an important

population of patients, patients with severe

hypercholesterolemia, heterozygous familial

hypercholesterolemia. This represents an important

population of patients because of the severe nature

of their hypercholesterolemia. They are difficult

to treat and have a frequency in the United States

population of approximately 1 in 500.

\[Slide.\]

We assessed the effects of rosuvastatin

comparatively in this population in Trial 30. This

is the design of that trial. It was a large,

multicentered, multinational trial. After a

six-week dietary lead-in, patients were randomized

in a double-blind fashion to rosuvastatin or

atorvastatin 10 milligrams.

In view of the severe hypercholesterolemia

at baseline these patients had, and the increased

efficacy they needed at the start of therapy, we

chose a strategy of starting these patients to

evaluate a 20-milligram starting dose. After six

weeks of treatment, the patients were

force-titrated to the 40-milligram dose and then

ultimately to the 80-milligram dose.

Baseline characteristics were well matched

in both treatment arms. The mean age of the

population was 48, somewhat younger than the data I

previously presented. That is not unexpected with

patients with heterozygous familial

hypercholesterolemia. The baseline LDL-C

demonstrates the severe hypercholesterolemia of

these patients approaching nearly 300 milligrams

per deciliter.

The results of the 80-milligram dose will

be presented to show the potential added benefits

of increased efficacy. However, in view of our

proposed dosing recommendations, I will focus my

comments on the 20 and 40-milligram dose response

for rosuvastatin.

\[Slide.\]

This is the response in the percent change

from baseline in LDL-C at each of the time points

and doses evaluated. Rosuvastatin 20 milligrams

reduced LDL-C 47 percent and 54 percent reduction

at the 40-milligram dose, statistically greater

than the 20 and 40-milligram dose response seen

with atorvastatin.

\[Slide.\]

If we evaluate the effects on HDL-C, a 12

percent and 10 percent increase in HDL-C seen with

20 and 40 milligrams of rosuvastatin, statistically

greater than the 20 and 40-milligram response seen

with atorvastatin.

\[Slide.\]

The greater LDL-C reduction translated

into more patients achieving their ATP-3 target

goals. 37 percent of the patients with

rosuvastatin 20 milligrams achieved the target goal

and nearly 50 percent with rosuvastatin

40 milligrams, both statistically greater than the

20 and 40-milligram response of atorvastatin.

\[Slide.\]

If we focus in on that high-risk group of

patients requiring a target LDL-C of less than 100

milligrams per deciliter, 17 percent of the

patients achieved that target goal with

rosuvastatin 40 milligrams compared to 3 percent of

the patients with atorvastatin 40 milligrams. This

was statistically different.

\[Slide.\]

So, in summary, data from our Clinical

Development Program has demonstrated rosuvastatin

10 to 40 milligrams reduced LDL-C 50 to 62 percent

as presented in the dose-ranging studies.

Rosuvastatin lowered LDL-C and non-HDL-C more than

atorvastatin, simvastatin and pravastatin across

the dose range. Greater increases in HDL-C were

observed.

More patients achieved NCEP goals with a regimen of

rosuvastatin 10 to 40 milligrams than that with

atorvastatin 10 to 80 milligrams, simvastatin 20 to

80 milligrams and pravastatin 20 to 40 milligrams.

I thank you and, at this time, I would

like to introduce Dr. Howard Hutchinson who will

discuss the safety profile of rosuvastatin.

Clinical Development

Safety Review

DR. HUTCHINSON: Good Morning.

\[Slide.\]

I am Howard Hutchinson, Vice President for

Clinical Research at AstraZeneca. Today, I am

pleased to be here to present the safety profile

for rosuvastatin.

\[Slide.\]

Dr. Blasetto presented the efficacy data

showing the overall benefits of a rosuvastatin

10-milligram to 40-milligram dose range for the

treatment of patients with dyslipidemia. However,

the benefits of a new drug must also be placed in

the context of the potential risks associated with

its use.

With this in mind, I will now present data

which addresses the last two objectives of our

development program. This information will show

that the proposed 10-milligram to 40-milligram dose

range for rosuvastatin has a safety profile similar

to other marketed statins, and that rosuvastatin

will have a low potential for significant drug-drug

interactions.

\[Slide.\]

The safety data I am going to present

today comes from twenty-seven clinical trials

conducted worldwide.

About half the patients were from the United

States.

The overall database is comprised of over 12,500

patients who have had over 14,000 patient years of

treatment with rosuvastatin at doses up to and

including 80 milligrams.

\[Slide.\]

In presenting the safety data, I will

focus on several key areas. First, I will present

the overall demography of our patient population

followed by exposure data, and adverse events. I

will then focus on three areas of interest for

rosuvastatin and statins in general. They are the

liver, skeletal muscle, and renal effects.

I will finish with a brief presentation on

drug-drug interactions.

\[Slide.\]

This slide represents the overall

demography for patients in our

all-controlled/uncontrolled plus Real Time

Laboratory Data or RTLD Pool. This pool represents

our largest pool with 12,569 patients and includes

patients exposed to rosuvastatin in both controlled

trials and in open-label extension trials.

As shown, the mean age for subjects in our

program was 58. Approximately one-third of the

patients were 65 years or older, and over 900 were

75 or over. Almost half of the population was

female, and two-thirds of the women were

post-menopausal.

\[Slide.\]

With regard to ethnicity, most patients

were Caucasian; however, over 1000 patients were of

non-Caucasian descent.

\[Slide.\]

We set up our development program to be

inclusive. Patients with co-morbid conditions were

permitted to enter studies provided they were

stable at baseline and we allowed patients to enter

most trials with a serum creatinine level up to 2.5

milligrams per deciliter.

As shown, over half of the subjects

enrolled in the program had baseline renal

impairment as determined using the Cockroft-Gault

formula. In addition, over half of the subjects

had baseline hypertension, 36 percent had

documented atherosclerotic cardiovascular disease,

and 16.5 percent had diabetes.

\[Slide.\]

This slide shows the maximum continuous

duration of treatment with the 5-milligram to

80-milligram doses of rosuvastatin from the

clinical trial program. As shown, over 1000

patients were treated with each of these doses.

Importantly, over 7800 patients were treated with

10-milligram proposed starting dose, over 3900

patients were treated with the 20-milligram dose,

and over 4000 were treated with the 40-milligram

dose. Of the 4000 subjects treated with the

40-milligram dose, over 2000 initiated therapy at

this dose.

Highlighted are the 24-week and 48-week

exposures. Note that over 1300 and 1800 patients

were treated with the 20-milligram and 40-milligram

doses for 24 weeks or longer. 545 and 276 were

treated with these doses for greater than or equal

to 48 weeks. As previously discussed, patients on

80 milligrams were back-titrated to 40 milligrams

during the development program. The 40-milligram

exposures seen in this table represent patients

back-titrated from 80 milligrams and patients never

exposed to 80 milligrams. Importantly, however, all

of the exposures greater than 48 weeks are in

patients who were never exposed to the 80-milligram

dose and over 3700 patients in this pool were never

exposed to the 80-milligram dose.

The last column is the greater than or

equal to 40-milligram treatment group. In this

group, patients treated with 80-milligram dose and

back-titrated to 40 milligrams were considered to

have been treated continuously with rosuvastatin

with at least 40 milligrams of drug.

This group is important because it gives

information regarding the potential for adverse

events to occur very late into therapy. Note that

1165 patients were treated for greater than or

equal to 48 weeks in this group and 874 for greater

than or equal to 96 weeks in this group.

As you will see, the exposures generated

for this analysis are appropriate for evaluating

the overall safety of rosuvastatin at doses up to

and including 80 milligrams.

\[Slide.\]

Today, a detailed review of

patient-reported adverse events will not be

presented so that I can focus on the more critical

issues addressed in the FDA briefing document.

Shown here are the key points summarizing the

adverse event data.

First of all, the data showed that the

frequency and types of adverse events reported for

rosuvastatin were similar to that of the comparator

statins in our program. Second, the frequency and

types of adverse events were similar for the

5-milligram, 10-milligram, 20-milligram and

40-milligram doses of rosuvastatin.

However, at the 80-milligram dose,

increased frequencies of nausea, myalgia, asthenia,

and constipation were observed, in particular,

nausea, myalgia, asthenia and constipation.

Importantly, rosuvastatin was well-tolerated in a

broad spectrum of patients regardless of age, sex,

ethnicity, the presence comorbidities such as

diabetes, hypertension, or renal impairment, and in

patients on medications used to treat comorbid

conditions such as anti-hypertensive agents and

anti-diabetic agents.

\[Slide.\]

I would now like to turn our attention to

the effects of rosuvastatin on three organs, the

liver, skeletal muscle, and kidneys. I will start

with the liver.

As Dr. Orloff had mentioned earlier, in

general, statins are well tolerated from the

perspective of the liver. Asymptomatic

transaminase elevations are reported for all

statins, and the frequency of the elevations

appears to increase with dose. Importantly, these

elevations have almost never been associated with

liver failure. The effects of rosuvastatin on the

liver are similar to that observed with other

members of the class.

\[Slide.\]

In the rosuvastatin program, liver

function tests were performed at each visit. In

this section, I will present the percentage of

patients with ALT elevations greater than three

times the upper limit of normal on two occasions.

Note that the ALT elevations greater than three

times the upper limit of normal on two occasions is

consistent with the definition of persistent

elevations used in the labels for other marketed

statins.

I will not present data on AST elevations.

However, AST elevations in our program mirrored the

ALT elevations.

We also evaluated patients for ALT

elevations associated with increases in bilirubin.

Importantly, these elevations were rarely observed,

and, in those instances where they were observed,

they were almost always associated with another

illness such as a malignancy or infectious

hepatitis.

\[Slide.\]

Shown on this slide is the frequency of

persistent ALT elevations in patients treated with

rosuvastatin from 5 to 80 milligrams in the all

Controlled/uncontrolled plus RTLD Pool. The data

shows that the frequency of þpersistent ALT

elevationsþ ranged from 0.1 percent to 0.5 percent

at rosuvastatin doses from 5 to 40 but increased to

1.4 percent at the 80-milligram dose.

\[Slide.\]

This figure helps to put the overall ALT

results from the rosuvastatin program into context

with that reported in the prescribing information

or summary basis of approval documents for other

marketed statins, specifically fluvastatin, 20, 40,

and 80 milligrams, lovastatin, 20, 40, and 80

milligrams, simvastatin, 40 and 80 milligrams,

atorvastatin, 10, 20, 40, and 80 milligrams and the

data for rosuvastatin.

On the x-axis is plotted the percentage

LDL-C lowering for the various doses of drug which

represents the potential benefits that can be

achieved at a particular dose. On the y-axis, the

frequency of persistent ALT elevations at a given

dose represents a potential risk of the dose. Note

that rosuvastatin at doses from 5 to 40 milligrams

has a low frequency of elevations similar that

observed with other statins. Only at the

80-milligram dose is an increase in frequency of

persistent elevations seen. The increase in

frequency with rosuvastatin at the 80-milligram

dose, however, is in the range observed for

marketed statins. However, the increase observed

with the other marketed statins occurs at lower

levels of LDL-C reduction.

Overall, the data pertaining to possible

liver effects of rosuvastatin obtained from our

development program support its safety with regard

to this organ.

\[Slide.\]

I would now like to turn our attention to

skeletal-muscle findings. Similar to persistent

ALT elevations, adverse skeletal-muscle effects are

a recognized complication of statin therapy.

Adverse effects such as myopathy and rhabdomyolysis

have been reported for all statins. However, the

frequency of such reports is very low within the

recommended dose range.

\[Slide.\]

Similar to the routine evaluation of

liver-function tests in our program, creatine

kinase or CK measurements were performed at each

visit also.

In this part of my talk, I will present

the following information.

First, I will present data on CK

elevations greater than ten times the upper limit

of normal. This is an objective measure of the

potential of a statin to cause muscle effects.

Next, I will present our cases of

myopathy. In our program, we used a well

established definition of myopathy which is CK

elevations greater than ten times the upper limit

of normal with associated muscle symptoms.

Some of the patients in our program had

rhabdomyolysis at the 80-milligram dose.

Currently, rhabdomyolysis is defined

several different ways in the literature. In the

FDA review, rhabdomyolysis cases are defined as

those patients with myopathy who required

hospitalization to receive intravenous fluids.

\[Slide.\]

Shown on this slide is the frequency of

both symptomatic and asymptomatic CK elevations in

patients treated with rosuvastatin at doses from 5

to 80 milligrams, once again in our largest pool,

the all controlled/uncontrolled plus RTLD Pool. Our

data shows that the frequency of elevations ranged

from 0.2 to 0.4 percent at rosuvastatin doses from

5 to 40 but increased to 1.9 percent at the

80-milligram dose.

If we now look at these cases for patients

with muscle-related symptoms, we have our overall

myopathy group.

\[Slide.\]

Shown on this slide are all symptomatic CK

elevations and those with a possible relationship

to treatment. Note that the overall number of

symptomatic CK elevations at doses from 5 to 40

milligrams is low and similar. The overall

frequency increases to 1.0 percent at the

80-milligram dose.

However, many of these patients had

symptomatic elevations related to causes such as

heavy exercise or injury and many resolved on

continued therapy at the same dose of rosuvastatin.

If we exclude those cases with clearly identified

other causes, we have left the cases with a more

likely association to rosuvastatin therapy.

A total of thirteen possibly

treatment-related cases have been identified, one

case each at 20-milligram and 40-milligram doses

and eleven cases at 80-milligram dose. The one case

observed at 20-milligram dose was in a patient who

was also found to have a Coxsackie Type IV viral

infection at the time of the event. Coxsackie Type

IV viral infections have been associated with

myopathy.

The patient at 40 milligrams had a history

of asymptomatic CK elevations as high as 10,000 off

statin therapy who had a CK elevation to 15,000

three days after initiating a weight-lifting

program. Because the patient had associated arm

pain, he was hospitalized to rule out a myocardial

infarction. After ruling out for myocardial

infarction and being discharged, the patient was

restarted on rosuvastatin 40 milligrams and has now

remained on this dose for several months and has

been asymptomatic without CK elevations.

The eleven cases of possibly

treatment-related myopathy at the 80-milligram

gives a frequency of 0.7 percent at this dose.

Importantly, all eleven of these patients recovered

following discontinuation of therapy. Seven

patients were hospitalized to receive intravenous

fluids. During the program, we also had two cases

of myopathy observed in patients on simvastatin 80

milligrams which gave us a frequency of myopathy

for that group of 0.4 percent. One of these

patients was hospitalized to receive intravenous

fluids.

\[Slide.\]

The eleven 80-milligram myopathy cases do

allow us an opportunity to evaluate the possible

risk factors for myopathy with rosuvastatin. The

three major risk factors that we identified at the

80-milligram dose were age, renal insufficiency,

and hypothyroidism. It is important to note that

these are also identified as risk factors for

myopathy with other marketed statins.

With regard to age, the frequency of

myopathy was 0.2 percent in subjects less than 65

years old and 2.3 percent in subjects 65 years of

age or older. Patients with a creatinine clearance

less than 80 milliliters per minute had a myopathy

frequency of 1.2 percent at the 80-milligram dose

compared to a frequency of 0.2 percent in patients

with a normal renal function or a creatinine

clearance greater than 80 milliliters per minute.

However, whether renal insufficiency is

truly an independent risk factor for myopathy is

difficult to determine from our data since we used

the Cockroft Gault formula and age is a significant

component in the creatinine-clearance calculation.

Although hypothyroidism was an exclusion

criterion in our program, two patients with

myopathy did have an elevated TSH at the time of

their event.

With regard to gender, we did not find a

sex-based predisposition to myopathy. However, of

the seven patients hospitalized to receive

intravenous fluids, five were females.

\[Slide.\]

The data from our program show that

rosuvastatin was well tolerated from a

skeletal-muscle perspective. An increased

frequency of adverse skeletal-muscle effects

compared to lower doses of rosuvastatin was

observed at the 80-milligram dose. However, the

vast majority of patients were safely treated even

with the 80-milligram dose.

How do the skeletal-muscle data generated

from this program compare to data for other

statins? To look at this, we looked back at CK

elevations greater than ten times the upper limit

of normal because this provide an objective measure

for evaluating the potential for a dose of a statin

to cause muscle toxicity.

In this slide, we compare the effects of

rosuvastatin on this parameter to results reported

for cerivastatin at 0.2 to 0.8 milligrams,

pravastatin 40 and 80 milligrams, simvastatin, 40

and 80-milligrams, atorvastatin, 10 to 80

milligrams and rosuvastatin.

In this figure, we evaluate the overall

benefits of a dose of a statin with regard to LDL-C

lowering versus the risk of having a CK elevation

greater than ten times the upper limit of normal.

Note that at rosuvastatin doses up to and including

40 milligrams, the frequency of CK elevations is

low and similar to that observed with other

statins. Only at the 80-milligram dose where LDL-C

is reduced 65 percent does the frequency of

elevations increase above that observed for the

highest doses of pravastatin, simvastatin, or

atorvastatin.

Also observe the marked difference between

rosuvastatin and cerivastatin where at 35 to 40

percent LDL-C lowering, the frequency of CK

elevations is high.

One potential reason that the number of myopathies

with cerivastatin was high is that a much larger

percentage of hypercholesterolemic patients need

LDL-C lowering in the range of 35 to 40 percent.

In order to get this lowering with

cerivastatin, patients needed to be exposed to

doses with a greater likelihood of affecting

skeletal muscle.

\[Slide.\]

Overall, the skeletal-muscle data for

rosuvastatin program show that it was well

tolerated at doses up to and including 40

milligrams. At these doses, the frequency of

adverse effects was similar to that observed for

other marketed statins, but as you have seen in an

earlier presentation, greater lipid modification

can be achieved with rosuvastatin.

At the 80-milligram dose, patients

achieved an additional 2 to 4 percent LDL-C

reduction over the 40-milligram dose. However, the

frequency of adverse skeletal-muscle effects at

this dose increased above that observed for

rosuvastatin 40 milligrams and the highest doses of

other marketed statins.

Although a small number of patients

experienced adverse skeletal-muscle effects at the

80-milligram dose, many patients were safely

treated. 1200 patients under the age of 65 were

treated with the 80-milligram dose and the

frequency of myopathy in this group was 0.2

percent. Importantly, all patients who had a

significant adverse event at this dose recovered.

\[Slide.\]

I would now like to turn our attention to

the effects of rosuvastatin on the kidney.

\[Slide.\]

Adverse statin effects on the kidney are

well documented in terms of renal failure secondary

to myoglobinuria associated with rhabdomyolysis.

However, other potential effects on the kidney are

not well documented. Following the completion of

the initial Phase III studies for rosuvastatin, an

increased frequency of proteinuria was detected

predominantly at the 80-milligram dose.

In response to this finding, additional

investigations were performed to characterize the

frequency, magnitude, and nature of the proteinuria

and to determine the potential for rosuvastatin to

cause acute or progressive injury to the kidney.

In this section, I will present the results of

these analyses.

\[Slide.\]

In the rosuvastatin program, proteinuria

was evaluated primarily using dipstick testing. In

the general population, a prevalence of proteinuria

up to 10 percent on dipstick testing has been

reported.

Proteinuria can have an organic etiology,

such as that which occurs in patients with

diabetes, hypertension, and urologic infections or

it can be functional. Functional causes of

proteinuria include exercise, orthostatic

proteinuria, and proteinuria associated with

pregnancy.

Proteinuria can occur due to changes in the

glomerulus, the renal tubules or both sections of

the nephron. The types of proteins excreted can

help identify the source of the proteins.

Glomerular proteinuria is due to leakage

of albumin and other larger molecular weight

proteins through the glomerulus and is the type of

proteinuria associated with diabetic kidney disease

and hypertension.

Tubular proteinuria, which you will see is the

pattern of proteinuria seen with rosuvastatin, is

due to reduced absorption of normally filtered

low-molecular-weight proteins. The acute and

long-term consequences of this type of proteinuria

are less well defined and must be defined in the

context of the drug or environmental factor causing

the proteinuria.

\[Slide.\]

Shown here is Table 15 from the FDA

briefing document. For comparative purposes, the

data from the uncontrolled, open-label extension

trials are omitted so that the pool only contains

data from controlled clinical trials.

Presented in this table are the frequency

of developing proteinuria at any time, hematuria at

any time, or the combination of proteinuria and

hematuria at any time for a given dose of statin.

The data in the proteinuria column shows that the

frequency of proteinuria for rosuvastatin at doses

up to and including 40 milligrams is similar to

that observed for comparator statins. However, at

the 80-milligram dose, an increased frequency is

observed.

The next column shows the frequency of

hematuria with and without proteinuria. The

frequency of hematuria with rosuvastatin ranged up

to 12 percent compared to a frequency of up to 8

percent on the comparator statins. Other

evaluations, not shown here, have demonstrated that

isolated hematuria is not associated with either

rosuvastatin therapy or therapy with other statins.

The last column shows the frequency of

proteinuria in combination with hematuria from the

program. When comparing the data for rosuvastatin

with the data obtained for other statins, we find

an increased frequency of proteinuria/hematuria at

the 80-milligram dose and possibly a signal at the

40-milligram dose. But note that, at the

40-milligram dose of simvastatin, we also see a

frequency of 0.8 percent.

\[Slide.\]

The observation of an increased frequency

of proteinuria and proteinuria in combination with

hematuria predominantly at the 80-milligram dose

led to a series of investigations to characterize

the magnitude and nature of these findings.

First, we evaluated the patients with the

most significant shifts from baseline in urine

protein levels to determine the amount and types of

proteins excreted. Shown in this table are total

protein and albumin excretion normalized for

urinary creatinine excretion in patients with a

shift from none or trace at baseline to 2-plus or

greater levels of urine protein.

In these patients, the median protein

excretion was only 0.6-milligram protein per

milligram of creatinine. This value correlates to

about 600 milligrams per day. Note that 150

milligrams of protein excretion per day is

considered normal.

Of the total protein excreted, only about

one-third was albumin. In disease states where the

glomerulus is affected, the vast majority of urine

protein excreted is albumin. Thus our, data

suggested that the proteinuria was not glomerular

in origin.

\[Slide.\]

Electrophoresis results and analyses of

urinary proteins from patients who developed

proteinuria showed that it was primarily tubular in

origin. Our analyses showed that the proteins

excreted were predominantly alpha-1 microglobulin,

beta-2 microglobulin, and retinol-binding protein.

These are proteins typically filtered at the

glomerulus but normally reabsorbed at the level of

the tubules.

Back-titration of patients in our program

from 80 milligrams to 40 milligram allowed us

another opportunity to assess the nature of the

proteins in patients with proteinuria as well as

the reversibility of the proteinuria. The data

showed that at the 80-milligram dose, the greatest

elevation in urine proteins was for

low-molecular-weight proteins and that following

back-titration to 40 milligrams, the greatest

decrease was in these same urine proteins.

Our evaluation of hematuria in patients

with proteinuria revealed that red blood cells were

present on microscopic evaluation. Myoglobin

levels were not elevated in these patients

confirming that the hematuria was not secondary to

muscle breakdown. Importantly, in our

back-titration study, the combination of

proteinuria and hematuria also reversed with

back-titration.

Since the predominant effect observed with

high doses of rosuvastatin was a tubular

proteinuria, we performed a series of preclinical

evaluations to explore a possible mechanism for the

effect.

\[Slide.\]

I will start with the Preclinical data.

Preclinical toxicology studies for the various

statins show that all have tubular effects at very

high exposure levels.

However, in almost all of these animal models, the

doses of statin leading to this effect also caused

the animals to be moribund. Therefore, whether the

effects are a primary effect of the statin or due

to other secondary causes cannot be determined.

However, in one animal model, the

cynomolgus monkey, the effect was observed at high

doses of rosuvastatin and pravastatin, but the

doses were not high enough to cause the animal to

become moribund. The fact that the tubular

toxicity was observed in animal models with all

statins, that the types of proteins present in our

clinical studies suggested a tubular proteinuria,

and that these observations appeared to be dose

related, led us to postulate that the proteinuria

was due to an HMG-CoA-reductase inhibitory effect

in proximal tubule cells.

To explore this hypothesis, we evaluated

the effect of statins on albumin uptake in Opossum

kidney tubule cells. This is a well characterized

model for evaluating the potential effects of a

drug on renal tubules.

The results of the studies I am going to

show you were later confirmed in a human

renal-tubular-cell model.

\[Slide.\]

Shown in this figure is the effect of

increasing concentrations of various statins on

albumin uptake in the Opossum kidney cells. The

statins that we are looking at are rosuvastatin,

atorvastatin, simvastatin, pravastatin and

fluvastatin. Note that with all of these statins,

with increasing concentrations, albumin uptake is

inhibited.

\[Slide.\]

The degree of inhibition is closely

related to the degree of cholesterol inhibition in

these cells. Note that once approximately 80 to 90

percent inhibition is observed, the percentage

inhibition in albumin uptake begins to rapidly

rise.

\[Slide.\]

To examine whether the observed effects

were due to HMG-CoA reductase inhibition, we also

examined the effects of adding mevalonate, the

down-stream product of HMG-CoA reductase, to the

cells along with the statin.

This is the result of one experiment. The

data show that the effects are consistent with an

HMG-CoA-reductase inhibitory mechanism. The

addition of mevalonate reverses the inhibition

observed with simvastatin and rosuvastatin and this

experiment has been repeated several times with

different statins.

\[Slide.\]

Having explored a potential mechanism for

the effect, we are still left with an important

question. Why is proteinuria observed following

therapy with high doses of rosuvastatin?

Two major characteristics of rosuvastatin

help to address this issue, First, rosuvastatin is

a highly effective inhibitor of HMG-CoA reductase.

Second, approximately 28 percent of rosuvastatin

systemic clearance is by the kidney, and this

occurs predominantly by tubular secretion.

For other statins, the degree of renal

excretion or the overall effectiveness in

inhibiting HMG-CoA reductase is less than that

observed with rosuvastatin.

\[Slide.\]

Although we have shown that the

proteinuria was predominantly tubular in nature and

probably related to HMG-CoA reductase inhibition,

the next important question to address is whether

treatment with rosuvastatin leads to either short

or long-term renal complications.

To address the issue of short-term or

acute complications, we present here our cases of

acute renal failure from our program. Out of the

12,569 patients treated with rosuvastatin in our

program, eleven patients were reported to have

acute renal failure, one case each at the 5, 10,

and 20-milligram doses, two cases at the

40-milligram dose, and six cases at the

80-milligram dose.

For the five cases at doses below

80-milligram, none were attributed to therapy with

rosuvastatin. Of the six cases at the 80-milligram

dose, four of those were associated with myopathy.

We are left with two cases of acute renal failure

at the 80-milligram dose.

In these two patients on this dose, the

etiology of the renal failure is unclear. Both

patients had symptomatology suggesting a dehydrated

state prior to the onset of renal failure and both

had other comorbidities requiring treatment with

medications which could predispose them to renal

failure independent of therapy with rosuvastatin.

These cases represent two cases out of

264 patients who initiated therapy at the

80-milligram dose and out of a total of 1583

patients treated with this dose. The current

database contains over 4000 patients treated with

rosuvastatin 40 milligrams of whom over 2000

initiated therapy with this dose. No cases of

renal failure have been attributable to therapy

with the 40-milligram dose of rosuvastatin.

Overall, the number of cases of acute

renal failure observed in this program are not

unexpected given the size of the current database

with over 14,000 patient years exposure to

rosuvastatin.

\[Slide.\]

Having shown that rosuvastatin is unlikely

to cause acute or short-term detrimental effects on

renal function at doses up to and including 40

milligrams, we next explored the potential for

long-term treatment in patients with proteinuria

and proteinuria in combination with hematuria to

lead to decrements in renal function.

To do this, we used a creatinine elevation

greater than 30 percent as a marker for a potential

renal effect. This is a sensitive marker and

represents a level of change of about three

standard deviations above the mean change in

creatinine observed in our placebo group for our

program.

In evaluating long-term effects, we once

again to go our all Controlled/uncontrolled and

RTLD data pool. It is, again, our largest pool of

patients and includes patients with the longest

durations of treatment with rosuvastatin.

This analysis includes patients who had a

shift from none or trace proteinuria at baseline to

2-plus or greater proteinuria at the end of

treatment. Using this level of change identifies

subjects with a greater likelihood of developing

treatment-related proteinuria and a level of

proteinuria that should lead to changes in renal

function if an association exists.

Note that similar to the previous

analyses, the frequency of proteinuria was low and

similar at rosuvastatin doses from 5 to 40

milligrams but increased at the 80-milligram dose.

Of the patients who developed proteinuria, no

patient had a 30 percent creatinine elevation at

the end of treatment at the 5-milligram,

10-milligram, or 40-milligram doses of

rosuvastatin.

Two patients had an increase at the

20-milligram dose and eleven patients at the

80-milligram dose did have an elevation. Of these

thirteen patients with elevations, only four

patients had a 30 percent increase above the

highest creatinine value observed during the

pre-randomization period. All four of these

patients were at the 80-milligram dose and two of

the patients had myopathy. For the remaining two

patients, the elevations were less than 0.5

milligrams per deciliter.

\[Slide.\]

If we now look at patients with

proteinuria and hematuria, who represent a subset

of the patients shown on the previous slide, we

find similar results.

The data show that the number and

frequency of patients with this finding is

extremely low at doses up to and including 40

milligrams. An increased frequency is observed at

the 80-milligram dose.

\[Slide.\]

An evaluation of patients treated for 96

weeks or longer gives additional information

regarding the long-term effects of proteinuria. In

this slide is shown information regarding

proteinuria observed at any time, at the last

visit, and the associated creatinine changes

observed at the last visit.

The data show that the frequency of

proteinuria observed at any time is greater than

the frequency observed at the last visit at a given

dose of drug. This suggests that although

proteinuria can occur, in many patients it does

decrease or resolve. This is demonstrated best in

the 80-milligram group where the frequency at any

time is 16.8 percent but decreases to 6.3 percent

at the final visit.

The back-titration data, the greater than

or equal to 40-milligram group, is also helpful

because it contains important information in almost

800 patients, in over 800 patients receiving high

doses of rosuvastatin. Note that the frequency of

proteinuria observed at any time is similar to that

observed at the 80-milligram group. However, at

the last visit, in patients who are now almost

entirely on the 40-milligram dose, the frequency of

proteinuria is similar to that observed with lower

doses of rosuvastatin.

Out of 37 patients with proteinuria at the

80-milligram only eight had proteinuria following

back-titration to 40-milligram demonstrating that

proteinuria was reversible.

The creatinine data is also helpful. Note

that no patients with proteinuria had a creatinine

elevation greater than 30 percent at rosuvastatin

doses up to 40 milligrams. Seven patients on

80-milligram had an elevation. In all seven of

these patients, the elevation resolved on

back-titration to 40 milligrams showing that the

creatinine elevations, like the proteinuria

findings were reversible.

\[Slide.\]

The results for patients with proteinuria

in combination with hematuria, which is again a

subset of the patients in the previous slide,

showed similar results, no evidence for a treatment

effect at rosuvastatin doses up to and including 40

milligrams. At the 80-milligram dose, both

proteinuria and hematuria and the creatinine

elevations were reversible on back-titration.

\[Slide.\]

In the FDA briefing document is a

description of a patient who had an abnormal

urinalysis with a creatinine elevation and a renal

biopsy. The clinical course for this patient has

relevance to the long-term safety of rosuvastatin

and is presented on this slide.

The patient is a 69-year-old African male

with a history of childhood renal disease, stasis

ulcers, and back pain treated with aspirin,

paracetemol, intramuscular penicillin injections,

and topical steroids. At baseline, the subject had

two urinalysis tests. One showed active sediment.

The other showed 1-plus proteinuria without active

sediment.

After 18 months, the subject had a serum

creatinine measurement of 1.6 milligrams per

deciliter from a baseline of 1.1 milligrams per

deciliter. The urinalysis showed proteinuria and

hematuria. A renal biopsy was performed which

showed acute on chronic tubulointerstitial changes.

The laboratory abnormalities resolved

following discontinuation of rosuvastatin, but

proteinuria recurred upon rechallenges with

rosuvastatin 80 milligrams and atorvastatin 40

milligrams. This case shows that proteinuria can

be observed with another statin if the patient is

susceptible.

\[Slide.\]

Another method for evaluating the

potential adverse effects of a drug on renal

function is to evaluate the long-term effects of

high-dose treatment in patients with baseline renal

laboratory abnormalities since these patients might

be expected to show a greater susceptibility to

adverse renal effects of drugs.

In this slide, we compare the effects of

treatment with at least 40 milligrams of

rosuvastatin for greater than or equal to 96 weeks

in patients with normal and impaired renal

function. Note that, in general, serum creatinine

levels tended to decrease in all groups and the

percentage of outliers was similar in patients with

normal or impaired renal function.

\[Slide.\]

In summary, we have carefully evaluated a

proteinuria and proteinuria/hematuria signal with

regard to frequency, magnitude, nature, and the

potential for rosuvastatin to cause acute or

long-term renal parenchymal damage.

Our data shows that dipstick positive

proteinuria, primarily tubular in origin, was

observed predominately at the 80-milligram dose.

In a small percentage of patients, this finding was

associated with microscopic hematuria. The data

show that the finding was transient in many cases,

reversible and not associated with long-term

detrimental effects on renal function. Although

two cases of renal failure had a temporal

relationship to therapy with the 80-milligram dose,

both of these cases had other identifiable causes.

At doses up to and including 40 milligrams,

rosuvastatin was well-tolerated from the renal

perspective.

An important question to address is

whether the prescribing information for

rosuvastatin should include renal monitoring. As

shown by the data, routine urinalysis or creatinine

monitoring is not necessary. The data show that

treatment wit rosuvastatin at doses from 5 to

40 milligrams does not result in acute or long-term

adverse effects on renal function. Even at the

80-milligram dose, any changes that were seen were

reversible with back-titration or stopping therapy,

so even at this dose, there is no evidence of a

long-term irreversible effect on renal function.

\[Slide.\]

Having now reviewed our clinical safety

database, I would like to speak to the last

objective that we set for our program, to determine

whether rosuvastatin would have a low potential for

significant drug-drug interactions.

In this regard, I will present the results

of our drug interaction studies in the following

areas; interactions with drugs that are metabolized

through interactions with cytochrome P450

isoenzymes or PgP transporters and interactions

with drugs known to result in an increased

potential for myopathy. in particular, cyclosporine

and gemfibrozil.

\[Slide.\]

Our drug interaction studies with the

cytochrome P450 3A4 inhibitors, ketoconazole and

erythromycin, show that rosuvastatin is not

metabolized by this route. No effect on

rosuvastatin AUC was observed with ketoconazole,

and with erythromycin, a clinically insignificant

0.2-fold decrease in AUC was observed.

Interactions with these same two drugs

along with the results of the digoxin-interaction

study also show that rosuvastatin does not interact

with PgP transporters.

Finally, the result of the fluconazole interaction

study shows that rosuvastatin is not metabolized by

cytochrome P450 2C9 or 2C19.

\[Slide.\]

I would now like to address the issue of

interactions with cyclosporine and gemfibrozil.

Our drug-interaction study with cyclosporine

revealed a 7.1-fold increase in rosuvastatin plasma

concentrations.

Shown in this figure are the results for

rosuvastatin compared to data reported for other

statins in the literature. The results for

rosuvastatin are similar to the other statins

except for lovastatin, which appears to have the

largest interaction.

Based on the 7.1-fold increase in

rosuvastatin AUC, the dose of rosuvastatin should

be limited to 5 milligrams when used in conjunction

with cyclosporine.

\[Slide.\]

Shown next is our drug interaction study

with gemfibrozil. In this trial, a 1.9-fold

increase in rosuvastatin AUC was observed. This

increase was similar to that reported for

simvastatin, lovastatin, and pravastatin but less

than the interaction observed with cerivastatin.

Once again, based on the level of increase in AUC

and the known risk for myopathy when statins are

co-administered with gemfibrozil, the dose of

rosuvastatin should not exceed 10-milligram in this

population.

\[Slide.\]

Because of the increasing use of other

fibrates, we performed a drug-interaction study

with fenofibrate. As opposed to the 1.9-fold

increase in AUC observed in the gemfibrozil

interaction study, no interaction was observed when

rosuvastatin was co-administered with fenofibrate.

\[Slide.\]

Our drug interactions studies show that

rosuvastatin will have a low potential for

significant drug interactions. However, other

factors besides drug interactions may impact

exposure to rosuvastatin and could therefore impact

on safety. Data from our clinical pharmacology

program revealed that systemic exposure to

rosuvastatin was not affected by age, sex, or the

presence of mild to moderate renal impairment.

In patients with severe renal impairment,

rosuvastatin plasma concentrations increased

approximately 2 to 3 fold. Based on these

findings, we propose that the dose of rosuvastatin

is limited to 10-milligram in this population.

Rosuvastatin plasma concentrations were also

increased in patients with severe hepatic

impairment. Note that, similar to other statins,

rosuvastatin is contraindicated in patients with

active hepatic disease.

Pharmacokinetic evaluations were also

performed to assess effects based on ethnicity. We

did find that exposure to rosuvastatin was

increased approximately 2-fold in Japanese patients

in Japan. However, we do not know whether this was

due to environmental or genetic factors.

Importantly, no differences in exposure were

observed among Caucasians, Black, or Hispanic

patients.

\[Slide.\]

This morning, I have reviewed for you the

safety results from our program. In this program,

doses of rosuvastatin up to and including 80

milligrams were thoroughly explored in over 12,500

dyslipidemic patients. This is the largest NDA

ever submitted for a statin.

This program was inclusive. Approximately

one-third of the patients were 65 years or older

and a high percentage of patients had

co-morbidities such as hypertension, diabetes,

renal insufficiency, and atherosclerosis.

The data show that within the proposed

5-milligram to 40-milligram dose range, the safety

profile of rosuvastatin was similar to other

marketed statins.

At the 80-milligram dose, the frequency of adverse

skeletal-muscle and renal effects increases above

that observed for currently marketed statins.

However, even at this dose, the majority of

patients were safely treated. Importantly, all

patients with an adverse event at the 80-milligram

dose recovered.

We have also demonstrated that

rosuvastatin will have a low potential for

significant drug-drug interactions.

For those patients at risk for significant adverse

events due to drug interactions, our proposed

labeling will reflect the necessary information.

\[Slide.\]

Having now reviewed the overall safety

database, the issue of selecting appropriate doses

of rosuvastatin to market involves weighing the

potentials risks of a dose versus the potential

benefits afforded by its use.

A rosuvastatin 10-milligram to 40-milligram dose

range is appropriate for the general population of

patients with dyslipidemia.

Our data which clearly demonstrate the

excellent lipid modifying benefits of the proposed

10-milligram to 40-milligram dose range at both the

starting dose and across the dose range compared to

other currently marketed statins.

Also, within the proposed dose range, rosuvastatin

brings a high percentage of patients to recommended

NCEP lipid goals.

\[Slide.\]

Why is a 10-milligram start dose

appropriate for the general population of patients

with dyslipidemia?

The reason is once again the overall favorable

benefit to risk of this dose.

Our data shows that the 10-milligram dose

provides additional lipid efficacy compared to the

5-milligram dose, without showing a difference in

overall safety. As previously stated, for patients

on cyclosporine, a 5 milligram dose is available.

\[Slide.\]

And last, why is a 40-milligram dose an

appropriate top dose for patients with

dyslipidemia?

First, our data show that the 40-milligram dose of

rosuvastatin provides additional lipid-modifying

benefits compared to the 20-milligram dose.

With regard to safety, our program has

evaluated rosuvastatin at doses up to and including

80 milligrams. Doing this has allowed us the

opportunity to understand our drug and the

potential risks associated with its use.

The 40-milligram dose was studied in over 4000

patients with a demographic similar to that of the

80-milligram group. Over 2000 subjects initiated

therapy at this dose. Our data clearly show that

this dose was well-tolerated.

Adding to the favorable benefit to risk

profile for this dose is the fact that this is not

a recommended starting dose. The 40-milligram dose

is for those patients who do not achieve the

necessary lipid-modifying effects at the

20-milligram dose of rosuvastatin.

So, in summary, using 40-milligram as the

top dose for rosuvastatin will provide an overall

rosuvastatin dose range, which is safe and provides

additional lipid-modifying benefits over current

statin therapies.

I would now like to introduce Dr. Daniel

Rader from the University of Pennsylvania who will

briefly discuss the potential role of rosuvastatin

in the treatment of dyslipidemic patients.

Dr. Rader.

The Role of Rosuvastatin

in the Treatment of Dyslipidemia

DR. RADER: Thanks very much.

\[Slide.\]

I am Dan Rader. I direct a preventive

cardiology program at the University of

Pennsylvania in the Lipid Clinic there. I do

research in lipids and atherosclerosis and I see

patients with lipid disorders. I am happy to be

here today to present to you my thoughts, briefly,

on the potential role of rosuvastatin in the

treatment of dyslipidemia.

\[Slide.\]

I would like to start again by reminding

you, and I think you all know at this point, that

we have had a major evolution in the Lipid

Management Guideline from 1988 to the most recent

ATP-3 Guidelines in 2001. These guidelines have

been reflected by increasing aggressiveness of

cholesterol-lowering therapy from initially a focus

on non-statin therapy to, most recently, because of

the more aggressive guidelines, a focus on

high-dose statins and combination therapy in order

to be able to achieve the kinds of aggressive

targets that are recommended in these guidelines.

I would like to point out that Dr. Don

Hunninghake, who is here with us today, has been

part of the NCP from the beginning and, in fact,

chaired the Drug Therapy Section for all three of

the adult treatment panels. So any questions you

have about NCP, we will certainly forward to Don.

\[Slide.\]

What I would like to do so sort of set the

stage and explain to you why I think rosuvastatin

is an important addition to the therapeutic

armamentarium for dyslipidemia is really to point

out that, in fact, we have difficulty achieving

goals in a lot of our patients with dyslipidemia.

To go back to data that is really based on

the ATP-2 Guidelines, this slide reflects four

different studies, all performed in the mid- to

late-90\'s and published between \'99 and 2001 really

asking, in an observational sense, how well were we

doing in terms of getting patients to the ATP-2

goals.

I will just point out here that even the

low-risk patients on the left, only about

two-thirds of them were at goal. The medium-risk

patients in the middle, only about a third were at

goal. The high-risk coronary heart-disease

patients who need to be targeted to LDLs less than

or equal to 100 by these guidelines, only about a

fifth to a quarter were at goal. So, clearly, at

that time, many patients were not at goal.

Now, you might ask, maybe patients are not

being treated or maybe they are not being

appropriately titrated and maybe many of them are

just almost at goal but not quite. But, in this

study, one of those four studies, the L-TAP Study

directed by Dr. Tom Pearson, who is also here with

us today, really shows that that is not the case.

In fact, in L-TAP, a lot of the patients who were

not at goal were actually quite far from goal.

Note that on the right a full l6.6 percent

of the patients, nearly as many as were at goal, as

shown at the left, were over 160 milligrams per

deciliter, far from their goal of 100 and 45

percent of the patients in L-TAP who needed to be

targeted to LDLs less than 100 were actually over

130\. So I think this demonstrates that it is not

just in terms of getting people to goal, that we

are getting almost there but not quite there.

A lot of people have a long way to go

before they actually get their NCP goals.

\[Slide.\]

This is a study by Ross Simpson and his

colleagues that looked, in a real-world setting, at

following nearly 3,000 patients asking what is

actually happening in these high-risk patients who

need to be targeted to LDLs less than 100. You can

see that, among these patients, when they were

started on a statin, 47 percent, shown on the

right, got to goal at the starting dose. But over

half did not get to goal at starting dose.

I think this is an important point. Many

patients don\'t get to goal on starting doses of

statins. Of that group of patients, 47 percent

were titrated but more than half were not titrated,

again reflecting an important point. Physicians

often don\'t appropriately titrate patients to get

them to goals.

Finally, I think perhaps most importantly,

among the patients who were titrated, only

one-third of those patients actually got to goal.

So even among titrated patients, two-thirds of the

patients did not actually get to goal. I think

this illustrates, and is something I am going to

come back to, it is actually difficult to get many

patients to goal even with appropriate titration.

\[Slide.\]

This is recent data. This came out in

Circulation a few months ago from the NHANES Study.

This is data collected between 1999 and 2000 so it

really reflects treatment in the modern era with

all the current statins that we currently have on

market.

There is a lot of data in this report but

I just thought I would focus on one key issue which

is only 47 percent of the hypercholesterolemic

patients who were being actively treated with drug

actually were adequately controlled. So I think,

again, this suggests that yes, failure to treat is

a problem but even among treated patients, failure

to actually get adequate control and treat patients

to goal is a real issue.

Now, maybe it is just that patients are

not being titrated appropriately. Certainly, that

would be a reasonable question to ask. But I want

to bring you back again to this study directed by

Dr. Christie Ballantyne who is also here with us, a

ACCESS Study, which took hypercholesterolemic

patients, randomized them to five different statins

and then titrated as needed to get to goal.

You will see again that, for LDL goals,

even patients randomized to atorvastatin titrated

as needed up to a maximum of 80 milligrams, only a

little over 70 percent of these patients actually

got to goal of LDL less than 100. For HDL

cholesterol, which, in general, is even harder to

reach, only about 60 percent of the patients on the

atorvastatin arm got to goal.

So you can see that even when

appropriately titrated in a controlled setting like

this trial, it is difficult to get many patients to

goal.

\[Slide.\]

I have been focusing on our current goals

but I do have to tell you that, in the lipid field,

many of us feel that our current goals may not be

aggressive enough. I am going to show you two

slides that kind of address that issue. One is

this slide that really plots the on-treatment LDL

cholesterol levels on follow up in all the big

statin trials on the x-axis and the percent with

coronary heart-disease events on the y-axis.

You will note that, for both secondary

prevention and primary prevention, there seems to

be a clear linear relationship between the

on-treatment LDL cholesterol level and the percent

with coronary events. This is, admittedly, a crude

way to look at this but I think it gives us some

idea of this relationship.

I also want to point out that there are

two studies on this slide; the Heart Protection

Study, HPS, and the ASCOT Study that came out since

the ATP-3 Guidelines. So we have new data coming

out even since those guidelines that address this

issue of, perhaps, maybe even lower targets would

be appropriate.

You will note that, in both of those

studies in the treated groups, the LDL cholesterol

levels in the treated group, the mean level, was

well less than 100.

\[Slide.\]

I wanted to actually explore the Heart

Protection Study in just a little more detail with

this slide. I think this is really quite important

for this concept of should we be treating people

even lower. So the Heart Protection Study enrolled

people almost regardless of their cholesterol

levels.

I just thought I would show you this

analysis that the investigators did where they

looked at baseline LDL cholesterol by tertile. You

will note, in the highest tertile group, where the

mean LDL cholesterol was about 140, treatment with

simvastatin lowered LDL to a little over 100 and

lowered cardiovascular events as you can see here.

In the lowest LDL tertile in this group,

the mean LDL was slightly less than 100 at baseline

and you can see that treatment there lowered LDLs

into the 60s and also significant reduced risk. Of

course, we don\'t really know, if we took everybody

and lowered their LDLs into the 60s, whether we

would see even greater event reductions than we see

in the current statin trials.

But I think, based on data like this, many

of have concluded that the guidelines are very

likely to become more aggressive with regard to the

need to treat LDL. Certainly, speaking for myself,

based on data like this, I treat my high-risk

patients, patients with coronary disease and

diabetes, somewhat more aggressively than just

targeting 100. I think I would really like to see

the LDLs even lower.

I think you can imagine, as our targets

get even lower, as our practice gets even more

aggressive, it is going to be even harder to target

patients appropriately to these goals. So I would

suggest to you that, in fact, despite all the good

drugs that we have on the market, there is still a

medical need in treatment of dyslipidemia. There

is a need for more efficacious therapy to achieve a

few different goals, one of which is greater LDL

and non-HDL cholesterol-lowering at the start dose.

I have already explained to you how many

patients don\'t get to goal on start dose and,

unfortunately, many physicians don\'t appropriately

titrate.

\[Slide.\]

I thought I would show you just one slide

with a little bit of sort of composite data that

really addresses direct head-to-head comparisons of

rosuvastatin at its 10-milligram start dose with

commonly used start doses of other statins. So

these two panels can\'t be compared with each other.

They are really self-contained but if you look at

the left, these are three different trials, Trials

24 to 26, comparing rosuvastatin 10 milligrams to

atorvastatin 10 milligrams in a head-to-head

comparison.

What I have selected to show you here is

actually the achievement of both the LDL

cholesterol and the non-HDL cholesterol goals,

really the ultimate goal of the ATP-3 guidelines.

You should be targeting both of these. You can see

that rosuvastatin 10 brought substantially greater

number of patients to this combined goal than

atorvastatin 10.

Shown on the right, Trials 27 and 28,

involved direct head-to-head comparisons of

rosuvastatin 10 with simvastatin 20 and pravastatin

20\. Again, you see significantly greater bringing

patients to this combined LDL and non-HDL goal with

rosuvastatin 10 compared to the other two statins.

So I think it is safe to say that use of

rosuvastatin 10 milligrams will bring a greater

number of patients to NCP goals and, I would

suggest to you, could have substantial

public-health benefit with regard to that.

\[Slide.\]

Now, I think the second need for more

efficacy therapy in treatment of dyslipidemia is

clearly to achieve greater LDL and non-HDL

cholesterol lowering at maximal dose. We really

need therapies that will get our difficult-to-treat

patients down closer to the goals that we need to

treat these patients to.

\[Slide.\]

Now, to illustrate this point, I would

like to just briefly bring up familial

hypercholesterolemia. The heterozygous form of

this condition is common. There are about 500,000

patients in the U.S. with heterozygous FH for a

frequency of about 1 in 500, more common, I

believe, than Type 1 diabetes, for example.

FH is a serious disease. Even with

treated with our current drugs, the average age of

onset of coronary disease is about 45 to 50 in men

and about 55 to 60 in women and it is difficult to

treat. As I will show you in a second, most FH

patients cannot be adequately treated to NCP goals

using our current therapies.

\[Slide.\]

In this slide, what I decided to do is

show you two different studies. These are two

independent studies both in heterozygous FH

patients, both directed by Dr. Evan Stein, who is

actually here with us today as well. One is a

study that you have already seen from Dr. Blasetto

on the left, but I just kind of encapsulated it

here, looking at rosuvastatin 40 milligrams and

atorvastatin 80 milligrams in these high-risk FH

patients who are being targeted to LDL less than

100\.

You can see that the rosuvastatin, as you

saw previously, got substantially more of these

high-risk FH patients to goal.

On the right, for comparison or to flesh

out this concept, I show you another study directed

by Dr. Stein that compared atorvastatin 80

milligrams, so the same comparator, to atorvastatin

40 milligram plus ezetimide, 10 milligrams. You

will note that, although these are different

studies in different populations both involving

over 600 patients, by the way, you will note that

the atorvastatin 80 performed about the same. Only

about 4 percent of these high-risk FH patients got

to goal, and the combination of atorva 40 plus

ezetimide got, again, about 17 percent of the

patients to goal.

So I think the main point here is

rosuvastatin 40 does do better than any other

single monotherapy statin that we have on the

market in terms of treating these

difficult-to-treat patients. But note that still

less than one in five patients are getting to goal.

So I think clearly, with this type of

severe hypercholesterolemic patient, the future is

being able to use rosuvastatin 40\--we really need

that dose for these patients\--and then adding on

combination therapies including the additional of

ezetimide to the rosuvastatin 40 to try to get more

of these patients to goal.

\[Slide.\]

I would like to turn for a minute to HDL.

HDL is a common condition, low HDL, and represents

an important medical need. It is one of the most

common risk factors in patients with coronary

disease. ATP-3 importantly placed new emphasis on

low HDL as a risk factor and as a potential target

for intervention.

Data are increasingly suggesting that even

modest increases in HDL may translate into

substantial cardiovascular risk reduction. So I

would like to suggest that, in fact, another need

in treatment of dyslipidemia is getting better at

raising HDL cholesterol.

\[Slide.\]

Dr. Blasetto already showed you data from

the STELLAR Trial looking at the comparison with

rosuvastatin with other statins in terms of HDL.

I thought what I would show you here is looking at

the same trial but asking the question what did

rosuvastatin do in terms of raising HDL in a

low-HDL group, people with HDLs less than 40.

You can see here on the left that the HDL

raising in this subgroup with rosuvastatin was

between 12 and 20 percent. So HDL raising

certainly compares favorably to the best

HDL-raising drugs we currently have on the market.

\[Slide.\]

Admittedly, it is difficult to predict

what incremental reductions in LDL and incremental

increases in HDL will do in terms of reduction in

cardiovascular risk. But the NCP and the ATP-3

report did make these following estimates based on

observational studies as well as the randomized

controlled trials that we have available, and that

is that, for every 1 percent decrease in LDL

cholesterol, there would be expected to be a

reduction of coronary heart-disease risk by

approximately 1 percent and that, for every 1

percent increase in HDL cholesterol, there might be

expected to be a reduction in coronary

heart-disease risk by about 3 percent.

So I think you can imagine that if, in

fact, these do hold true, that even incremental

further reductions in LDL, further increases in

HDL, could, in fact, translate into substantial

further risk reduction for the patient.

\[Slide.\]

So, in summary, I suggest to you that

there is a role for rosuvastatin in treatment of

dyslipidemia, that, first of all, the greater LDL

cholesterol and non-HDL cholesterol lowering at the

start dose will, in fact, bring more patients to

goal at start dose and I believe have public-health

benefits as a result.

Second, the greater LDL cholesterol and

non-HDL lowering at the maximal dose of 40

milligrams will make it easier for us to treat our

patients with FH, other forms of severe

hypercholesterolemia, diabetics, many of whom are

also difficult to treat, and I would suggest to you

that we really do need this 40-milligram dose to

more effectively treat these patients.

Finally, the HDL raising of rosuvastatin,

although incremental, certainly would be suggested

to result in increased reduction in cardiovascular

events as well.

So, in summary, I would suggest to you

that, in fact, rosuvastatin does provide an

important and valuable addition to the therapeutic

armamentarium for the treatment of dyslipidemia.

Thank you very much.

DR. BRAUNSTEIN: Thank you for a lovely

comprehensive overview.

We will now take a fifteen-minute break

and reconvene at 10:45 for questions from the

committee to the sponsor.

\[Break.\]

Questions from the Committee

DR. BRAUNSTEIN: We will open up the

session for questions and answers from the

committee. The committee will also have an

opportunity for questions, both the FDA and the

sponsor, following the FDA\'s presentation. But now

we will restrict ourselves to sponsor\'s

presentation.

Questions? Dr. Hennekens?

DR. HENNEKENS: I was extremely favorably

impressed with the size and scope of this

development program as well as the comprehensive

presentations. Dr. Orloff, in his comments, gave

us some two focused sets of charges that, perhaps,

might merit further consideration. One was he

spoke of perhaps the need for further safety data

directly comparing the 20 and 40 milligrams at the

40-milligram start dose and talked about 600

patients or more. Secondly, further clarification

of the new onset of proteinuria directly at the 20

and 40-milligram doses, Dr. Hutchinson\'s Slide

CS24, if taken at face value, suggested that those

rates were 0.3 at 20 and 1.3 percent at 40 which,

if real, would be a relative risk of 4.3.

So, perhaps, further clarification of

those two issues might be helpful in our

deliberations, either now or sometime during the

day.

DR. BRAUNSTEIN: Do you want to respond to

that?

DR. HUTCHINSON: Just to clarify your

question, Dr. Hennekens, you are interested in the

frequency\--

DR. HENNEKENS: The second part related to

your presentation was from your Slide CS34.

DR. HUTCHINSON: Yes; the FDA\'s analysis

of our data.

\[Slide.\]

DR. HENNEKENS: Yes. If you look at the

right-hand column for the 20 versus the

40-milligram dose, it was 0.3 to 1.3, just further

clarification of that would be helpful to me.

DR. HUTCHINSON: If I can show you the

data from our largest pool of patients which will

give you a better feel for the overall frequency of

proteinuria-hematuria in our program, I may be able

to address your specific questions.

\[Slide.\]

This was data that was presented during my

presentation. Now, this takes all patients in our

program that had urinalysis and creatinine

measurements. It looks at what happens in patients

with the most significant degrees of change

regarding proteinuria and hematuria from baseline

and then what happened in those patients at the end

of treatment with regard to creatinine changes.

As you can see, the percentage of patients

that had proteinuria along with some level of

hematuria ranged from 0.10 to 0.2 percent at doses

up to 40 milligrams. We see an increased frequency

of this finding at the 80-milligram dose.

What is critical here is to know whether

or not this finding is associated with any effects

on renal function so we use this sensitive marker,

which is creatinine elevations greater than 30

percent, to evaluate whether or not the proteinuria

and the hematuria that was there had an effect on

the kidney.

As you can see, 0, 0, 1, 0, 8. When we go

back and evaluate these patients because, in our

program, what we use for creatinine baseline was

the value of creatinine closest to Week 0.

However, a number of these patients had multiple

baseline creatinine measurements.

This identified a group of nine patients.

If you go back and evaluate those patients, what

you find is that, in almost all cases, what happens

here is that the patients don\'t even have an

elevation in creatinine greater than 30 percent of

the maximum value observed the baseline. In the

few numbers of patients, the one or two patients

that do have an elevation, the creatinine elevation

in these patients is less than 0.5 milligrams per

deciliter.

We do have, in a couple of these patients

also follow up after discontinuation of therapy.

Following discontinuation of therapy, what happens

is that creatinine elevation resolved in those

patients where we had follow up.

I think the 96-week data which looks at

proteinuria, hematuria and the creatinine

elevations also gives you some important

information here as well. These are patients that

are going to be exposed for a mean of 2.4 years

with our drug.

\[Slide.\]

Here in these patients we are once again

looking at this combination of proteinuria and

hematuria to determine whether or not it was

associated with any change in serum creatinine,

this 30 percent marker. Just to give you an idea

if somebody had a creatinine change from

0.6 milligrams per deciliter to 0.8 milligrams per

deciliter, they would fulfill this criterion.

But, if we look at this, what we find,

first of all, after 96 weeks, we had one patient in

the 40-milligram dose group that met this

criterion, one patient at the 10-milligram group.

If we look for creatinine increases, we find that

none of these patients had a creatinine increase.

We see that, at 80 milligrams, five patients had an

increase but, in our program, because we

back-titrated patients from 80 to 40 milligrams, we

had the opportunity to follow many of these

80-milligram patients longer term.

What we find is that, in these patients

once they get back-titrated, look at the frequency

of proteinuria and hematuria. It now approximates

what we see at very low doses of rosuvastatin.

These are patients receiving high doses.

Importantly, those five creatinine elevations are

gone.

So, from our patient, we have a very large

dataset. We have a very large dataset in general

looking at the 5, 10, 20, 40, and 80-milligram

doses. I think we have provided very good data to

show what the estimates of this finding will be at

the various doses and we have also provided very

substantial data regarding what the short and

long-term consequences of the findings are.

What we have found is that, in general,

transient, reversible, not associated with any

effects on renal function and, at the same time,

that 40-milligram dose is giving patients

additional significant LDL-C reductions which

provide value.

DR. BRAUNSTEIN: Could you explain what

the difference is between your table that you just

showed and Table 15 from the FDA? I know there are

minor differences in numbers of patients but it was

1.3 versus\--you had 0.2 percent up there and they

had 1.3. So why the difference?

DR. HUTCHINSON: The difference is simply

the type of evaluation that was done. In the FDA

evaluation, we are looking here at proteinuria,

hematuria and the combination at any time during

the program. So this takes into account if someone

had proteinuria at Week 2 but didn\'t have anything

at the end of the day, they would get picked up in

this analysis.

It is a very good analysis if you want to

look for potential signals. But if you want to

evaluate what is happening with regard to renal

function, you need to follow these patients out

long-term and see what occurs. That is the

analysis that I followed up with.

DR. BRAUNSTEIN: Dr. Woolf?

DR. WOOLF: Can you put those back?

DR. HUTCHINSON: Yes.

DR. WOOLF: Sort of following up on the

same issue, what is the time course of the

development of proteinuria and hematuria? Is it

seen within a few weeks? Is it seen in a few

months? You talked about the etiology of

proteinuria but not of the hematuria. Do you have

any idea where that is coming from?

Then I have a final comment about your

suggestion about not really\--a recommendation that

we do not need to put I guess the term is a

\"warning\" in the labeling about monitoring for

proteinuria.

DR. HUTCHINSON: Several questions to

address here.

DR. WOOLF: Time course, etiology.

DR. HUTCHINSON: Yes; time course, first.

Thank you very much. With regard to time course,

you can see that proteinuria occurs as early as two

weeks following treatment. We observed this

predominantly at the 80-milligram dose. However,

proteinuria can occur later. But the tendency for

the proteinuria, as I showed you with the 96-week

data, is for the proteinuria, should it appear, to

resolve. But it can occur as early as two weeks.

Now, the second question was with regard

to the hematuria. With regard to the hematuria, we

don\'t have an explanation for the hematuria. If I

can please see the Trial 99 table from the FDA

document, that does address, in some respects, the

hematuria.

\[Slide.\]

In response to our earlier findings from

the program, we went forward and did a prospective

study looking at rosuvastatin 40 milligrams versus

simvastatin 80 milligrams to try to characterize

the frequency of this finding in other statins and

also to understand a little bit about what was

happening with the proteinuria,

proteinuria-hematuria.

This study did not have a placebo lead-in,

a placebo treatment arm, but there was a dietary

lead-in, a six-week dietary lead-in period. During

that time period, patients had one or two

urinalysis samples. They were off statin therapy.

As you can see, during this time period,

we had a 3.4 percent frequency of proteinuria. The

proteinuria greater than 2-plus was 0.6 percent and

hematuria greater than 1-plus was 7.9 percent

during this period.

Following treatment with simvastatin 80

and rosuvastatin 40, we find that hematuria, it was

roughly similar in both of the treatment groups.

We do see a suggestion, however, that there tended

to be slightly more proteinuria with rosuvastatin.

We are not completely clear on where the

hematuria is coming from with regard to the

proteinuria-hematuria potentially seen with

rosuvastatin, particularly at the 80-milligram

dose. What we know about the proteinuria-hematuria

is it seems to follow the same type of course as

the proteinuria does, which is it is transient,

resolves with back-titration from 80 milligrams to

40 milligrams and, once again, not associated with

any acute or long-term effects on the kidney.

DR. WOOLF: Then, in regards to your

suggestion about the labeling, you have roughly 100

patients who have been followed on a 40-milligram

dose for, I think you said two-and-a-half years.

DR. HUTCHINSON: Yes.

DR. WOOLF: One of whom developed

hematuria-proteinuria. We are talking about

patients who are going to be on this essentially

for a lifetime. While two-and-a-half years is

rewarding, a lifetime is, hopefully, a lot longer

than that.

If you don\'t monitor for it, you will

never be able to know that it disappears when

it\--to back-titrate. So it is non sequitur. You

have to monitor to able to know that you have to do

something about it. So, to me, it is a disconnect.

DR. HUTCHINSON: That\'s true if you are

using the 80-milligram dose. However, we are not

suggesting that we are going to be treating

patients with the 80-milligram dose. Now, you say

100 patients, but if I can please see the 96-week

data again, because it is not really just 100

patients that we looked at in this program.

People were not dropping out of our

program because of proteinuria and because of

increased creatinine. So we had the opportunity to

follow these patients long-term.

\[Slide.\]

If we look at the 96-week data, which I

showed earlier, you are talking about 761 patients.

We are also talking about over 1,165 patients in

our program that have been exposed to doses greater

than or equal to 40 milligram for 48 weeks. So,

again, it is not only 100 patients. It is over

1,000 patients.

DR. WOOLF: At the 40-milligram dose, it

is 100.

DR. HUTCHINSON: At the 40-milligram dose,

here, that have never been exposed to the

80-milligram dose; correct. It is 100. But, once

again, if this drug was causing significant effects

on the kidney, one would expect that what we are

seeing at 80 milligrams, you would expect to see

the residual of that effect once you drop these

patients back to 40 milligrams.

We don\'t see it. In fact, the frequency

of the finding approximates the lower dose. So,

with regard to monitoring, you are dealing with

patients with atherosclerosis, diabetes,

hypertensions. These people have fluctuations of

30 percent in creatinine that can occur at almost

any time.

It is more likely that they will get a

fluctuation of 30 percent in their serum creatinine

from the other medications that they are on or

their disease than they will due to rosuvastatin or

another statin.

DR. BRAUNSTEIN: Dr. Follman.

DR. FOLLMAN: I would like to make a

comment about reversibility. I think it will be

easiest to make this comment if you bring up Slide

CS35.

\[Slide.\]

I think that is not the one I want but I

think I can make the point with this anyway. When

were are looking proteinuria and hematuria and so

on, these are parameters that will wax and wane

with time with biological processes that the

patients are undergoing with measurement error and

who knows what. So, if you look over the course of

the trial and say, \"Oh; I have a high rate of

proteinuria,\" and then you look at the very last

visit and note that it is lower, to what extent is

that evidence of reversibility or to what extent is

that evidence that you have a biological process

that fluctuates some.

So to really sort that out, you would need

a control group in some way. So this relates to

your comments when you say when you back-titrate I

think from 80 milligrams to 40 milligrams amongst

those who had proteinuria, the rate went down.

Once again, I would like a control group

to really feel comfortable that this is evidence

primarily of reversibility rather than just

fluctuations where you happen to catch them when

they had proteinuria and then, when you

subsequently measure it one more time, it is gone.

So we would like to believe that is

evidence of reversibility, I think. But we just

can\'t really conclude that without a control group.

DR. HUTCHINSON: Let me show you some data

from a substudy that we performed in one of our

open-label extension trials where we took patients

that were on the 80-milligram dose and, when we

were back-titrating these patients, we performed

very careful timed urine measurements as well as

other analyses in these patients.

DR. FOLLMAN: So this is where the group

as a whole is back-titrated at basically a fixed

point in time?

DR. HUTCHINSON: This is within four weeks

of back-titration of patients from 80 to 40

milligrams.

DR. FOLLMAN: What was the reason for

back-titration? Was it based on the patient\'s

evidence of proteinuria or clinical

characteristics?

DR. HUTCHINSON: Not at all.

DR. FOLLMAN: So it was done to everyone?

DR. HUTCHINSON: This was done to everyone

in the program because we had looked carefully at

our 80-milligram data and it felt, at that time,

that the efficacy that we were getting did not

justify its use in the general population because

of some of the adverse events we were seeing.

However, this is very strong evidence here

that the proteinuria was reversing. These are

patients on rosuvastatin 80 milligrams with

proteinuria. These are patients with elevated

urinary total proteins when they are on the

80-milligram dose and subsequently back-titrated to

40 milligrams. This is four weeks later.

DR. FOLLMAN: This is the whole group?

DR. HUTCHINSON: This is not everyone on

80\. This is done in selected sites. The reason it

had to be done that way is because we were doing

careful timed urine collections as part of the

study.

I will show you the whole group in a

second.

DR. FOLLMAN: Okay.

\[Slide.\]

DR. HUTCHINSON: But, in a very careful

evaluation of these patients, you see that going

from 80 milligrams to 40 milligrams, we get a

substantial reversal and decrease in the

proteinuria so, once again, suggesting that the

proteinuria was resolving.

\[Slide.\]

Now, if we take the patients overall, and

there are 752 patients back-titrated here, from 80

milligrams to 40 milligrams, we see that the

frequency of 1-plus or greater proteinuria goes

from 12 percent down to 4.8 percent and greater

than or equal to 2-plus 7.5 percent down to

1.9 percent.

With regard to proteinuria-hematuria, 21

out of 46 of the patients here at a urine protein

dipstick blood greater than or equal to 1-plus. 20

of the 21 no longer had that combined effect at

four weeks after the back-titration, once again

showing the reversibility, showing this goes away.

DR. FOLLMAN: Did you do the previous

slide in all the patients, the one with the figure

where you showed it went down nicely? It seemed

that that was in the selected group that had high

protein, high urinary protein\--

DR. HUTCHINSON: This one was in patients

with elevated urinary total protein.

DR. FOLLMAN: So, once again, this is not

surprising to me that there would be a tendency for

it to go down. Once again, I want to sort out the

reversibility versus just fluctuations going down.

You select them with high values, look at them

again, and they go down.

DR. HUTCHINSON: I believe what we need to

look at is the totality of the data here. This

signal is not seen in a lot of people, first of

all. It is seen predominantly at the 80-milligram

dose. We were not going to be treating patients

any longer with the 80-milligram dose so, in order

to be able to do these types of evaluations, these

patients provided a very nice cohort to study and

we used them to study the reversibility of the

phenomenon.

What is very important here is the

consistency of the findings. The key issue here is

if proteinuria or proteinuria-hematuria is

important from the standpoint of causing an effect

on renal function, then, certainly, the patients

that had the greatest levels of proteinuria and

proteinuria-hematuria and have it for the longest

duration, which would potentially be those with it

at the end of the day, would be the most likely

group to have a creatinine elevation if an

association existed.

But what is amazing here is, out of the

thousands of patients in the program, you evaluate

these people and then you come down with one or two

people at up to 40 milligrams and a handful at 80

milligrams. When you back-titrate the patients on

80 milligrams, the findings seem to reverse.

DR. BRAUNSTEIN: Dr. Carpenter?

DR. CARPENTER: Related to the same issue,

it seems that the concern that the proteinuria is

trying to predict is the concern of progressive

loss of creatinine clearance. We are using

proteinuria here as an overall marker of glomerular

function.

Yet, the studies that you have shown us

that examine the nature of the proteins in the

urine are evidence that this is primarily a tubular

problem. I wondered if you had explored the

tubulopathy any further; that is, maybe some of

this discordance is related to the fact that

glomerular disease is not what is happening but

tubulopathy is what is happening. Have you looked

at other tubular functions such as potassium

wasting, renal-tubular acidosis, things that could

potentially be comorbid events here that the

proteinuria could be marking and that we have not

really seen any data to effect.

DR. HUTCHINSON: Yes. We certainly did

that.

\[Slide.\]

I can show you some data here regarding

serum calcium, phosphorous and potassium in the

patients with or without proteinuria on

rosuvastatin 80 milligrams. You can see that there

are really no differences in the level of serum

creatinine, serum phosphorous, or serum potassium

in patients with or without the proteinuria. So

this seems to be an effect predominantly on tubular

transport within the tubules. We are not getting a

Fanconi\'s type of picture here with other

abnormalities present as well.

DR. BRAUNSTEIN: Dr. Watts?

DR. WATTS: Just to clarify. To me,

titrate means that you are adjusting the dose based

on some indicator. In the changing from 80

milligrams to 40 milligrams, it seems to me that

back-titrate is not the correct term, that you

simply reduce the dose.

DR. HUTCHINSON: That\'s fair.

DR. WATTS: I want to explore what Dr.

Woolf raised and what Dr. Follman raised and that

is the time course and is this resolution or is

this variability? The slide you just showed

indicated that 20 percent of patients in the

80-milligram group had proteinuria.

Table 15, and that analysis that you

had\--Table 15 of the FDA shows, by my calculations,

there are probably 180 patients in the 40 and

80-milligram dose who had proteinuria and over 300

patients who had hematuria.

It seems to me you can look at the

occurrence of these events by visit. That would be

more convincing to me than what you see at the last

visit represents a resolution rather than

variability because my bet is, if this is sort of

an erratic process, that what you would see at any

visit is what you see at the last visit. It is

only if you look over the totality of the exposure

that you see when it shows up.

Whether or not this is a problem, a

clinically meaningful problem, I don\'t know but I

share Dr. Carpenter\'s concern that changes in serum

creatinine may not be the best way to determine

whether or not this is a clinical problem.

DR. HUTCHINSON: Can I please see the data

that looks at our control pool and looks at the

evaluations of proteinuria at various time points,

please. I will try to address your question using

some of our control data.

\[Slide.\]

This slide is a little complicated. I was

hoping to avoid this. But, having said that, what

we are doing here is using the controlled-trial

database. One of the issues within any time

analysis is it can certainly be influenced if one

of the groups has more visits, if the durations of

therapy are longer.

We do know that for the 40-milligram dose

group in our program, we started a large controlled

trial and we had more visits and we were

specifically trying to characterize some of the

findings in our program using that trial. So, in

general, there was a tendency for patients on 40

milligrams to have more visits and we know that,

from our data, if you look at the placebo data, you

can see proteinuria even on placebo.

But here, what we are looking at, is there

are patients in our program that had shifts in

urine protein to 2-plus or greater. This was our

standard definition when we were analyzing our

data. So that is why I am showing you this.

Numbers may change a little bit, if you

are looking at slightly different levels of

proteinuria but I think the trends are roughly the

same. We are looking at Week 4, Week 6, Week 8 and

Week 12. Notice, for some of the doses you see

zeros, and that is because, in the trials that

those patients were involved in, there just wasn\'t

a visit at that time.

But here, at four weeks, in the

rosuvastatin trials, we can see a signal up to 1.9

and 1.7 at the 40-milligram dose and, at the

80-milligram dose of rosuvastatin, it is 7.3, 8.4

percent at Week 6 ranging anywhere from 1 to 1.5.

If we go out here to Week 8, what we are seeing is

1 percent, 1.2 percent. If we go out here to Week

12, we see 0.8 percent.

Now let\'s look at our comparators. At

Week 4, we saw 0.3 percent here with simvastatin,

80 milligrams. If we go over to Week 6, we see a

rate as high as 1.6 percent on placebo, 1 percent

on atorvastatin 20. If we go out now to Week 8, we

see 2 percent here in atorvastatin, 22 percent in

simvastatin 20 and, if we go out here to Week 12,

we see rates as high as 1.3 percent.

So, at the end of the day, the proteinuria

can be seen as early as Week 2 but it appears at

various time points. There is no consistency with

regard to, \"I can tell you by Week 6 you are going

to see all the proteinuria.\"

As you can see from this analysis, you can

see rates as high as 2 percent in patients on the

comparators where there is a reasonable number of

patients on the comparators. So what we are seeing

at 40 milligrams does not appear to be

significantly different than what we are seeing

with the comparators.

The fact that we did more measurements at

40 milligrams is probably contributing in part to

the signal that you start to pick up at the

40-milligram dose group when you look at

proteinuria at any time.

I hope that helps.

DR. WATTS: I would like to see that slide

for a little bit longer.

DR. HUTCHINSON: Sure.

DR. WATTS: It could be made less

complicated if, where you have no patients, you

simply put an X and not a 0 because there are lot

of 0s in the incidence column where there are 0 in

the number-of-subjects column.

But, following the 40-milligram dose

across, it looks like there is I don\'t know whether

to call it an incidence or prevalence as it

continues, because I don\'t know whether they are

the same patients or new patients, but it is

between 1 to 2 percent. That is not consistently

seen for any of the other groups.

DR. HUTCHINSON: Part of the reason is

because they haven\'t been measured at some of these

weeks so you are not picking it up. But, at the

end of the day, I think the important point here is

that you can pick up proteinuria with the other

statins. It is there. Whether or not that

represents background or whether or not the statin

is causing an effect, we don\'t know.

But, if you remember, we presented one of

the cases in a South African patient who had a

creatinine elevation along with proteinuria and

hematuria and, in that particular patient, the

rosuvastatin was stopped. The abnormalities went

away. The patient was rechallenged with

rosuvastatin. The abnormalities, the urinalysis

abnormalities, came back. It was stopped. It went

away.

The patient was then rechallenged with a

lower dose of rosuvastatin, 40 milligrams. And the

urinalysis findings came back. So I think in some

patients there is the potential that this effect

can be seen.

But whether or not the numbers we are

seeing here are background or actually a

statin-related effect, especially for the other

statins, it is difficult to know. I think, with

rosuvastatin at 80 milligrams, we are certainly

seeing a signal and there is potentially a signal

at the 40-milligram dose.

But, once again, the key thing here is

what happens in this patients with small amounts of

proteinuria? Is the proteinuria at the end of the

day resulting in any long-term or short-term

detrimental effects on renal function? This

program is a huge program and we are just not

seeing it.

DR. BRAUNSTEIN: Dr. Kopp?

DR. KOPP: I have a couple of comments.

Maybe I could start with this slide. One of the

problems here is that it only twelve weeks of data.

You could conclude, on the basis of what you said,

that 80 milligrams of rosuvastatin is safe because

there is no proteinuria at Week 8 and Week 12. I

think it simply points out the more valid issue is

what happens after 48 weeks and 96 weeks.

DR. WATTS: There are no patients in the

80-milligram group at Week 8 and Week 12.

DR. KOPP: Oh; is that right? Sorry.

DR. HUTCHINSON: That\'s right. Exactly.

There are no patients.

DR. WATTS: That is why I am saying it is

an unnecessarily complicated slide because there

are 0s where there are zero potential to have data.

DR. KOPP: Fair enough. Thank you for

clarifying that. There are two issues I would like

to make as comments. The first, one of the reasons

for this variability is that dipstick proteinuria

is not the ideal way to measure it. It may be the

only practical way in a database of 12,000 patients

but I think we need to recognize that urine

concentration has a lot to do with whether the

dipstick is positive or not.

In fact, if you want to be devil\'s

advocate, you could say, with progressive

tubulointerstitial disease, one of the first

features of renal function to decline is the

ability to concentrate. In a more dilute urine,

you would tend not to see the proteinuria.

I am not necessarily sure that that is

what is going on here, but I think some of this

variability of proteinuria here, say, 4 percent of

the time and then only present in 2 percent of the

patients at the end of the study, may have to do

with the limitations of dipstick proteinuria. So

that is one comment.

The other comment is I think the model

that I am thinking about, and I suspect some of the

other people are, too, is this an agent that causes

tubulopathy that may take a year or two to appear

and cause proteinuria in a small fraction of

patients, maybe 2 percent, maybe 4 percent, of

patients which eventually will damage glomerular

filtration by damaging the effect of glomeruli as

well and lead to a rise in creatinine. But that

may go on at three and four and five and six years.

I think we can\'t exclude that possibility.

Many tubular toxins, in fact, take many years to

cause their damage. Lithium would be a chronic

class example. So that is two comments.

A couple of specific questions. Could you

put Slide CS25 which was your data about

protein-to-creatinine ration and

albumin-to-creatinine ratio. The point here is

that glomerular proteinuria typically has more than

50 percent albumin; that is, more than 50 percent

of the protein in the urine is albumin.

As you point out, 0.3 is less than 50

percent of 0.8. The probability is that that

represents a mean of many patients. So, do you

have the specific data what fraction of these

roughly 300 patients had glomerular proteinuria?

Was it, in fact, zero or was it a few?

DR. HUTCHINSON: It is not zero. Where we

have SDS page information, it does show that the

predominant pattern that you see is the SDS page,

the tubular pattern.

If I can please see the data from-we

looked at patients in our program that developed

1-plus or greater proteinuria to look at what types

of patterns would be seen on gel electrophoresis.

I want the slides with the patients\--

DR. KOPP: While we are looking for that,

the page data are nice, but, in fact, you can get

it from the 300 patients where you measured

albumin, measured protein, measured creatinine and

simply determine. That might be interesting to do.

DR. HUTCHINSON: I can show you some data

in that regard, too, because we did so some of

these measurements as well. After I speak to these

two slides, I think it would be worthwhile with

regard to evaluation of our renal findings, we had

several experts in the field of nephrology look at

our data and advise us on how to appropriately

evaluate our data in this large database.

We have Dr. Ed Lewis with us today. I

think it would be appropriate for Dr. Lewis to make

a couple of comments in this regard as well. But

here we are looking at patients on the 80-milligram

dose in our program. I think that this has\--

\[Slide.\]

No; this is not the slide I would like to

see. Can I please have the slide with the patients

who went from 0 to 1-plus proteinuria. That has a

couple of things reversed on it. Give me the data

on the back-titration from 80 to 40 with the

different types of proteins that were measured.

DR. BRAUNSTEIN: While they are looking

for that, perhaps we can take the next question.

DR. KOPP: Can I ask a second question

which changes, now, to the use of the drug in

cyclosporine. Cyclosporine is also a

proximal-tubule nephrotoxin. Do you have any

comment about the occurrence of increased

proteinuria in patients who were on cyclosporine,

rosuvastatin was added, and then the same question

with regard to creatinine elevation. Again,

cyclosporine elevates creatinine by hemodynamic

mechanisms, later by fibrosis. Does rosuvastatin

potentiate those effects?

DR. HUTCHINSON: The studies with

cyclosporine were very short-term. Predominantly,

they were pharmacokinetic studies and we did not

pick up issues with regard to proteinuria or with

creatinine elevations in those patients. But, in

those studies, we were using low doses. I

apologize for the time it took to get this slide.

Hopefully we will find the other one in a second.

\[Slide.\]

These are patients in the substudy who had

timed overnight urine collections, back-titration

from 80 milligrams to 40 milligrams. These are the

various proteins that were looked at along with

n-acetal-glucose aminidase activity. What we see

at the 80-milligram dose is that the proteins that

were most prevalent in the urine were alpha-1

microglobulin, retinal-binding protein. We had

lower levels of beta-2 microglobulin, albumin

transferrin and IgG, but part of this was just due

to stability issues with beta-2 microglobulin.

What is critical here is, once we

back-titrated patients to 40 milligrams, the

largest changes that we were observing were in the

alpha-1 microglobulin and retinal-binding protein

groups. We saw smaller changes with regard to the

other groups.

Have we found the other slide? We will

have to try to find that over the break.

DR. KOPP: One other question, and I can

yield the floor. How about glycosuria, a follow up

on Dr. Carpenter\'s question. Any glycosuria in

these patients?

DR. HUTCHINSON: No.

If the Chairman will allow, I can have Dr.

Lewis come up and comment.

DR. BRAUNSTEIN: I think what we would

like to do is to actually continue this discussion

after the FDA\'s presentation. But I wanted to give

Dr. Neylan an opportunity to ask his question.

DR. NEYLAN: Thank you, Mr. Chairman. Two

question, both relating to renal effects. The

first, as the sponsor has shown, I think the

tubular-protein composition is certainly

consistent\--or, rather, the protein composition is

certainly consistent with a tubular site. I am not

convinced yet that I understand whether this is a

functional or more structural effect, though.

The reason I raise that is that this issue

of hematuria arising in roughly the same incidence

or prevalence as the proteinuria suggests the

possibility that, indeed, there is a structural

element here. As we know, a protein in the urine

can be found in a variety of otherwise normal

states. Hematuria is quite a bit less frequent.

The dipstick is certainly a convenient way

of looking for the presence of hemoglobin but it is

a surrogate for a microscopic examination of urine

sediment. Urine sediment that shows a lot of cells

and casts certainly raises the possibility of an

activity or inflammatory state or even a state of

increased turnover, be it tubular cells or

glomerular cells.

So my question is when you received the

approvable letter roughly a year ago and went back

to do more detailed analysis of these renal

findings, did you have opportunity to incorporate

some evaluations of the microscopic elements of the

urinalysis, look at sediment beyond just the

dipstick and so could you share those with us?

DR. HUTCHINSON: I don\'t have a slide to

show that, but we did have urine sediment

evaluations on our patients with proteinuria and it

did not show that these patients were having an

active urine sediment.

DR. NEYLAN: How about in those patients

that had hematuria by dipstick? Were you able to

do any microscopic examinations of those urines?

DR. HUTCHINSON: We know it is red blood

cells. Unfortunately, it is impossible now to go

back at this stage and look at those previous

urines simply because you need to look at fresh

samples for the appearance of the red blood cells.

This is something that we are doing now in our

studies going forward but we don\'t have the samples

to go back and evaluate them for red-blood-cell

morphology.

DR. NEYLAN: My second question relates to

cyclosporine. You mentioned that you were able to

do a small study in heart-transplant recipients who

were receiving cyclosporine as presumably one of

the elements of their maintenance immunosuppressive

regimen.

I am going to guess that, since most

heart-transplant patients are not on cyclosporine

monotherapy, that this was a multidrug regimen.

Were you able to tease out the potential impact or

interaction of cyclosporine from any other elements

in this regimen since there are well-known

interactions with a variety of other

immunosuppressants?

DR. HUTCHINSON: No; we have not done

that.

DR. NEYLAN: I noticed the labeling of

other statins does not necessarily get as specific

as cyclosporine but mentions that, in the face of

immunosuppressants, there can be warnings attached.

DR. HUTCHINSON: One thing that we did do

was go back and look at our database and look at

our hypertensive patients on various types of

antihypertensive treatments because some

antihypertensive treatments certainly can have

effects on the tubules to see if patients having

treatment with those antihypertensive agents

increased the possibility of having proteinuria.

\[Slide.\]

So here we are looking at our highest

proposed dose of rosuvastatin, the 40-milligram

dose. We are looking at the association with

various antihypertensive drugs of proteinuria, so

we are looking at ARBs, ace inhibitors, calcium

channel blockers and diuretics.

As you can see, yes would mean that they

were on the drug. No means not on the drug. This

is the percentage with 2-plus or greater

proteinuria, the percentage with 1-plus or greater

proteinuria. As the data shows, there is no

evidence that patients on these drugs would have an

increased frequency of proteinuria.

So, once again, if there was some

susceptibility there, we would expect to see an

increased frequency and that is not happening.

DR. BRAUNSTEIN: Thank you.

We will now have the FDA\'s presentation.

Following that, there will be some more questions

from the committee, both to the FDA and to the

sponsors.

DR. BRAUNSTEIN: Ms. Mele will give the

efficacy presentation.

FDA Presentation

Efficacy

MS. MELE: Good morning.

\[Slide.\]

My name is Joy Mele. I am the FDA

statistical reviewer for the Crestor application.

\[Slide.\]

I will be giving a short presentation on a

few efficacy issues, so we are back to efficacy

now. First, I will show the dose-response effect

on LDL for rosuvastatin in three studies, Studies

8, 33 and 65. Then I will present a detailed

comparison of rosuvastatin to atorvastatin using

data from Studies 33 and 65. Lastly, I will

describe the effect of rosuvastatin on HDL.

\[Slide.\]

To show the dose-response effect on LDL, I

will presenting data from three dose-response

studies in Type IIa and IIb patients, Studies 8, 33

and 65. You have already seen data today from

Studies 8 and 65. 8 was combined with Study 23 in

the sponsor\'s presentation. I will show you the

data from these two studies and also from Study 33.

Recall, the doses in Study 8 were 1, 2.5,

5, 10, 20 and 40. In Study 33, dosing ranged from

5 milligrams to 80 and, in Study 5, an open-label

study, dosing ranged from 10 milligrams up to 80

milligrams.

Studies 33 and 65 both included

atorvastatin arms. The sample sizes in each

treatment group varied considerably across these

studies with only about 15 in each group in Study 8

to about 40 in Study 33 and about 160 in each

treatment group in Study 65. The baselines were

similar across the studies at about 190 milligram

per deciliter.

\[Slide.\]

This is a plot similar to what the sponsor

has already shown you. Here is plotted the mean

LDL percent change from baseline for the full dose

range of rosuvastatin studied in the three trials I

just described. I wanted to show here the

consistency of the results across these individual

studies.

Study 8 is shown in blue, Study 33 in

green and Study 65 in red. The Y axis goes from 0

to 70 percent.

Looking at each dose, and taking into

consideration the variability of these estimates, I

would conclude that the responses are very similar

across these studies. A dose response is evident

in each study although, at the high end of the dose

range, the 40 and 80-milligram doses, we see small

differences of about 2 to 3 percent suggesting a

leveling off of effect.

The benefit of doubling 20 milligrams to

40 is evident in Studies 8 and 33, and the sponsor

showed this very nicely on a side earlier, but not

so evident in Study 65, the very large trial. Note

that the 5-milligram dose, which is plotted here,

provides about two-thirds of the lowering seen for

the 40-milligram dose, about 42 percent for 5 and

60 percent for 40. Dr. Lubas will make some

additional comments about the 5-milligram dose in

his presentation.

\[Slide.\]

From the data presented earlier by the

sponsor, it was evident that the rosuvastatin is

more potent than any other marketed statin on a

milligram-per-milligram basis. Looking across the

dose range, though, at what doses are rosuvastatin

and atorvastatin comparable? Is twice the dose of

atorvastatin needed to obtain comparable LDL

lowering? How about four times the dose? I will

address these questions in the next few slide

slides by showing the treatment differences in the

96-percent confidence intervals.

\[Slide.\]

First let\'s look at a comparison of

rosuvastatin versus two times atorvastatin. Using

the data from 33 and 65, the two largest

dose-response studies in Type IIa and IIb patients,

I have plotted the mean treatment difference in the

90-percent confidence interval for the difference.

The values to the left of the 0 line favor

rosuvastatin while the values to the right favor

atorvastatin.

At the top of the graph is 5 milligrams

versus atorvastatin 10. Then there is 10 versus

20, 20 versus 40 and 40 versus 80. Study 33 is

plotted above Study 65 for each of the pair of

estimates.

Focusing first on the blue boxes, the

results look quite consistent, a difference of

about 4 percent in favor of rosuvastatin is seen.

The confidence intervals for Study 65 are tighter

than for Study 33, as would be expected, given the

large sample size, and the differences seen in

Study 65 are statistically significant. This is

the 0 line, and so you can see that these estimates

do not overlap 0.

I just wanted to point out about the

confidence intervals. These confidence intervals

suggest that it is plausible that differences as

small as 1 to 2 percent could be seen, not a

clinically important difference. But they also

suggest that differences as large as 8 percent

could be seen as well, which would be an important

difference.

Since 40 is the highest proposed dose for

rosuvastatin and 80 is the highest marketed dose

for atorvastatin, I would like to examine this

comparison further.

\[Slide.\]

Looking first to the graph on the left,

these box plots show that 25th, 50th and 75th

percentiles. The individual observations are

plotted over the boxes. The overlap of the box

plots show that some patients taking atorvastatin

80 can achieve LDL-lowering comparable to changes

seen for 40 milligrams of rosuvastatin although the

relationship of the boxes shows that a higher

percentage of rosuvastatin patients will achieve

significant decreases. The cumulative

distribution plot to the right here, reiterates

this point. The red line is rosuvastatin and the

blue line is atorvastatin 80. The difference

between the lines is illustrated by this vertical

line at 60 percent.

About 23 percent of atorvastatin patients

had a decrease of 60 percent or more while about

twice as many rosuvastatin patients had a decrease

of 60 percent or more.

\[Slide.\]

What about four times the atorvastatin

dose? Notice that all the confidence intervals

overlap 0. Three estimates favor atorvastatin and

two favor rosuvastatin, so there is no consistency

across the estimates although the two estimates

from Study 65\--that would be these two

estimates\--are close to 0 and suggest

comparability.

Now let\'s go on to HDL.

\[Slide.\]

There were four placebo-controlled,

fixed-dose, phase-III, trials in the original

Crestor application. The HDL results for these

trials are listed here. The second column shows

the baseline. The baseline in Studies 8, 23 and

24, all studies in Type IIa/IIb population, is

about 50 milligrams per deciliter. In the Type

IIb/IV population of Study 35, the baseline is

about 35.

The underlying values indicate those

changes significantly different from placebo. In

general, the results are variable across the

studies in significance and also in magnitude of

effect although some consistency is seen for the

10-milligram dose which would be this column here.

Note that the placebo subtracted estimates

for the last two studies are both 8 percent. The

lack of a dose effect is evident in both Studies 8

and 35 where higher doses show lower mean

responses. You can see that here.

Now we will examine further the

rosuvastatin dose response for HDL using the data

from the large trial, Study 65.

\[Slide.\]

These box plots are of the HDL percent

change from baseline for rosuvastatin in red and

atorvastatin in blue. The grey boxes represent the

confidence intervals about the medians. You can

see a slight shift upwards of the confidence

interval when going from 10 milligrams to

20 milligrams of rosuvastatin. This represents

about a 2 to 3 percent more increase in HDL. Doses

about 20 appear to afford no additional benefit so

there is no clear dose-response relationship.

The results from Study 33, the other trial

I showed you earlier, show a very similar pattern

of research for rosuvastatin that is shown here.

The box plots for atorvastatin are clearly

shifted downward. You can particularly see this if

you focus on the 75th percentile at the top of the

boxes. The atorvastatin response is more variable

compared to the rosuvastatin response. If I showed

you again the results from Study 33, you would see

even more variability among the atorvastatin arms.

\[Slide.\]

So, in summary, rosuvastatin is marginally

more effective than two times the dose of

atorvastatin achieving about a 40 percent more

lowering on LDL. It is clear that some patients

may achieve comparable effects to rosuvastatin 40

with atorvastatin 80. The HDL effects are

variable. There is no clear dose-response

relationship with only a further increase of about

2 to 3 percent seen when doubling the dose from 10

to 20.

This lack of a dose response is consistent

with what we see in the statin class although the

atorvastatin results suggest more variability at

the higher doses than what was seen for

rosuvastatin.

Thank you.

DR. BRAUNSTEIN: Thank you.

MS. MELE: Dr. Lubas will speak next.

DR. BRAUNSTEIN: We will go on to the

safety and dosing presentation by Dr. Lubas.

Safety and Dosing

DR. LUBAS: Good morning.

\[Slide.\]

My name is William Lubas. I am a medical

officer in the Division of Endocrine and Metabolic

Drug Products.

\[Slide.\]

I will be speaking to you today focusing

on the issues of safety and dosing of rosuvastatin.

In the first part of this talk, I will focus on

safety.

\[Slide.\]

I will first address the issue of muscle

toxicity associated with the use of statins.

Statin-associated muscle toxicity has included CK

elevations alone, myopathy, which is defined as CK

elevations greater than ten times the upper limit

of normal associated with muscle symptoms, and

rhabdomyolysis, which is a clinical diagnosis which

commonly refers to patients with very high CK

elevations such as greater than 10,000 units per

liter and/or patients requiring hospitalization for

IV hydration.

Since safe and effective statins with a

low risk for the development of rhabdomyolysis are

already currently available, any future statins

which would be approved need to have a comparable

or lower risk for this adverse event.

\[Slide.\]

This slide shows the incidence of CK

elevations and myopathy seen with the use of

statins. It summarizes the data from the

clinical-development programs from Baycol,

rosuvastatin, and for the pool of currently

marketed statins. The incidence of myopathy

includes all cases regardless of etiology.

While rosuvastatin doses of 40 milligrams

and lower are within the range seen for other

approved statins, there is a clear break at 80

milligrams. The two highest marketed doses of

Baycol of 0.4 and 0.8 milligrams and the

rosuvastatin dose of 80 milligrams had a similar

frequency of CK elevations greater than ten times

the upper limit of normal and myopathy, as you can

see comparing here to here.

The frequency of CK elevations and

myopathy is still higher for the 80-milligram dose

of rosuvastatin compared to all marketed statins

even if one looks only at treatment-related cases

as reported in the sponsor\'s presentation earlier

this morning.

Baycol, at the highest dose, was found to

cause severe myopathy and rhabdomyolysis in

open-market use with a frequency not acceptable for

the benefits of the drug with regard to LDL

cholesterol lowering. Rosuvastatin, at 80

milligrams, is only marginally more effective than

the 40-milligram dose and, relative to currently

marketed statins, was associated with

rhabdomyolysis in phase III of clinical

development.

The expectation of greater risk in the

less-structured and less-monitored setting of

market use led to the conclusion of the

unapprovability of this high dose.

\[Slide.\]

Now I will switch to the discussion of

treatment-emergent renal adverse events now

previously observed with statins which the sponsor

has discussed in detail in their presentation and

which they attribute to the decreased protein

uptake by renal tubular cells due to

statin-mediated inhibition of HMG CoA-reductase in

these cells.

\[Slide.\]

This slide shows the percentage of

patients in the largest rosuvastatin safety data

pool shown here, including all patients from all

controlled and uncontrolled trials as well as

real-time data with proteinuria by treatment group

at any visit.

Proteinuria is defined as

dipstick-positive urine of plus-plus or greater

with at least one grade increase from baseline

during the trial. The n here refers to the total

number of patients in each group. The simvastatin,

pravastatin and atorvastatin data came from

controlled trials only while the rosuvastatin data

included both controlled trials and open-label

extensions and so had more patients as can be seen

here. It also had longer duration of patient

exposure.

The rosuvastatin data gave an appearance

of an increase across the range of those who were

studied, but there was a clearly visible transition

at the 80-milligram dose where the peak incidence

was 17 percent compared to all other statins which

had a frequency of less than 4 percent and were

similar to the frequency of 3 percent seen with

placebo.

This was true for patients on rosuvastatin

in both the controlled and open-label extension

trials which I will show more clearly in a

subsequent slide. Patients who were back-titrated

from the 80-milligram dose to 40 milligrams of

rosuvastatin according to the sponsor, as discussed

already earlier today, had a decrease in the

frequency of proteinuria from about 8 percent at

their last visit on 80 milligrams to about 2

percent at their first follow-up visit on 40

milligrams. This suggests the reversibility of the

proteinuria seen here at 80 milligrams.

\[Slide.\]

This slide shows the percentage of

patients with proteinuria at any visit summarized

by the numbers on top of the bars subgrouped by

dose and categorical increase in creatinine from

baseline, as shown in the box. Proteinuria, again,

refers to dipstick-positive urine of plus-plus or

greater with at least one grade increase from

baseline during the trial.

In this slide, the data are presented for

both the controlled trials, the lighter colors, and

the open-label extension, the darker colors and

labeled OLE. The serum-creatinine data is

superimposed on the bars using tricolors subdivided

by each group, as shown in the insert.

Red corresponds to an increase of greater

than 30 percent from baseline. Green corresponds

to an increase of between 20 and 30 percent from

baseline and blue corresponds to patients with less

than 20 percent increase from baseline.

So, for example, looking at the

80-milligram dose of rosuvastatin in the open-label

extension trials, 17.2 percent of the patients had

proteinuria at any visit. 11 percent of these

patients also had an increase of less than 20

percent; that is, this would also include patients

with creatinine decreases from baseline.

About 2 to 3 percent of these patients had

an increase of 20 to 30 percent represented by the

green bar and 3 to 4 percent had an increase of

greater than 30 percent represented by the red bar.

I should just focus again that this data,

in contrast to what the sponsor has presented, is

data at any visit. The creatinine data is taken at

the exact same time as the proteinuria data.

The higher incidence of proteinuria seen

with the 80-milligram dose is also associated with

higher incidences of serum-creatinine increases of

both greater than 20 percent and greater than 30

percent from baseline. The greater-than-20-percent

increase from baseline increase would correspond to

the red and green bars, and the

greater-than-30-percent increase from baseline

would correspond to the red bars alone.

At doses below 40 milligrams, the

frequency of proteinuria and creatinine increases

from baseline is much lower. So it is hard to draw

clear conclusions about these dose effects. The

fact that the frequency of proteinuria appears to

be higher in the open-label extensions compared to

similar doses in the controlled trials suggests

that the incidence of proteinuria increases over

time. But this can be confounded by the irregular

frequency of sampling of these trials.

\[Slide.\]

In addition to proteinuria, a subset of

these patients had also had microscopic hematuria.

This slide shows the percentage of patients with

combined proteinuria and hematuria at any visit,

subgrouped, again, by dose and categorical increase

in creatinine from baseline. Again, this is at any

visit, not just at the last visit.

Here hematuria represents

dipstick-positive urine of plus or greater with at

least one grade increase from baseline. Over half

of the patients with proteinuria at the

80-milligram dose shown in the previous slide also

had hematuria shown here. So, for example, for the

closed-label trials, 6.1 percent of the patients

out of 11.8 in the previous slide and for the

open-label extensions it was about 10.5 percent out

of 17.2 percent of the patients.

This suggests that these two effects may

be related. About 2 percent of the patients on 80

milligrams had a visit at which they had combined

proteinuria, hematuria and an increase in

creatinine of greater than 30 percent shown by the

red boxes. This was true for both the open-label

extension and the controlled trials at

80 milligrams and suggests an effect on renal

function.

In contrast, only about a third or less of

the cases of proteinuria at doses of 40 milligrams

and lower, seen in the previous slide, also had

hematuria in this slide. The incidence of

hematuria at these doses shown here is below 2

percent.

Again, at doses below 40 milligrams of

rosuvastatin, the frequency of combined proteinuria

and hematuria associated with the creatinine

increases from baseline is much lower and so it is

hard to draw any clear conclusions about dose

effect.

While statin-mediated inhibition of

protein uptake in renal tubular cells, described by

the sponsor, may partially explain the proteinuria

seen with rosuvastatin, it does not explain the

hematuria or increase in serum creatinine seen

primarily at the 80-milligram dose.

\[Slide.\]

These are cases that the sponsor has

already addressed but I would like to focus on

these a little more. In addition to the

proteinuria and hematuria seen with rosuvastatin,

there were two cases of acute renal failure of

unclear etiology in patients receiving 80

milligrams of rosuvastatin for 15 to 31 days.

One of these patients had acute tubular

necrosis noted on renal biopsy. There was also one

case of chronic tubulo-interstitial nephritis after

18 months of therapy on 80 milligrams of

atorvastatin. The renal biopsy was consistent with

acute and chronic interstitial inflammatory changes

and this patient had a positive rechallenge test

with worsening proteinuria and hematuria with

repeat exposure to rosuvastatin. This patient also

had a positive rechallenge test, as mentioned

before, to another less potent statin suggesting

that this may, in reality, be due to a class

effect.

These three cases, while serious,

represent a small number of the patients out of the

total of 12,000 exposed to rosuvastatin or the

1,500 exposed to the 80-milligram dose. It is

important to note that all of these cases were seen

at 80 milligrams and all patients improved after

the drug was discontinued.

\[Slide.\]

There are still several unanswered

questions about the renal findings. First, have

the renal findings been adequately addressed?

Clearly, most of the findings were at the

80-milligram dose which will not be approved. They

were largely reversible on back titration from 80

to 40 milligrams and even patients with serious

adverse events recovered after the drug was

stopped. But the effects at lower doses are less

clearly understood.

Next, is some sort of monitoring needed,

possibly at higher doses? Would urinalysis looking

for proteinuria, hematuria and/or serum creatinine

be useful for monitoring? Also, what further

investigations are warranted to better understand

the mechanism and the clinical course of these

effects? Finally, is this a class effect of

statins?

\[Slide.\]

In summary, the frequency of CK elevations

and myopathy at doses of 40 milligrams or less is

similar to that seen with other statins. The

frequency of a 30 percent increase in serum

creatinine above baseline in patients with

proteinuria of plus-plus or greater is higher at

doses of 80 milligrams compared to lower doses.

There is a suggestion that there also may

be an increase with 40 milligrams but the overall

incidence of proteinuria is so much lower at 40

that it is hard to draw conclusions from the

current data. Clinical evidence suggests the renal

findings may not be entirely explained by the OK

model of inhibition of protein uptake by renal

tubular cells.

\[Slide.\]

The final issue the advisory committee

will be asked to address is dosing. This slide

presents mean LDL cholesterol data from two pooled

trials, 8 and 23, in patients with Type IIa and

IIb, primary hypercholesterolemia and mixed

dyslipidemia with mean baseline LDL cholesterol

levels in the range of 185 to 194.

The sponsor is proposing a start dose of

10 milligrams which would produce a mean LDL change

of minus 50 percent. However, the 5-milligram

dose, which is also available, is very effective at

lowering LDL cholesterol and would produce mean

reductions in LDL of minus 43 percent.

In one study of Type IIa and IIb patients,

the 5-milligram dose resulted in 67 percent of the

cohort reaching ATP-3 goals compared to 80 percent

at the higher dose of 10 milligrams, a difference

of only 14 percent more at the higher dose. It

should be emphasized that, for many patients, the

5-milligram dose may be an adequate start dose

based on baseline LDL levels and targets of

therapy.

\[Slide.\]

This slide summarizes the recommended

start dose for all currently marketed statins and

the proposed start dose for rosuvastatin. The

sponsor is currently proposing a start dose of 10

milligrams, 20 milligrams for patients with severe

hypercholesterolemia with LDL cholesterol baseline

levels above 190 milligrams per deciliter and 5

milligrams only for patients who are also receiving

cyclosporine.

The 10-milligram proposed start dose for

rosuvastatin would give mean LDL

cholesterol-lowering greater than seen with all

other currently approved statin start doses, yet

the 5-milligram dose is also very effective.

\[Slide.\]

This slide describes the mean

LDL-cholesterol reduction in statin-therapy

clinical-event trials and it compares them to that

seen with 5 milligrams of rosuvastatin. Although

there are currently no clinical outcome data for

rosuvastatin, it should be noted that the mean LDL

reduction achieved with the 5-milligram dose

exceeds those observed with other statins studied

in large outcome trials.

This is true for both primary and

secondary prevention trials. It is reasonable to

assume, therefore, that, all else being equal,

rosuvastatin, 5 milligrams, would be clinically

effective as well as effective in treatment of LDL

cholesterol to goal.

\[Slide.\]

This slide shows changes in AUC and Cmax

with concomitant use of certain drugs or in special

patient populations. Since no drug-drug

interactions can increase serum rosuvastatin levels

from two-to-seven-fold and specific patient

populations may have two-to-four-fold increases in

AUC over the average, labeling will need to address

these situations shown in this slide.

The sponsor is currently proposing to

limit the dose of rosuvastatin to 5 milligrams in

patients taking cyclosporine to 10 milligrams in

patients taking gemfibrozil and to 10 milligrams in

patients with severe renal failure.

At present, the sponsor has not proposed

alternative dosing for Asian Americans or patients

with severe liver failure, even though the sponsor

is currently seeking only a maximum dose of 20

milligrams in Japan. The sponsor does not feel the

need to cap the dose in the case of severe liver

failure since they propose contraindicating the use

of rosuvastatin in patients with active liver

disease or unexplained persistent elevations of

serum transaminases.

It is important that a wide dose range be

available for these subgroups to permit optimal

balancing of risk and benefit. Clearly, patients

that have a decreased clearance for rosuvastatin

will need to take lower doses of this highly potent

statin.

\[Slide.\]

This slide shows steady-state rosuvastatin

levels in asymptomatic patients receiving either

20, 40 or 80 milligrams of rosuvastatin in trials

8, 23, 33 and 35. These values are compared to

samples taken 10 to 15 hours after the last dose of

rosuvastatin from patients with rhabdomyolysis,

myopathy or renal failure of unknown etiology shown

in this last column.

These patients had all been taking the

80-milligram dose. There is no overlap in exposure

among patients receiving 20 milligrams and those

showing evidence of toxicity. There is a small

overlap of less than 2 percent in exposure among

patients receiving the 40-milligram dose and those

showing evidence of toxicity while about one-third

of the patients on 80 milligrams had a steady-state

plasma concentration above 50 nanograms per

deciliter which was the lowest observed plasma

concentration associated with toxicity in these

patients.

These data suggest that drug-drug

interactions or use in special populations with

diminished metabolism or compromised clearance

could result in increased serum rosuvastatin levels

similar to those seen in patients with muscle and

renal toxicity.

\[Slide.\]

In summary, as is seen with other statins,

conditions that result in increased serum

rosuvastatin levels above those normally seen with

40 milligrams may be associated with renal and

muscle-related adverse events. Restrictive

labeling will be necessary to limit dosing in

patients at risk for higher serum rosuvastatin

levels because of concomitant drug use or decreased

drug clearance.

The sponsor is currently seeking to limit

the maximum daily dose only in patients on

cyclosporine, gemfibrozil or in patients with

severe renal failure as shown in this slide. We

are asking if the sponsor\'s proposal to limit

dosing is adequate and are there other conditions

that may require limiting the maximum dose such as

patients with Asian ethnicity.

\[Slide.\]

Also, in summary, the sponsor is proposing

a start dose of 10 milligrams for patients with

hypercholesterolemia and mixed dyslipidemia with

baseline LDL less than 190. We are asking should

the 5-milligram dose also be recommended as an

alternate start dose. Unless we have

clinical-outcome data, we cannot tell whether the

greater LDL lowering obtained by starting all

patients on 10 milligrams on rosuvastatin is of

greater benefit than treating patients with lower

doses of rosuvastatin or different, less-potent,

statins to reach each patient\'s recommended LDL

cholesterol goal.

While it is true, as the sponsor mentioned

earlier this morning, that the safety profile of

the 5 and 10-milligram doses of rosuvastatin in

these trials was similar, clinical trials are

always subject to limitations regarding conclusions

about absolute safety.

The possibility, therefore, always exists

that higher doses of any drug are more likely to

produce more adverse events especially when a much

larger and more diverse population is exposed to

the drug once it is available on the open market.

Thank you for your attention and we look

forward to the advisory committee\'s discussion.

DR. BRAUNSTEIN: Thank you.

Question from the Committee

I will now open it up for further

questions, both for the FDA representatives as well

as to the sponsors. I would actually start with

the sponsors since their pharmacokinetic studies is

carried out in Japanese individuals in Japan showed

an increase in serum levels, have you broken down

the data as far as Japanese Americans are

concerned? Is this an ethnic issue or is it an

environmental issue?

DR. HUTCHINSON: Very good question.

Certainly, after we saw the results of the our

Japanese study conducted in Japan, we were

interested in understanding whether or not the

effects that we observed were due to either

environmental or genetic factors.

There is only a small number of Japanese

patients that have been exposed to our program

outside of Japan so we can\'t draw any definitive

conclusions from those patients. However, in

response to the findings, what we have done is

initiated a series of studies in order to

understand this issue better.

We are conducting a study in Singapore,

currently, that will be enrolling patients of Asian

descent along with Caucasian patients. That will

help determine whether or not we are seeing an

environmental versus a genetic effect here.

But, in general, when we look at the data

from the rosuvastatin programs in the Asians that

have been exposed in the U.S., the frequency of

adverse events, overall was similar to what we were

seeing with the other comparator groups and there

is no evidence that the Asian patients in our

program were having an issue regarding tolerability

to the drug.

If I may, Mr. Chairman, I would like to

put up a slide to address Dr. Kopp\'s previous

question. Do we have that proteinuria slide,

please?

\[Slide.\]

You saw this data previously. It is just

the headers were incorrect and I apologize for

that. This is some data from the program regarding

urinary protein electrophoresis patterns in

patients with dipstick-positive proteinuria. Here

we are looking at thirteen patients that have had

pretreatment levels of proteinuria at 1-plus and

the breakdown of the electrophoresis patterns in

this patients.

Out of these patients, we saw eight with a

normal pattern. None had a tubular pattern, two

had a mix, and three with a glomerular pattern.

With regard to patients on treatment who develop

1-plus proteinuria\--there are 53 patients that we

have in this cohort right now. We see fifteen of

these patients had a normal pattern. Twenty-two of

the patients developed a tubular pattern, nine a

mixed and seven glomerular.

So the predominant finding on

electrophoresis was a tubular pattern or a normal

pattern

DR. BRAUNSTEIN: Thank you.

DR. LEVITSKY: Perhaps a point of

information. I hadn\'t looked this up before I

left. The other statins out there don\'t have any

suggestion that one should be checking for renal

function or checking urinalyses, do they?

DR. BRAUNSTEIN: Dr. Orloff?

DR. ORLOFF: That is correct.

DR. BRAUNSTEIN: Dr. Kopp?

DR. KOPP: I had a question about

monitoring for CPK, if we could leave renal for a

minute. With regard to other statins, actually, is

that presently monitored and do you have any

proposals on monitoring your patients on

rosuvastatin?

DR. HUTCHINSON: I will allow Dr. Orloff

to answer the monitoring question for other statins

or Dr. Lubas.

DR. ORLOFF: Unfortunately, I didn\'t bring

my stack of statin labels with me but the basic

principles of the instructions with regard to the

potential for myopathy that are included in the

labeling for the other statins hold that, while

routine monitoring, per se, is not recommended,

symptoms should be followed up and the finding of

an abnormal CK requires follow up to assure

spontaneous resolution or to guide reduction in

dose or discontinuation of therapy if it is deemed

potentially to be drug-related.

DR. KOPP: Is there a suggested cutoff

above which, in terms of CPK-fold elevation, some

change in therapy should be initiated?

DR. ORLOFF: Ten times the upper limit of

normal is the action level that is recommended.

DR. BRAUNSTEIN: Dr. Neylan?

DR. NEYLAN: A question, again, about the

muscle. There is clearly a spectrum of signs and

symptoms associated with statin use. I have a

specific question about a tolerability issue. Even

in the absence of elevations of CK, myalgias are

not infrequent with this class of drugs and can

potentially be an obstacle to the patient and the

prescriber.

I am wondering, is this a new entrant that

looks to emerge in the market\--I believe there are

a total of seven now. Do you have any data

relating to myalgia either overall frequency or

intensity in comparison to some of the active

controls you have had in your many trials?

DR. HUTCHINSON: Yes; we do have that

data.

\[Slide.\]

Here is data from our controlled-trial

pool. It is patient-reported adverse-event data

and we are looking at information on rosuvastatin

in the comparators and placebo group in this pool.

What you see in general is that the

frequency of any adverse event reported for

rosuvastatin. This particular table contains

information on the 80-milligram dose in addition to

lower doses of rosuvastatin. With regard to any AE

roughly similar to that reported with the

comparators, we have, in general, a longer duration

of therapy with rosuvastatin in this group and that

needs to be taken into consideration.

But, with regard to myalgia, what we found

is that the frequency of myalgia on placebo was 1.3

percent and we found a similar finding with

rosuvastatin, 3.5 percent, atorva, 3.4, simva, 3.4

percent. Our pooled pravastatin gave us a 2.3

percent frequency.

DR. NEYLAN: You may be doing yourself

some disadvantage by including the 80-milligram

dose in this overall prevalence. Can you give us

the breakdown minus the 80 milligram?

DR. HUTCHINSON: Yes. We can look at one

of our other pools which is broken down by dose.

\[Slide.\]

This is a fixed-dose controlled pool. It

doesn\'t match up exactly with the other pool

because, in this particular pool, what we are

looking at is patients who initiated therapy at a

specific dose in a fixed-dose trial or, in a

titration trial, the data stops prior to titration

of the patient. So whatever dose they start on

prior to titration, that is the information that is

included.

So, in general, what we found, looking at

placebo and the doses of rosuvastatin from 5 to 80

milligrams in this pool was that the frequency of

any adverse event reported was roughly similar.

If we now look at myalgia, we find the

frequency on the placebo group was 1.4 percent and

then we see that the frequency was relatively

similar at doses from 5 to 40 but did increase at

the 80-milligram dose.

DR. NEYLAN: Then, again, my question

about whether you were able to compare it to the

incidence of your active controls.

DR. HUTCHINSON: In this particular pool,

we did not do that. But, in general, as you saw

from the previous slide, the all-controlled slide,

even including the 80-milligram dose, we don\'t see

an issue with myalgia.

You did ask also the intensity. In the

vast majority of the cases, the intensity of the

myalgia was mild.

DR. NEYLAN: Okay.

DR. BRAUNSTEIN: Dr. Follman?

DR. FOLLMAN: I had a question of

clarification for Dr. Lubas. Slide 5, you looked

at the percentage of patients with proteinuria at

any visit and there was a clear, dramatic

dose-response relationship within the rosuvastatin

group and, as a whole, they had higher rates than

the other groups.

I was wondering if that was based on

common follow-up period for all of the groups or

were rosuvastatin groups followed longer which

would tend to make their rates larger?

DR. LUBAS: It is sort of a complicated

question because it is more than just the length of

time of exposure. It also has to do with the

number of urine samples that were done. This data

is combined for rosuvastatin for both controlled

trials and for the open-label extensions.

Now, I could tell you that, in the

controlled trials, it was more similar across all

statins, that generally there were about two to

four samples, is what we are talking about in all

these trials. Some of the open-label extensions

had as many as nine or ten samples. But I don\'t

think that is true for all of them and I could

probably get you the data if you are interested.

So it is not just the length of exposure

but it is also the number of samples at each of the

doses that makes it very confusing. So it is hard

do know exactly what the picture is in terms of

whether the proteinuria is going away or being

intermittent or what.

DR. FOLLMAN: My concern is whether it was

sort of treating the different classes of statins

fairly or not, was rosuvastatin being followed

longer, did they have more visits where you were

checking proteinuria than the other statins. It

sounds like there is some difference between the

classes of statins and this isn\'t really a fair

shake to all the different statins in this picture.

DR. HUTCHINSON: I can give some

information in that regard.

\[Slide.\]

This is our controlled-trial pool with

rosuvastatin and the comparators, rosuvastatin 5 to

80, atorvastatin, 10 to 80, simvastatin 20 to 80,

and pravastatin 20 to 40. The number of patients

in each of the group, mean days on dose; you can

see it ranged up to 105, 106 days on rosuvastatin.

You can see the range for the comparators. Patient

years of treatment, much greater in the

rosuvastatin group than in any of the comparators.

If you look at the number of follow-up

visits, more in rosuvastatin than in the

comparators. Now, if you look at the median number

of follow-up visits to give some idea of did

follow-up visits contribute to seeing a higher

frequency of proteinuria here, you see, for

rosuvastatin, 40 milligrams, as I had stated

previously, there was more sampling performed on

average.

Now, the only other group that also had

three was the simvastatin, 80-milligram group.

But, in general, for atorvastatin, there was a

median of one follow-up visit and, at most, two for

the other comparators.

DR. BRAUNSTEIN: Dr. Carpenter?

DR. CARPENTER: Yes. A question that

arises from the efficacy data presented by Joy, and

I believe it is her Slide 10, this is the HDL data.

Although the mean and median increases in HDL with

statins is impressive and particularly for

rosuvastatin, there are outliers that appeared on

the slide that I don\'t think are visible on the

handout that would suggest that there are actually

some people who get quite significant reductions in

their HDL. I wondered if we could get a better

sense of that from the slide and, two, if there is

any way to predict who these people are and if the

drug was, for some reason, not effective in other

parameters with this particular group.

MS. MELE: I will defer to the sponsor to

answer that question.

DR. HUTCHINSON: I am going to ask Dr. Jim

Blasetto who presented our efficacy data to please

come and address the issues around HDL response,

consistency of response.

DR. BLASETTO: Certainly, there is some

variability in HDL raising with rosuvastatin that

we saw. What we have looked at, as far as response

to HDL raising that we have seen, we did see an

increase in augmentation of effect in patients who

had lower baseline HDLs, the slide that was shown

by Dr. Rader in his presentation.

Also, we have looked at patients

stratified by their baseline triglyceride and it

showed the patients with higher baseline

triglycerides had more of an HDL-raising effect.

So it appears that baseline lipid parameters

clearly plays a role where we see a further

increase in HDL.

\[Slide.\]

This is just to bring back what we had

seen earlier. This is data from Trial 65, the

STELLAR Trial, where we did look at response

stratified by the cutpoint used by the ATP-3

guidelines as low HDL and higher HDL. We can see

that, in the patients with low HDL, there was an

augmentation of the HDL raising compared to lower

HDL patients. We have seen that in other clinical

trials where we have stratified the patients by

HDL.

We have not particularly looked at the

stratification of patients by other parameters for

HDL effect. The effect has been really geared

towards the baseline lipid parameters.

DR. CARPENTER: I just wondered if we

could look at that slide again from the FDA

presentation, I believe it was Slide 10.

\[Slide.\]

Thank you. I can barely see the blue

dots, but I believe that is what I was picking up.

Some were down as low as 20 percent but, even

within the confidence limits, some are down to 15

or so.

MS. MELE: That is 60 to 55.

DR. CARPENTER: That\'s right. I think it

would be useful if the sponsor had any information

about the people that have significant reductions

in HDL and if, in fact, the ultimate outcome of

therapy in some of these patients could be more

detrimental than helpful.

MS. MELE: I just want to mention that

this is LOCF data and that it is possible that

those outliers could be patients who were not on

therapy very long. But I wouldn\'t know the

specifics. I didn\'t actually examine the outliers.

DR. BLASETTO: We have not looked

specifically at individual\--there are very few

cases, actually. The outlier cases are very few

and, in fact, if we look at the response seen with

the atorvastatin doses, we see, also, outliers with

reduced HTLC. As Joy said, in a

last-observation-carried-forward response, I don\'t

know what those individual patients represent, as

to whether they were patients earlier on that could

have been carried forward without further therapy.

So that I can\'t specifically address those

individual outliers. But, again, I think that we

look at the response seen with the atorvastatin, we

see, also, the outlier, several outliers, also.

DR. BRAUNSTEIN: Dr. Hennekens?

DR. HENNEKENS: I found the FDA

presentation by Joy Mele and William Lubas to be

very thoughtful and informative. Their

presentations emphasized the effects of different

doses of rosuvastatin from 5 to 80 milligrams on

LDL, HDL, CK, myopathy, proteinuria and combined

proteinuria and hematuria.

Based on these data, the agency raised the

possibility of adopting a 5-milligram rather than a

10-milligram starting dose but made no comment on

the possible desirability of 20 versus 40

milligrams as an upper limit of the dose.

I wondered if they would make a comment on

that end of the range based on their analysis.

DR. LUBAS: I\'m sorry; is the question

about efficacy of 20 versus 40 or safety of 20

versus 40?

DR. HENNEKENS: I was thinking about the

overall risk-benefit ratio because you presented

not only efficacy data but safety data on a wide

range of parameters at the different doses but then

made the conclusion about the starting dose

possibly being 5 rather than 10 but made no comment

at the other end of the spectrum about the use of

20 versus 40 as the upper limit.

DR. LUBAS: Right. The sponsor is only

proposing the start dose of 20 for patients with

LDL cholesterols of greater than 190 which would be

a small percent of the population. I guess the

sponsor could probably address this better, but

they have a large number of patients that were

started on 20 milligrams and it did have a good

safety profile.

DR. HENNEKENS: I think, in part, the FDA

would like to have the input of the committee

concerning starting dose and maximum dose rather

than to have the FDA, itself, take a stand at this

point in time.

In terms of the tubular dysfunction that

you see with the 40-milligram dose, have you looked

at the interaction with possible other tubular

toxins that patients may take; phenacetin, for

instance, and other agents that can affect the

tubules. Is there a potentiation of tubular

toxicity in those groups of patients because you

certainly have a lot of patients on the drug at 40

milligrams?

DR. HUTCHINSON: I showed you a slide

previously that did look at a number of

antihypertensive agents and the potential effects

of proteinuria. We can put that up one more time,

but I don\'t have data on it.

DR. BRAUNSTEIN: But I think that had

glomerular flow more. Wouldn\'t it be more of a

glomerular issue rather than a tubular issue, the

antihypertensives?

DR. HUTCHINSON: The diuretics, for

example, were in the tubules so the expectation

there is that there is the potential for synergy or

some type of added effect on the tubule if a

diuretic is given.

\[Slide.\]

When you look at our data in combination

with the diuretic on this slide, we don\'t see, in

patients with diuretics, that there is any

potentiation of the proteinuria. We have also

looked at patients in our program taking

nonsteroidal antiinflammatory agents and we saw

that patients on nonsteroidal antiinflammatory

agents, once again, there was no evidence of any

renal dysfunction compared to patients not on

nonsteroidal antiinflammatory agents. There was no

evidence of a potentiation of proteinuria in

patients on nonsteroidal antiinflammatory agents

versus those not on those agents.

DR. BRAUNSTEIN: Thank you.

Dr. Temple, you had a question?

DR. TEMPLE: Dr. Lubas listed two patients

with liver injury where he wasn\'t quite sure that

there was a full explanation. You mentioned that

they were rare, infrequent. I forget the word you

used\--patients who, in addition to transaminase

elevation, had other problems. Can you say

something about those or any of them, sort of pure

hepatocellular cases or what are they?

DR. HUTCHINSON: There are two cases of

patients, as Dr. Lubas mentioned in his briefing

document, of patients that did have an increase in

ALT associated with an increase in bilirubin. I

can present the first case here.

\[Slide.\]

One was a 68-year-old Caucasian male, had

seventeen weeks of rosuvastatin, 10-milligram

treatment. This was a patient outside of the

current database so, presently, the 10-milligram

database, if you include patients outside of our

current database, is around 17,000 patients\--so

these are patients outside of that database\--who

was noted to have icterus and brown urine. When

they evaluated the liver-function test in this

patient, note that he did have an elevated ALT and

AST with a mildly elevated bilirubin of 2.1

The patient was hospitalized, was on

several medications. All were withdrawn. Liver

histology showed normal parenchyma and he was

discharged. Follow-up liver function one week

after the event showed that everything went away.

DR. TEMPLE: Was the alkaline phosphatase

slightly elevated in that one? I thought that is

what I saw.

DR. HUTCHINSON: I don\'t recollect that.

Somebody could look at the case, but I am not sure.

DR. TEMPLE: So the normal histology makes

you think that it is not what you are worried

about; right?

DR. HUTCHINSON: Right.

\[Slide.\]

The second patient that is in the briefing

document is a 73-year-old Caucasian male subject

who, after 11 weeks of rosuvastatin, 10-milligram

treatment, reported icterus, ALT and AST values, as

you can see here, bilirubin, 11.8. However, this

patient had a workup for hepatitis and the

hepatitis showed hepatitis B surface-antigen

negative but a positive IgM anti-hepatitis-B core

antibody and hepatitis A IgG antibodies.

Also, in this patient, following

discontinuation of rosuvastatin, the abnormalities

resolved. But, in this particular patient, there

is also a possibility that this could have been

hepatitis related.

DR. TEMPLE: That one, for sure, had an

elevated alkaline phosphatase of 300.

DR. HUTCHINSON: Right.

DR. TEMPLE: So that blurs it, too.

DR. BRAUNSTEIN: Dr. Kopp?

DR. KOPP: I would like to hear, if I

could, from the nephrology consultant for the

sponsor, Dr. Ed Lewis, who I know has thought a lot

about this. Could you comment on your thoughts

about mechanism, the possibility of a glomerular

proteinuria and what your thoughts are about

screening patients?

DR. LEWIS: This is my security blanket.

I am not sure it answers\--

\[Slide.\]

Perhaps I could address some of the

comments that you have made during the meeting, Dr.

Kopp, and then you could tell me whether my

comments are along the lines that you are looking

for.

I think, first of all, just to remind

everyone because tubular proteinuria is actually a

rare phenomenon. So I don\'t want to indulge you

about things that you already know, but I would

point out that, in the normal person, albumin, a

small amount, is filtered, as are

low-molecular-weight proteins. 95 percent of these

proteins are reabsorbed.

Microalbuminuria, which does vary, over

the course of weeks and months, would be a slight

increase in the permeability to albumin akin to the

large permeability of albumin that occurs with

glomerular proteinuria. Even though 95 percent of

proteins are reabsorbed in glomerular disease, a

great deal ends up in the urine primarily albumin

and other proteins, but not low-molecular-weight

proteins.

So what we are talking about here is

tubular proteinuria where the amount of normally

filtered albumin and low-molecular-weight proteins

are not normally reabsorbed. One of the questions

that came up, for example, is could the fact that

there are variations in urine protein excretion,

since dipsticks are what was used\--could that be

due to a change in how dilute the urine is.

I think, in answer to that point, first of

all, in terms of specific gravities that have been

done during the study, there is no evidence that

specific gravities went down. The serum sodiums

were absolutely fine. There was no report of

polyuria or polydypsia in the clinical reports so I

think that this is not a dilution phenomenon.

Now, conceivably, and certainly it would

be within the hypothesis that is being put forward

about HMG-CoA-reductase alteration of tubular

function, conceivably, there are variations in that

from time to time and that could account for

variations in tubular protein and certainly tubular

proteinuria could go down well below what would be

picked up with a dipstick, given those variations.

Can I have CO56?

\[Slide.\]

For me, the bottom line, actually, ends up

being when you look in all of the controlled and

uncontrolled pool, leaving out the 80 milligrams

which we are really not discussing today\--if you

look at the number with the creatinine increase of

greater than 30 percent, you really don\'t have very

much here.

When you look at the absolute changes in

serum creatinine up to two years, even though there

were greater than 30 percent increases in some of

the studies in a few patients, these were almost

entirely less than 0.5 milligrams per deciliter so

that it is very difficult to predict what the

future will bring. But I think that I would say

that, on the basis of the data that I have seen

longitudinally, these patients are not losing renal

function.

Now, I would like to be able to tell you

that I have seen forty renal biopsies and tell you

what I saw in that. But I have seen one renal

biopsy. This was from a patient who had

proteinuria, hematuria and an elevation of serum

creatinine of greater than 30 percent. It was

perfectly normal. The histology was perfectly

normal. The light microscopy fluorescence, there

was little C3 in the arterioles and the EM was

normal. The only abnormality on that biopsy was

that there was a fairly large arteriole in that

biopsy which showed medial hyperplasia and I

suspect that the hematocrit after the biopsy can\'t

be related to the rosuvastatin therapy directly. I

am sure it went down.

So that is the only thing that I can say,

that there was no interstitial nephritis in that

one case.

In terms of the hematuria, I think, and I

am sure knowing your interests, I hope you will

concur, that microscopic hematuria in a

noninflammatory glomerular-nephritis situation is a

mystery. It is seen actually very frequently, for

example, after exercise. It is glomerular

hematuria that occurs after exercise, just as an

example, because, when you are exercising, actually

your renal blood flow goes down so you can\'t say it

is a hyperemic kidney losing blood in the urine.

Somehow, red cells do go through the

glomerular capillary wall. It doesn\'t take very

many, I think, to give a 2-plus dipstick but there

is a transit and we have no way of knowing what

that is about. The factors that are involved, be

it an alteration in the glomerular epithelial cell,

that might allow slightly more of this than normal

and so forth, I think it is not known.

Certainly, noninflammatory glomerular

diseases like minimal-change nephrotic syndrome in

children, a very large proportion of them have a

very great increase in red-cell excretion. We know

nothing about that. We have absolutely no

understanding of the mechanism of how that happens

and I think we can say the same is true here with

rosuvastatin.

I think that all that we can really say is

that the microscopic hematuria does track with this

tubular proteinuria. It doesn\'t occur in an

isolated sense. When the proteinuria goes away,

the microscopic hematuria goes away. Whether that

means that, given the common embryologic origin of

glomerular epithelial cells and proximal tubular

cells, and there is some change in function there,

I think is a matter of significant speculation.

But I think that that is what we are left

with. I don\'t know; has that answered all of your

questions?

DR. KOPP: Yes. Just one final question

with regard to screening. If you were putting a

patient on rosuvastatin 40 milligrams with a plan

to leave them on it for the rest of their life,

which somebody said earlier we hope to be a long

time, would you want to screen annually with

dipstick urinalysis.

DR. LEWIS: My feeling about that is, and

I think it is particularly appropriate in this

large number of patients who I think represent the

people who are going to see this drug. They have

cardiovascular risks. Half of them are

hypertensive, probably using our more recent

definitions of hypertension. I am sure well more

than half of them are hypertensive. One out of six

of them was diabetic and so forth.

They are on a host of drugs. My feeling

about that is that the likelihood of getting not a

spurious but a positive dipstick and a slight

increase in the serum creatinine randomly is much

higher than picking up something that is going to

be related to rosuvastatin. I think that the

physician will be left with, \"Well, it is a

positive dipstick, now what should I do?\"

I think that since, especially in doses up

to and including 40 milligrams, this appears to be

a relatively unusual phenomenon. Since that is the

case, I think that, both in a clinical sense and in

a cost-effective sense, it is not going to help

greatly to routinely test the dipstick or test the

serum creatinine.

I think that this population just has too

many variations in those tests.

DR. BRAUNSTEIN: Thanks, Dr. Lewis.

Dr. Watts, you were next.

DR. WATTS: I want to go back to the

efficacy issue and the HDL cholesterol. I am not

sure that percentage change across the board is the

right way to do it because some of the patients in

the trial have reasonably good levels of HDL

cholesterol.

Can you help me understand what happens to

HDL cholesterol in patients whose levels are less

than desirable who take the drug and what happens

to patients whose levels are above desirable

levels. In other words, a 30 percent decrease in

somebody who has an HDL of 90 is not bad. Still,

they are left with an HDL of 60 which is pretty

good. But a reduction of 30 percent in somebody

who starts at 30 is pretty meaningful.

DR. BLASETTO: I don\'t have individual

specific data on patients on the baseline\--you are

talking about at baseline and then subsequently

achieved HDL. I think that the clearest answer on

the HDL, who gets the most benefit, is really seen

when we looked at the patients with low HDL and the

response in the population and the patients with

the HDLs above the 40 cutoff that showed less

response.

The ones that would potentially benefit

the most, the lower HDL patients, had the largest

rise. As far as the mechanism of HDL effect there,

Dr. Rader, who has done a lot of work on HDL

metabolism and function, may want to comment on the

rise we are seeing in the low HDL patients versus

the higher HDL patients.

DR. RADER: I am actually not sure if you

are referring to increases in HDL or decreases in

HDL, kind of a follow up of that previous issue.

DR. WATTS: Changes in HDL.

DR. RADER: Changes in either direction.

DR. WATTS: The confidence intervals for

all the doses suggested that there were some

patients who had an increase and some patients who

had a decrease. While, on average, the increase

was 8 to 10 percent, the range suggested that some

had significant decreases. There is also a partial

artifact in looking at percent changes in a lower

group versus a higher group because the absolute

change can be the same, yet the percent change

looks greater in the lower group simply because you

have started with a lower number.

DR. RADER: Let me just briefly address

the decreases. In the clinical world, all of us

always get asked by physicians, \"Gee; I put a

patient on a statin and their HDL dropped ten

points, or fifteen points.\" It is a rare event. I

think we have to emphasize that HDL measurement is

the least reliable of all the lipid measurements.

It requires a step involving precipitation. So

there is technical variability and there is

biological variability in HDL, actually quite a lot

more than cholesterol in terms of issues that can

happen on a day-to-day basis.

So I think these very small numbers of

people who are having apparent drops in HDL, which,

as Dr. Blasetto also said, is really not unique to

this drug. It happened in the other statins, too,

in the comparative trials. We have to interpret

that very carefully.

I would say my bias, and Evan Stein might

want to comment on this, too, as director of a

major laboratory, is that these decreases in HDL in

these very small numbers of individuals is probably

not a clinically substantial issue.

I think you are also raising the issue of

percent increases in HDL and the clinical

significance. I will be honest with you. As I

sort of alluded to, we really don\'t know exactly

how to interpret changes in HDL from a clinical

standpoint. That is why I showed you that very

simplistic 1 percent increase in HDL, 3 percent

reduction in risk. That is integrated from lots of

observational and clinical-trial data. It is our

best guess right now.

But it is important that that is expressed

as a percent, not as a milligram per deciliter

because it does seem that, at least the data as far

as we can tell, we are better addressing that with

regard to percent changes than absolute changes.

But I have to tell you, we have a lot more to learn

about the HDL side of how it relates ultimately to

risk.

DR. ORLOFF: Dr. Braunstein, I would like

to make one clarification. The interpretation of

those box plots that Dr. Mele showed, in fact the

bars that go to the extremes of high and low are

the range, are the full range, of values culled

from the database.

The 95 percent confidence interval around

the median is actually the little grey box within,

in the case of the rosuvastatin plot, the red box

that represents, at the low end, 25th percentile,

at the middle, 50th, and, at the top, 75th. So the

95 percent confidence interval around the median is

actually very tight. In other words, there is a

very small percentage of patients who fall into

those outlier areas.

DR. BRAUNSTEIN: Dr. Follman?

DR. FOLLMAN: I was curious to hear the

sponsor talk about a trial that they are planning

in 18,000 people where they are going to look at

CVD events which was initiated a few months ago. I

was wondering if they could describe that a little

more and, in particular, how they will be

monitoring kidney function in that study.

DR. HUTCHINSON: We would be happy to talk

about those two trials. I am going to ask Dr. Jim

Blasetto to mention it.

DR. BRAUNSTEIN: Maybe there could be very

brief discussions because we do want to break for

lunch. But I do want to finish this final round of

questions.

DR. BLASETTO: The large trial that we

have initiated in the United States and Canada is a

trial around 15,000 patients who have elevated CRP

levels and have baseline LDL levels below 130 so

that these patients are non-CHD patients who have

elevated CRP levels with LDLs below 130, who will

be randomized in a double-blind fashion to

rosuvastatin, 20 milligrams, or placebo and

followed up for cardiovascular events. It is the

Jupiter trial that we are doing. We will be

following routine labs throughout the conduct of

the trial as part of the follow up we will be

doing.

DR. WATTS: How long will that study go on

for?

DR. BLASETTO: We are anticipating that

that trial will be at least\--the patients will be

at least three years in duration.

DR. BRAUNSTEIN: Thank you.

Dr. Neylan?

DR. NEYLAN: A quick question back to the

hematuria. I was wondering if you had the

opportunity to model some of the potential

interactions of this very complicated patient

population that you are dealing with, patients who

have variable risks for hematuria or proteinuria,

diabetes, nonsteroidals, antiplatelet drugs and

whether, either with univariate or multivariate

modeling, any of these factors showed any

relationship to the emergence of proteinuria or

hematuria.

DR. HUTCHINSON: We haven\'t done any

specific modeling. What we have done is some of

the information which I showed you is to look at

specific agents that were used by patients in our

program to see if the use of those agents, in

combination with rosuvastatin, resulted in any

adverse effects on renal function. As I have shown

you, there was no evidence of any adverse effect.

I can also, just to give people the scope

of what we are doing with regard to the question of

specific studies that will be ongoing, just show

you types of studies that we are doing to

understand this drug because I think it is

important to know that we continue to study this

drug and learn about it.

We have got studies on atherosclerosis

regression. The METEOR is an IMT study using the

40-milligram dose. ASTEROID is an Ivus study,

intravascular ultrasound, using the 40-milligram

dose. We have outcome studies ongoing, one with

the GC group in Italy in heart failure, another

heart-failure study known as CORONA, a study in

patients with renal failure on dialysis called

AURORA and Jim Blasetto just mentioned to you our

JUPITER study which is in 15,000 patients with an

elevated CRP.

So we will be continuing to evaluate this

drug in ongoing work.

DR. BRAUNSTEIN: Dr. Woolf, you et the

last question.

DR. WOOLF: I will try to make it brief.

Continuing with the renal issue, if we are talking

about a tubular abnormality, would one expect

abnormalities in glucose transport? Would we see

glycosuria, abnormalities in uric acid, excretion.

Is it a different pathway or is it unique to

the\--the reabsorption unique to HMG CoA-reductase?

DR. HUTCHINSON: I am going to ask Dr.

Lewis to please address that question.

DR. LEWIS: I think it is apparent in this

particular situation that this is not a Fanconi\'s

syndrome situation so that it is not a multiple

renal-transport abnormality. What does appear\--and

I think that the in vitro cell-culture work may

shed some important light on this. It appears that

this is a matter of protein transport, which is

separate from the others and it probably somehow

does involve melanic-acid metabolism.

There are known biochemical pathways that

link melanic acid to the transport mechanism

responsible for the endocytosis of proteins. So I

think that that is what we really have here.

DR. BRAUNSTEIN: Thank you.

We will break now for lunch and reconvene

at 1:30 with the open public session.

Thank you.

\[Whereupon, at 12:48 p.m., the proceedings

were recessed to be resumed at 1:30 p.m.\]

A F T E R N O O N P R O C E E D I N G S

\[1:30 p.m.\]

DR. BRAUNSTEIN: We will now go into the

open public session. We have had one request from

Dr. Sidney Wolfe, Director of the Public Citizens

Health Research Group is going to make a very brief

presentation.

Open Public Hearing

DR. WOLFE: I think I was told I have ten

minutes. If that is brief, that is fine. Thank

you. I have a handout which I think has been

distributed to all the members on the committee. I

will just go through it as quickly as possible.

It starts out by looking at the data on

Baycol, the reason being that, like this drug,

rosuvastatin, Baycol also caused rhabdomyolysis.

In this first chart, what we have done is looked

for each dose that Baycol was used at, all of the

adverse-reaction reports that were filed with the

FDA as the denominator. The numerator is the

number of those cases, or proportion of those

cases, that were rhabdomyolysis.

What you can see, and it is also depicted

in the graph below, is that as you go from 0.1

milligrams\--remember, Baycol was 0.1 milligrams as

opposed to 10\--up to 8, you go from 3.5 percent of

all the adverse reactions being rhabdo up to 54

percent.

Since this is in clinical use, not a Phase

III trial\--it is clinical use\--these are all people

who took the drug long enough to have a problem,

although the latency period for Baycol is shorter

than for rosuvastatin or for the other statins.

The next chart points out something that

was briefly alluded to in the FDA\'s documents but

not discussed this morning at all which is that, if

you look at the average duration of treatment of

people in the trials as a function of dose, what

you see is that, at 40 milligrams, for

instance\--and this is derived from looking at

patient years divided by the number of patients\--at

40 milligrams, you see that the average duration

was about a quarter as long, 117 days, as opposed

to 453 days at the 80-milligram dose.

This is important because, for the cases

of rhabdomyolysis that the FDA has described and

the company has described, the average duration of

time was 280 days. So, not surprisingly, those are

all cases at 80 milligrams. There was one, as you

remember, at 10 milligrams. But, not surprisingly,

for the dose that, in fact, had a much longer

duration, it was much more likely, for that reason

amongst others, that you would see cases of

rhabdomyolysis.

For the 40-milligram dose, where people

are taking it for a quarter as long, it is less

than surprising that there were no cases of

rhabdomyolysis or that there wasn\'t a more regular

steeped increase with dose as we had seen with

Baycol.

Again, these are just taken from the data

that the FDA had in its presentation, just

transmitted into bar-graph form, vertical bar-graph

form as opposed to the horizontal that the FDA did.

But here what you see is that, for the

creatin-kinase elevations of 10 or greater, it

really kicked off mightily from 40 milligrams up to

80\. It was 0.4 percent of the patients at 40

milligrams at 1.9 percent at 80. Again, I think

that this is certainly consistent with the fact

that so few of the patients in the 40 and

20 milligram dose had a long enough duration. The

suggestion here was, in order to more accurately

assess the incidence of CK elevations at each dose,

you need to have duration-adjusted data for CK elevations.

For example, what was the incidence of CK

of 10 or greater in those patients who had longer

exposures to 40 or 20-milligram doses whereas 56.8

percent of the people getting 80 milligrams or

rosuvastatin were exposed to longer than 48 weeks,

only 6.5 percent of those getting 40 and

8.4 percent of those getting the 20-milligram dose

were exposed for more than 48 weeks.

As I just alluded to before, I think that

this is certainly a plausible hypothesis why you

don\'t see the gradual dose-response increase that

was there at least in the way in which we analyzed

it with Baycol.

I just have inserted here directly from

the FDA\'s presentation some of the further\--most

hospitalizations were preceded\--this is rhabdo\--by

a 3 to 28-day prodrome suggesting a viral illness

with subsequent dehydration as a possible

precipitating event.

We are just finishing for publication an

analysis of the Baycol data versus the other cases

of rhabdomyolysis. The latency period is much

shorter for Baycol than for all the others. The

latency period here is pretty much the same as for

the others. The mortality, if the denominator or

cases of rhabdo in the numerator or deaths is much

lower for Baycol, and I suspect that may have to do

with the fact that the sooner after starting the

therapy it comes, the more likely someone may link

it. I remember talking to someone whose father

died\--hey thought he had the flu\--after he started

Baycol at age 81 and they kept him on the drug in

the hospital and he died of acute renal failure a

couple of weeks later.

So these longer latency periods may make

it trickier to pick up things, particularly when

you are not in a trial.

On the renal damage, I think that the

combination of proteinuria and hematuria has been

described as a structural thing not just some

functional kind of problem. The chart here\--again,

this is taken from FDA\'s presentation\--increased

proteinuria with increased dose. These were people

with three or more increased grades in proteinuria

and it goes from 0 at 5 milligrams up to

5.4 percent at 80 milligrams.

The point that I just wanted to make

briefly here is that, whereas it looks like there

is a very long latency period for the

rhabdomyolysis, it appears that, in a much shorter

period of time, at least the early evidence of

renal damage, the hematuria and proteinuria, can

occur and, therefore, the problem with not seeing

cases at 20 and 40 of the rhabdo or even the CKs

seem to less of a \"problem\" here. There were

increases starting at 10, stepwise, up to 20, 40

and up to 80 milligrams.

The next chart is just looking at

atorvastatin from, again, the data that were in the

report showing that patients with increased

proteinuria and hematuria, it was pretty flat.

There were no data available at 5 milligrams, at

0.6, 0.3, 0.4 and 10, 20 and 40 milligrams and none

at 80 as opposed to the next chart which is showing

a very stepwise increase in proteinuria and

hematuria with increased rosuvastatin doses.

I just want to quote, because I think it

sort of summarizes the concerns that I and, I

think, many other people have about where does this

hematuria and proteinuria go, and there were these

three cases. I am just quoting from what was

written. It was described very briefly this

morning. These three cases of renal insufficiency

of unknown etiology are of concern because they

present with a clinical pattern which is similar to

the renal disease seen with rosuvastatin in these

clinical trials.

There is mild proteinuria associated with

hematuria and the suggestion of tubular

inflammation or necrosis. All cases occurred at

80-milligram dose which was also associated with

the greatest number of patients with abnormal renal

findings, the hematuria and proteinuria.

Proteinuria and hematuria could

potentially be managed. I was concerned to hear

the response to the question about should you be

screening for this. I think that the answer that

you don\'t screen because it might be confusing is

the wrong answer. I am sure that the company is

screening, or should be screening, not just with

dipsticks but, hopefully, even though they didn\'t

do them before, getting some urine sediments.

\"Proteinuria and hematuria could be

potentially managed with regular urinalysis

screening.\" This is the quote from the FDA\'s

document. \"However, they are the signals for

potential progression to renal failure in a small

number of patients. This may represent an

unacceptable risk since currently approved statins

do not have similar renal effects.\"

Then, just in summary, well within the ten

minutes, I think, we strongly oppose the approval

of rosuvastatin because of its unique renal

toxicity. We are also seriously concerned because

of the seven cases of rhabdomyolysis that were

common enough to have shown up in clinical trials.

Unlike preapproval studies with all previously

approved statins including cerivastatin in which no

cases of rhabdomyolysis showed up prior to

approval.

The fact that so few patients on the 20 or

40-milligram doses took the drug for a sufficient

period of time to have had a chance to develop

rhabdomyolysis seems to have imparted a false sense

of security about the safety of these doses

concerning muscle toxicity. The increased ability

of research to lower LDL cholesterol is most

clearly seen at the 20, 40 and 80-milligram doses,

although, as pointed out, there is some increase at

10 and 5.

If this drug is approved, it is highly

likely it will have to be removed from the market

after enough further damage to patients occurs.

If there is a minute or two, I would be

glad to try and answer any questions.

DR. BRAUNSTEIN: Thank you.

Does the committee have any questions for

Dr. Wolfe?

DR. KOPP: On Page 4, the y-axis is

greater than three grades, so that would mean going

from\--this is the proteinuria data\--going from

negative, greater than equal to three grades, to

going to only those patients who are negative at

the beginning, going to trace 1-plus, 2-plus?

DR. WOLFE: The greater or equal to three

grades is taken directly from, I guess it is Table

15 in the FDA presentation. This is what they

said. It had to have increased the degree, as

measured by dipstick, the proteinuria had to have

improved, increased, rather, at least three grades.

DR. HENNEKENS: Dr. Wolfe, as always, I

find your comments thoughtful and provocative. One

of the issues that you have gotten your hands

nicely around, in the issue about duration leading

to rhabdo, is the dose of the drug. But the other

idiosyncratic issue with gemfibrozil that is not

mentioned your analysis.

So I wondered if, in addition to the dose

issue, you have looked at the duration of the

combination therapy with gemfibrozil to see if that

long duration is confounded, if you will, by the

use of gemfibrozil which had the idiosyncratic

deleterious reaction with cerivastatin.

DR. WOLFE: We looked for that in this

dataset that we have analyzed, the Baycol and all

the other statins, and there was some interaction

there. I can\'t remember the numbers now. We

analyzed this a few months ago. This is not this

drug. It is the other ones. I don\'t know

exactly\--you saw, in one of the slides this morning

that, in combination with gemfibrozil, I think the

area under the curve went up twofold. I think that

was the number.

So your question is a good one. It sort

of has the effect of shifting the dose and it may

make at least a small subset of 40-milligram people

look like they are getting aid. But, again, the

duration is a problem. I was astounded when I did

these calculations based on the data in the FDA

that there is a four-fold difference in the

duration between the 40 and 80, and the average is

so far down there below what the average period of

onset of rhabdo is in the 80, that I don\'t think

that we have any kind of answers to the question of

how much CK elevations, how much rhabdo, there are,

particularly in the 20 and 40.

It is interesting that, at the lower dose,

at the 5 and 10, there is longer duration. But the

worry is less there, I think, than at the higher

dose, the higher doses being 10 and 20. I would be

very interested in the discussion\--I am going to

have to leave\--as to what you think the maximum

dose should be, because this starts getting into an

area that we don\'t have answers for in terms of the

paucity of long-term data in those two groups.

DR. HENNEKENS: That leads me to my second

and last query which is, if one looks at LDL, HDL,

CK, myopathy, proteinuria and combined proteinuria

and hematuria, and one looks at the range of doses,

the 5 to 20-milligram doses, one could say are at

least comparable or even more favorable than the

five marketed statins.

Yet, you came to the conclusion that it

should not be approved. So I was curious to your

thinking on looking at, if one looks at that subset

of patients with regard to the total\--

DR. WOLFE: Let\'s go back to the

suggestion that was made, or at least that put

forward for discussion, that 5 milligrams should be

the starting dose. At 5 milligrams, the

differences between the statins, particularly if

you go with this doubling effect, are not that

significant. You have other statins that do not

have, and I think everyone agreed on that. There

is no evidence of renal toxicity which is what this

is in any of the other statins. Now that Baycol is

off the market, none of the other ones are even

close in terms of the likelihood of rhabdomyolysis.

So you have two strikes against this drug

in terms of safety and if, by doubling up on the

dose of atorvastatin or whatever one you choose,

atorvastatin is the one that was looked at in these

studies, if you can achieve the same kind of LDL

lowering at 5 or 10 milligrams, why approve the

drug which has negative risks compared with the

other and the benefit is achievable by just a

higher dose of other statins. That is really the

basis for what our conclusion was.

DR. BRAUNSTEIN: Thank you, Dr. Wolfe.

The sponsor is going to address two issues

explicitly that were asked by the FDA and the

committee. One concerns 20 milligrams versus 40

milligrams being the top recommended doses and what

the rationale for the 40-milligram dose would be.

The second concerns a starting dose of 5 milligrams

versus 10 milligrams and what the rationale for

going to 10 milligrams is.

Sponsor Comments

DR. HUTCHINSON: If I may, I could also

shed some light regarding do we have sufficient

exposures at the 40-milligram dose to justify its

use.

\[Slide.\]

We have looked very carefully in the

myopathy and rhabdomyolysis cases in our program.

What we have found is that, in general, the hazard

for these events was relatively constant with

rhabdomyolysis cases just dispersed amongst the

myopathy cases.

Now, if we look at our data that I showed

you earlier with regard to continuous exposure to

rosuvastatin at the various doses, the data in this

column is extremely important data with regard to

whether or not there is a long-term effect with

regard to rosuvastatin at the 40-milligram dose on

myopathy and rhabdomyolysis.

We have over 1100 patients exposed for

greater than 48 weeks and, as you can see, close to

900 patients exposed for over two years. There is

no evidence in this group that we are seeing an

increased frequency of rhabdomyolysis or even any

additional rhabdomyolysis cases or myopathy cases.

So, in general, we have a large database

of patients with long duration of therapy to high

doses of rosuvastatin without any evidence that, at

the 40-milligram dose, we are seeing an increased

frequency of rhabdomyolysis or myopathy at later

durations of therapy.

Now, with regard to two key questions that

are going to be addressed by the committee, those

questions are regarding the top dose of

rosuvastatin. We have shown you some key efficacy

data regarding the importance of the 40-milligram

dose. I would like to have Dr. Christie Ballantyne

and Dr. Evan Stein just briefly discuss the

importance of having that 40-milligram dose. Dr.

Thomas Pearson is going to come up and talk about

the 5 versus the 10-milligram starting dose of

rosuvastatin for the general population.

Dr. Ballantyne?

DR. BALLANTYNE: Thank you. Christie

Ballantyne at Baylor College of Medicine. If I

could have CO63, please.

\[Slide.\]

As someone who is a cardiologist by

training and used to looking at the risks and

benefits of treating patients with cardiovascular

disease. It is sometimes interesting to see the

inconsistencies in regards to what we have

traditionally done in treatment atherosclerosis.

We routinely do bypass surgery and angioplasty

which do not reduce mortality and accept

extraordinarily high event rates of complications

with this.

I hear great hesitancy towards treating

lipids. It has evolved. When I started in 1988,

people said, \"You shouldn\'t do this at all. It is

dangerous.\" What I think is we have evolved

tremendously. You saw the data from the clinical

trials earlier today but I would point out that

don\'t forget in the 4S study, the five-year event

rate in the treated patients was 20 percent or MI

or death.

This is a very high\--it is a disease that

causes tremendous morbidity and mortality. It is a

leading cause of death in our society. As a

clinician, what I am faced with is, on a regular

basis, seeing patients who have either very severe

atherosclerosis that we are treating aggressively,

sometimes familial hypercholesterolemia or combined

hyperlipidemia, but very many patients who are

difficult to treat.

I routinely have been making the decision

of do I titrate 40 to 80 milligrams of simvastatin?

Do I go from 40 to 80 milligrams of atorvastatin.

I have done this on a routine basis based upon the

evidence that better reductions in LDL cholesterol

lead to greater event reductions.

Now, I do that despite the fact that there

is an increase in transaminase elevations as you go

from atorvastatin 40 to 80. Some of these also

include elevations of alkaline phosphatase. The

mechanism is not well understood, but it does not

seem to be a major problem. If it is discontinued,

it resolves.

With simvastatin, there is an increase

also in transaminases. With both agents, there is

an increase in the risk for myopathy with that. So

what I see is another opportunity to provide better

reductions in LDL cholesterol for my patients with

actually what appears to be, in comparative

studies, a lower risk for the ALTs, certainly no

increase in risk in terms of the CK elevations.

We do have this issue of proteinuria. But

I think if we look at this once again in terms of

numerically, it is small, a low percentage and if

we look at what happened with creatinine,

elevations that were 30 percent that persisted,

which would be 0 across the board, that, if one

weighs the risks and benefits for this in regards

to the pain, suffering and death from

cardiovascular disease, in my opinion, it is very

favorable with this for having 40-milligram dosage

which we can use to aggressively treat patients to

try to reduce cardiovascular morbidity and

mortality.

I would like to turn it over to Dr. Stein.

DR. STEIN: Thank you and good afternoon.

I am Evan Stein from the Cincinnati area. My

career has been spent in treating hyperlipidemia.

Specifically, my interests are in those groups of

patients with inherited high cholesterol.

We heard earlier about familial

hypercholesterolemia and a number of the studies

that were done and I am going to turn to this

population.

If we can have the first slide, CO40.

\[Slide.\]

Just to remind you that this is a common

genetic disorder that, although heterozygous

familiar hypercholesterolemia is not that well

recognized, there are over a half a million

patients in the United States and these patients

have a monogenic disorder which, from birth, gives

them very high LDL cholesterol levels, results in

very early coronary disease. Average age of onset

of coronary disease is 40 to 50 years of age in men

and 50 to 60 years in women and it is very

difficult to treat.

In addition to about these half million,

there are probably another half million patients

who have severe polygenic hypercholesterolemia. So

there is a population of about a million patients

out there who have high risk for coronary disease

due to very high LDL levels.

\[Slide.\]

Just to show you\--this is the largest

database. This is a database from Utah in

something called the MedPed Registry which is for

familial hypercholesterolemia. This is over 40,000

patients in this database. You can see here is the

coronary-artery disease risk or incidence in women

who don\'t have familial hypercholesterolemia. The

blue is men who don\'t have familial

hypercholesterolemia.

This is women. You can see by about age

60, these women exceed the incidence of even an 80

or 90-year-old woman and exceed generally all the

way along that of men. By age 50, this far exceeds

that of an 80-year-old man. This includes patients

who are currently treated. If you look at the very

high, by age 65 or 70, nearly eight out of ten have

coronary disease.

If I can have 42, please.

\[Slide.\]

When we look at the effects of the one

study which was shown earlier which was Study 30, a

large study, over 600 patients with familial

hypercholesterolemia, 432 on rosuvastatin, nearly

200 on atorvastatin, which is the current standard

for monotherapy for these patients.

You can see here that, at 20 milligrams,

we got a 47 percent reduction in LDL and, at 40

milligrams, a 54 percent reduction. Here is the

atorvastatin at its maximum dose of 80 milligrams.

Next?

\[Slide.\]

Now, that doesn\'t sound like very much in

terms of 7 percent. Now, remember whenever we are

looking at this percentage, we are going back to

their baseline LDL levels. So, if we go back to

the baseline LDL levels which were 290 for this

population, very high levels, you can see that the

47 percent reduction resulted in a new level now of

154 milligrams. That is a 47 percent reduction.

When you went to 40 milligrams, although

this difference is only 7 percent, because it is 7

percent of a base, we don\'t actually do that in

practice. We give somebody 20 milligrams and then

we look at their baseline and we give them another

dose or we add another drug.

When you do that, the mean here is 133

which is actually another 14 percent decrease in

LDL cholesterol, very similar to what we would get

by adding a second drug to any 20 milligrams of the

existing drug.

If we can go to the next slide.

\[Slide.\]

What this translates into, even though it

is only a 7 percent difference, it translates into

a big difference in terms of these severe patients

getting to an LDL goal of less than 100. So it is

an average of around about 21 milligrams per

deciliter reduction. It takes you from 6.5 percent

of these patients to nearly one in six now getting

to LDL control.

If one compares this to the standard

effect of monotherapy, atorvastatin 80 milligrams,

you can see less than 5 percent. One could say, we

could achieve this by adding a second drug.

If we can go to No. 46.

\[Slide.\]

If we now look at a similar study, and I

think that Dr. Rader mentioned this earlier, this

is also a study of over 600 familial

hypercholesterolemic and severe

hypercholesterolemia patients whose LDL goals were

also less than 100. Here the design was that

everybody started at 10 milligrams of atorvastatin,

had an LDL of above 130 and was then dose-titrated

depending on response aiming to get LDL below 100.

This is the FH group which makes it very

similar to this population. You can see that going

up to 80 milligrams of atorvastatin resulted in

remarkably similar number of patients, less than

one in twenty, achieving the LDL goal whereas this

was the combination of atorvastatin, 40 milligrams,

plus ezetimibe 10, achieved roughly the same amount

of patients getting to goal.

Now, while this is a big step for FH

patients, and I have over 400 patients in my clinic

on this drug, the majority of which are FH

patients, this was a big step for them to be able

to go to monotherapy because, in the past, they had

been on two or even three drugs including high-dose

niacin which is another potential adverse risk

factor when added to high-dose statins.

You can see that, with monotherapy, we now

have made at least progress. Not having this

40-milligram dose available for the FH patients is

going to basically leave us at the starting point,

at this endpoint, rather than using this as a new

potential starting point for these patients where

we can perhaps get, with the addition of a second

or third drug, maybe half of them onto treatment

that would provide them with optimal therapy.

Thank you.

DR. BRAUNSTEIN: Now we are going to

discuss the 5 versus 10 starting dose.

DR. PEARSON: Good afternoon. I am Tom

Pearson from the University of Rochester where I

direct a preventive cardiology clinic. I am a

cardiovascular epidemiologist by training and

interested in really population trends in lipids

and particularly in the extent to which goals are

attained according to the current guidelines.

I would like to address this

5-to-10-milligram issue on that basis and maybe

begin by saying, and maybe taking a chapter out of

Dr. Hennekens\' research, is that if you have a drug

with flat safety and efficacy across the dose

range, such as aspirin, you are likely to take the

lower dose to get the job done.

What I am going to suggest is you don\'t

really have flat efficacy even across the 5-to-10

range but we are going to have to go into

epidemiologic and modeling data to do that because

there is never probably going to be a clinical

trial comparing 5 milligrams and 10 milligrams.

So let\'s look and see what we could expect

in terms of a difference in benefits between 5 and

10 milligrams.

\[Slide.\]

These are data from a metaanalysis of

lipid-lowering trials which basically gets to the

point of there is thought to be a graded response.

The lower the LDL, the lower the event rate, even

at these lower percent reduction areas that we

have, even here, in terms of the middle ranges.

\[Slide.\]

This has led to this rule that we use, 1

percent reduction in LDL can confer a 1 percent

reduction in coronary-disease risk. Similar kinds

of analyses have led to a different equation with

HDL and that is, for every 1 percent increase in

HDL, we have a 3 percent reduction in coronary

risk.

So let\'s look at what we might surmise in

terms of the benefits we get between 5 and 10

milligrams. Here you have the LDL, about a 6

percent reduction, which should confer another 6

percent reduction and risk and perhaps about a 1.3

percent rise in HDL across and the

dose-response\--there is a dose response,

apparently, to HDL at these lower doses of

rosuvastatin. This should give an additional 4

percent.

So the point here is that I think what we

are talking about\--at least in lieu of randomized

head-to-head trials, you are talking about a 10

percent risk differential between the 5 and the 10

percent. The importance of this, as a population

scientist, is that this is the starting dose. This

is where the belly of the population curve is going

to be treated. These are where most of the

patients are going to be treated at in terms of

current practice patterns in terms of statin

therapy.

Therefore, this spread over a large number

of individuals, I think would be a very meaningful

effect.

\[Slide.\]

The second point I wanted to make is more

of a medical sociologic one and that is the extent

to which people are at goal when they start a

certain dose. This is the percent attaining ATP-2

guidelines with the starting dose. I think you can

see, between atorvastatin at 10 milligrams and

rosuvastatin at 10 milligrams dose, you have quite

a large difference in the percent of individuals

who will actually be at goal.

I want to have my primary-care providers

get this amount of efficacy at the starting dose.

I will remind you that the NHANES data from 1999 to

2000 currently shows that only 47 percent of

hypercholesterolemic patients are basically

controlled. This is a representative sample of the

U.S. and so would be even worse. If we had a more

efficacious starting dose of 10 milligrams, we

would get the vast majority of those individuals at

goal.

So I think, on a population basis, it is

important that we have a 10-milligram versus

5-milligram dose because I believe there is a

change in efficacy and there is a reluctance of

primary-care providers, in particular, to

accelerate doses above that and get to goal.

Thank you very much.

DR. BRAUNSTEIN: We will move into Dr.

Orloff\'s charge to the committee.

Charge to the Committee

DR. ORLOFF: I hope I am ready for that.

First, let me say that the discussion has been very

helpful. I just want to remind the committee that

this is a confusing, and to some extent,

frustrating process for you all. I understand. We

don\'t expect you always to be able to give us

absolute answers. So don\'t away discouraged if you

sometimes cannot produce them.

The question of risk versus benefit is

always the most difficult one we grapple with

because, by definition, it is an impossible

calculation. Benefit is apples and risk is

oranges. Last I checked, you can\'t subtract one

from the other.

I guess, by my way of thinking, actually

referring to just some of the recent remarks made,

there are a couple of points that come to mind.

One is that I do think that there is a compelling

argument in the issue of tolerance of risk and the

example of Dr. Ballantyne, surgical versus medical

intervention for cardiovascular disease. I do

believe that we all need to keep that in mind.

The other thing is, regardless of exactly

what calculations you want to go with and what

estimates of incremental benefit you are going to

believe or expect, I think there is compelling

evidence that exists today as well as much more to

come\--of course, what that evidence is, we can\'t

necessarily predict\--that lower LDL is better.

So I think it is reasonable to assume, on

the benefits side, that, on balance, having an

improved or an ability to lower LDL additionally

beyond what can be done with the current

armamentarium is going to benefit at least some

people at risk for recurrent or first

cardiovascular events.

With regard to risk, I guess all I can

leave you with is that when all is said and done,

we are going to be faced with making a call as to

the tolerability in, really, just an absolute

sense, of some degree of risk. Again, I will say,

it is impossible to reach a conclusion, at least on

earth, as to the relationship between, for example,

a small, admittedly a small, risk of myopathy and

an reduced risk of cardiovascular events.

I also want to remind people, furthermore,

that we talk a lot about the risk of myopathy with

this class of drugs, generally. Number-one thing

to remember is that there is absolutely no

expectation, regardless of how hopeful we are, that

we can obviate all myopathy with statins.

I would offer that, even if we reduced the

maximum doses across the board for the marketed

statins, we would still see cases.

I also remind you that, in the five-year

placebo-controlled trials of statins at a variety

of doses, most recently up to 40 milligrams of

simvastatin, there have been vanishingly few cases

of rhabdomyolysis and, to my knowledge, I don\'t

believe there have been any deaths attributable to

drug specifically related to myopathy. Frankly, I

don\'t know that anyone is positive there are any

deaths at all attributable to drug.

So let me come to our questions. There is

a long list here. Before the meeting, Dr.

Braunstein and I stood and thought that, in the

interest of time and in light of the fact that a

lot of issues will have been and, indeed, have been

discussed prior to this point in the meeting, we

don\'t need to ask\--we are not going to ask for a

yes or no tally of votes for every single question

on this list, unless you feel compelled to, or

someone otherwise objects.

Under efficacy, we are essentially asking

whether the dose-response data and the overall

efficacy data for this drug is such to support the

lipid-altering efficacy across the dosage range.

It is sort of, in some sense, a no-brainer

question. You have seen the data, but it is a

formality we need to ask; does the efficacy support

essentially the approval for the proposed

indications.

With regard to myotoxicity, as I said back

at the beginning, a central issue in one of the

prime of two reasons that this application was

brought before the advisory committee was to, in a

public forum, weigh the evidence and have the

evidence presented about the myotoxic potential per

LDL-lowering efficacy of rosuvastatin and, I

suppose, the absolute myotoxic potential at the

highest proposed dose, particularly in light of the

postmarketing experience with Baycol and in light

of the fact that, at 80 milligrams in trials of

rosuvastatin, there were cases of severe

rhabdomyolysis and myopathy seen.

So the question I have to you, again, is

maybe a relatively simple one. I am happy to hear

discussion. Based upon what has been presented to

you, are you convinced that the myotoxic potential

per LDL-lowering efficacy of rosuvastatin is

similar to that of other currently marketed

statins.

On the second question under myotoxicity,

obviously any comments you have are welcome. With

regard to renal effects, we spent a lot of time

discussing this and I guess now it is time, really,

for a vote. We are going to ask you whether you

think, yes or no, the risk of renal adverse events

has been adequately evaluated, whether there are

any further investigations needed of this, at least

it appears now, in the absence of definitive

evidence certainly a novel drug effect. Whether or

not it is unique to this drug is another question

that we are not going to necessarily ask you to

answer but to comment on what you think of those

data.

Finally, we are going to ask the question

that has been talked about a lot in the discussion

about whether monitoring of renal function or, for

example, for proteinuria is recommended for this

drug or potentially for all statins.

With regard to dosing, I think I need to

make a clarification. It sounds, from what we have

heard at the table, that there is some confusion.

The sponsor has proposed that 10 milligrams be the

starting dose for just about everybody, run of the

mill, that 5 milligrams be reserved for those

people who are on cyclosporine because of the

documented seven-fold increase in area under the

curve and therefore potential augmented risk for

myopathy or other adverse events when the drug is

given in conjunction with cyclosporine.

They have reserved 20 milligrams for those

people with severe hypercholesterolemia who

need\--we know going into the game that they are

going to need big drops.

The FDA\'s proposal is simply to say can we

add 5 as an option for across the board, as an

across-the-board starting dose. It is a dose that

will be available. There will be 5-milligram

tablets if this drug is approved. Our question

really is why shouldn\'t physicians be able to

choose that as an option in our conceptualization,

based upon the desired degree or the required

degree of LDL lowering from baseline to goal.

We have asked you to choose, really,

between the sponsor\'s approach and our approach.

Finally, we ask the overall recommendation question

which is an important aspect usually of these

proceedings as to whether you would recommend

approval by the FDA of the proposed\--across the

proposed dosage range for the proposed indications.

We do not, obviously, speak specifically

about the isolated hypertriglyceridemia indication.

I don\'t believe we did. So that is included there.

I think I would just ask that the committee rule on

the data that they have seen thus far.

Thank you very much.

DR. BRAUNSTEIN: Thank you, Dr. Orloff.

Before starting, I have also been asked to

remind the panel members as well as everybody else

in the audience who has received them to please

fill out the surveys concerning the FDA advisory

meetings.

Committee Discussion and Questions

DR. BRAUNSTEIN: I thought that what we

would do is actually go around and ask for votes on

the things that we need to vote on with or without

comments. A simple yes or no would be okay but if

there are comments, that is appropriate. There are

some areas that Dr. Orloff and his group would like

to have more input on and we ask for more verbiage

there.

If you feel that you want the sponsor or

the FDA to respond to a specific question that is

going to help you in the decision-making process or

in answering these questions, please feel free to

ask that also at this time. We want this to be as

informed as possible.

What I am going to do is I am going to

start off\--we will go around the room. I will

start with Dr. Kopp to tackle the first question.

Then we will go around and then, from there, we

will go to Dr. Carpenter to go over the next

question, et cetera.

So, Dr. Kopp, if you would weigh in on the

first two questions concerning efficacy; has the

sponsor provided sufficient evidence to support the

efficacy of Crestor in the proposed target

population and, 2, do the efficacy data support a

dose response with respect to LDL cholesterol

lowering sufficient to justify the use of the

40-milligram dose.

DR. KOPP: I will say yes to both

questions.

DR. BRAUNSTEIN: Dr. Carpenter?

DR. CARPENTER: Now, are you asking me to

move on to the second?

DR. BRAUNSTEIN: No. We have to go around

for each question. We are starting with Dr. Kopp

for Question No. 1. When we go to a fresh

question, we are going to start with you.

DR. CARPENTER: I agree with Dr. Kopp and

would answer yes to the questions positively.

DR. BRAUNSTEIN: I also agree; yes, yes.

Dr. Woolf?

DR. WOOLF: So do I.

DR. BRAUNSTEIN: Dr. Hennekens?

DR. HENNEKENS: Yes and yes.

DR. BRAUNSTEIN: Dr. Follman?

DR. FOLLMAN: I would like to talk a

little.

DR. BRAUNSTEIN: Go ahead.

DR. FOLLMAN: The thing that really struck

me about the efficacy was there was a lot of

discussion about comparing doses of rosuvastatin to

other drugs, atorvastatin and so on. To me, that

was not the most important issue. What I really

felt sympathetic to was the last talk that the

sponsor gave where they talked about achieving

goals. The me, that is the important thing and

when I am evaluating rosuvastatin, I am

particularly interested in whether it helps you

achieve the NCP goals or not and to what extent it

has a better profile than atorvastatin which it was

compared to.

So, for me, the most important studies

were the dose-titration studies. There we see a

significant benefit of the titration when you use

rosuvastatin compared to atorvastatin. You get, I

think, 96 percent achieving the goal with

rosuvastatin compared to about 87 percent with

atorvastatin.

So, to me, that is the most important

thing about efficacy. When I think about efficacy,

that is the reason I agree.

You can also think about the

dose-titration studies, though, in terms of

information about the 40-milligram dose and whether

we should have that in the armamentarium or not.

We saw a lot of, as I mentioned, dose-specific

studies and it would be interesting, I think, to

imagine what would happen with that dose-titration

study if, instead of capping it at 40 milligrams,

you capped it at 20. How many would reach the

goals at the end of the study.

Actually, with the information the FDA

provided, you can look at that. I did a little

calculation which suggests if you limit the upper

dose to 20 milligrams instead of 40, you get about

91 percent achieving the target instead of 96. So

it is still above 90 percent but there is some

additional modest benefit of having a 40-milligram

dose as opposed to a 20-milligram dose.

So the short answer now is yes, yes for

both of those but there is a diminishing benefit at

40 milligrams compared to 20 in terms of dose

titration.

DR. BRAUNSTEIN: Thank you.

Dr. Watts?

DR. ORLOFF: Dr. Braunstein, we need a

little clarification. I believe, Dr. Follman, you

are speaking about the percentages of patients

achieving goal within the low-risk category. I

just want to make sure for the record that we are

not talking about 96, 91 percent of rosuva patients

achieving goal in the high-risk category.

DR. BRAUNSTEIN: Yes; that was, like, 17

percent.

DR. FOLLMAN: Right; this is for the\--

DR. ORLOFF: I just wanted to say\--

DR. BRAUNSTEIN: Thank you.

Dr. Watts?

DR. WATTS: I will give the short answers

and I would like to speak a little as well. Yes,

yes are the short answers. My feeling is that we

have seven other agents out there that work pretty

well when they are used correctly and that the main

reason for wanting a drug like this on the market

is for the patients who don\'t respond, don\'t come

to target, with the maximum doses of the other

agents.

So worrying about 5 or 10 as a starting

dose to me doesn\'t seem terribly important when we

have seven other drugs that we could use for the

patients who respond to 5 or 10 milligrams of this

drug. But it seems to meet a need for patients who

require more potent agents than what we currently

have and I think we really need to focus on what

the 20 and 40-milligram dose would do. I think

without the 40-milligram dose, there is really very

little advantage to this drug over what is already

out there.

DR. BRAUNSTEIN: Thank you.

Dr. Wierman?

DR. WIERMAN: Yes, yes.

DR. BRAUNSTEIN: Thank you.

Dr. Levitsky?

DR. LEVITSKY: As a pediatrician, I like

to think small. I note that if you start off with

an LDL cholesterol which is 150 instead of 190, and

you extrapolate, you can do pretty well with 2.5

milligrams, also, so I don\'t know why we are

stopping at 5. This is not going to be a

second-order drug. This will just be added to the

group.

I am being tongue in cheek about this, but

I think that, considering that this drug will be

used for the range of people with mild

hypercholesterolemia to very severe, we need to

have the entire spectrum available. I have,

perhaps, some caveats about what I would like in

the package labeling for the 40-milligram dose, but

I think we need the smaller dose, too.

DR. BRAUNSTEIN: We will come to those

caveats under dosing recommendations. So, is your

answer yes, yes?

DR. LEVITSKY: Yes.

DR. BRAUNSTEIN: Thank you.

Dr. Neylan is not a voting member of the

committee but we don\'t want to stifle his ability

to comment.

So, do you have any comments about No. 1?

DR. NEYLAN: Thank you, Mr. Chairman. As

a member of this body without a vote but, like the

other members, with opinions I am very happy to

chime in. My response is definitely yes, yes, that

the sponsor has undertaken yet the most ambitious

trials in this area. They clearly, in their

magnitude, their scientific rigor, are the state of

the art. So, again, efficacy, yes, yes.

DR. BRAUNSTEIN: So we will go to Question

No. 2 on safety. We will start with Dr. Carpenter.

We will break this down first to the vote that we

have to take and then the discussion. So we will

ask Dr. Carpenter just to respond to Question No.

1; has the sponsor provided sufficient evidence

that the mild toxic potential per LDL-lowering

efficacy of rosuvastatin is similar to that of

currently marketed statins.

DR. CARPENTER: I think we have to look at

this across doses and, at first glance, eliminate

the 80-milligram dose because I think there are

clearly other issues with that dose that we all

agree are off the table here.

As one extrapolates from the data

presented, there is some concern, albeit the

numbers are very small, that there is a dose

relationship to the incidence of the myotoxicity,

whether these, up to the dosage range stated, get

above the other statins or not is, from the data I

could see, not significant in terms of the a

difference.

I would say that the evidence to date

would indicate that across 40, up to the

40-milligram dose, we are at levels comparable to

the other statins but with some reservation about

the 40-milligram dose in that more numbers may bear

this to be harder number with more data coming in.

DR. BRAUNSTEIN: So, do you think the

potential is similar to the other statins up to the

40-milligram dose?

DR. CARPENTER: I think, at present, there

is no difference with the other statins. However,

we may see the 40-milligram dose differ with time.

DR. BRAUNSTEIN: I also say yes, with the

current data.

Dr. Woolf?

DR. WOOLF: I concur.

DR. BRAUNSTEIN: Dr. Hennekens?

DR. HENNEKENS: Yes.

DR. BRAUNSTEIN: Dr. Follman?

DR. FOLLMAN: Yes.

DR. BRAUNSTEIN: Dr. Watts?

DR. WATTS: Yes.

DR. BRAUNSTEIN: Dr. Wierman?

DR. WIERMAN: Yes.

DR. BRAUNSTEIN: Dr. Levitsky?

DR. LEVITSKY: Yes.

DR. BRAUNSTEIN: Dr. Kopp?

DR. NEYLAN: Yes. Thank you.

Now we will go back to Dr. Carpenter for

the second part of the question. Has the risk of

muscle toxicity associated with rosuvastatin

therapy been adequately\--pardon?

MS. SPELL LeSANE: You forgot Dr. Neylan.

DR. NEYLAN: Actually, I said yes, the

non-voting yes.

DR. BRAUNSTEIN: Dr. Kopp?

DR. KOPP: I will add a voting yes.

DR. BRAUNSTEIN: Thank you.

Has the risk of muscle toxicity associated

with rosuvastatin therapy been adequately evaluated

in the clinical-development program with respect

to, among others, the number of patients studied

and duration of treatment over the proposed dosage

range, special populations such as the elderly,

renally impaired or those with comorbid medical

conditions and drug-drug interactions?

Again, this doesn\'t require a vote. It

does require any advice to the FDA that you wish to

give them along these lines.

DR. CARPENTER: This is a qualified yes

but, again, with the comment that I think there is

some concern about the 40-milligram dose and this

arises, in particular, in some of the special

populations. I think a complete and absolute yes

on that dosing is going to take some time to bear

out as more numbers come in on some of these other

groups.

DR. BRAUNSTEIN: I think the risk of

muscle toxicity at the 40-milligram dose is still

open to question. The data that has been presented

has shown that it falls within the range of the

other statins. I do think that after this is on

the market and a larger group of individuals with a

variety of other comorbid conditions are exposed to

it that we need to look at this very carefully.

I am concerned about special populations

such as the Japanese population. The

pharmacokinetic studies that were performed in

Japan did show that the Japanese in Japan had a

higher level for a given dose so that I am

concerned about certain populations and we may find

that, just as certain populations are more

susceptible to side effects of different drugs, the

Asian Americans, or Asians in general, may have the

same problem. So this has to be looked at very

carefully.

I would also like to see more extensive

evaluation of drug-drug interactions. Certainly,

the common ones have been looked at that have been

associated with statin myotoxicity and it doesn\'t

look\--and, certainly, rosuvastatin falls within the

range of what we see with the other statins as far

as the effect of other drugs such as gemfibrozil on

the drug levels.

But this is something that I think does

need to bear watching especially at the

40-milligram level.

DR. BRAUNSTEIN: Dr. Woolf?

DR. WOOLF: There are really three parts

to this question. I think A is yes. B, special

populations, we have talked about the Japanese but

clearly there are other Asian populations and so I

think it needs to be broadened to include,

obviously, Chinese, Southeast Asian, perhaps people

of Indian descent. Who knows? That is going to be

carefully looked at and whether it is a genetic

issue or whether it is an environment issue needs

to be sorted out. The study in Singapore will help

it. I think you need to go beyond that.

There are literally thousands of drugs.

You can\'t possibly determine the drug-drug

interactions of all the thousands no matter how

many people you study premarketing. So it is going

to have to be looked at. But, within the confines

of a study, I think the sponsor has done about as

well as can be expected.

DR. HENNEKENS: I would concur strongly

with Dr. Braunstein\'s position on these matters and

also with the caveat that this is the largest and

most comprehensive development program of any drug

of this class that has ever been undertaken, so it

is not about this drug or about this particular

dose as much as the issue that you may not be

finding something simply because the expected value

is zero in the population that is studied.

DR. BRAUNSTEIN: Dr. Follman?

DR. FOLLMAN: In terms of muscle toxicity

in terms of part A, I agree that they have been

studied adequately. They met the FDA guidelines

for duration and so on. I guess the concern would

be if we saw some additional evidence of

myotoxicity in the doses between 5 and 40 but, in

that range, they are similar to the statins that

are approved.

So, if we focus on that range, they have

studied enough and I think they have done an

adequate job on that account.

In terms of special populations, I have

sort of a question, something that I thought about

when I was reading this. It seems, in special

populations, say, cyclosporine patients who are

receiving cyclosporine, what happens is you will

notice that the pharmacokinetic parameters are much

larger, the area under the curve or Cmax is much

larger. Based on that, you decide that the dose

should be lowered.

So that sounds like a reasonable strategy.

These are relatively rare populations but the way

that they proposed doing this, with cyclosporine

there was ten-fold increase in Cmax at 10

milligrams compared to health subjects. So they

suggested cutting the dose in half to 5 milligrams.

I think it would be interesting to study what the

pharmacokinetic parameters would be 5 milligrams in

cyclosporine and, more generally, for other

programs where you are concerned about drug-drug

interactions or special populations.

DR. BRAUNSTEIN: Dr. Watts?

DR. WATTS: I am favorably impressed with

the large body of evidence and the long-term follow

up in the populations studied. So I think A is a

yes. I don\'t have anything to add to the concerns

about special populations but I think there is more

to be learned there and drug-drug interactions

don\'t seem to be an issue other than what has been

identified.

DR. BRAUNSTEIN: Dr. Wierman?

DR. WIERMAN: I agree with the comments

that have been made by the other members. The only

other potential question or comment I had is, as I

read the total packet, there was a comment of

drug-drug interactions with birth-control pills

changing the AUC of two-fold. But it seemed much

more relevant for me, for the population that was

going to be treated who are female, what the

interactions would be with different combinations

of hormone-replacement therapy and that would seem

to be of interest especially with all the new

information we have about a dose-response curve for

hormone-replacement therapy of benefit versus risk.

DR. BRAUNSTEIN: Along those lines,

because we didn\'t talk about this, as I recall the

data showed that the levels of hormones in the

birth-control pills actually go down with this. So

one would ask, does that decrease the efficacy of

the oral contraceptives and is that a class action.

DR. ORLOFF: I seem to recall\--again, I

don\'t have the labels with me\--I seem to recall

that that has been found with at least one other

statin. I believe it was\--the one I am recalling

is Lipitor, atorvastatin. Does the sponsor have

any comment on that? Also, while Dr. Hutchinson is

walking up there, I want to just make one more

point of clarification.

In cyclosporine-treated patients, the

sponsor is proposing 5 milligrams not just as the

start dose but as the dose, the only dose. So

there is no dose beyond that.

DR. HUTCHINSON: I am going to ask Dr.

Schneck from our Clinical Pharmacology Department

to come up. We did do an ethanol estradiol and

norgestrel drug interaction study with

rosuvastatin.

DR. SCHNECK: We did a drug-interaction

study with a commonly used oral contraceptive in

the United States. This is a combination product

that contains 35 micrograms of ethanol estradiol

and a great increase in concentration over the

three-way cycle of the progestin and norgestrel.

\[Slide.\]

This is the outcome in some eighteen women

in which they were dosed to steady state at 40

milligrams in our compound during one of the cycles

of the hormone and comparing the outcome from a

previous cycle in the absence of rosuvastatin.

The outcome of this trial shows you there

is about a 25 percent increase in the circulating

concentrations of estradiol in terms of Cmax and

AUC and a similar increase in the progestin

component of the combination tablet, 23 in Cmax, 34

in AUC. So there is a small increase in the

circulating concentrations of the hormones in the

presence of the rosuvastatin, certainly no

decrease. Certainly we would not anticipate any

reduction in efficacy as far as oral contraception

and we would leave it to the judgment of physicians

as to what that small increase might mean in terms

of long-term exposure on this combination.

DR. BRAUNSTEIN: Thank you.

Dr. Levitsky?

DR. LEVITSKY: Yes, with all the caveats

that have been expressed before me.

DR. BRAUNSTEIN: Thank you.

Dr. Neylan?

DR. NEYLAN: Yes to the first and then a

special plea for a population near and dear to my

heart, the organ-transplant population. That is a

group that is roughly a quarter of a million in the

U.S. today and double that globally and so a not

insubstantial number of patients. It is a group

with special needs in terms of lipid lowering.

Roughly 80 percent of renal-transplant patients are

on lipid-lowering drugs and that is a group of

patients in need of better efficacy.

The limited study done in the

heart-transplant population which, as a rule, has

less perturbations with lipids than some of the

other solid organs, especially kidney, could

certainly be amplified. Moreover, we need to

better understand interactions with the other

emerging immunosuppressants. Cyclosporine now

constitutes or is now, in less than half of newly

transplanted patients, part of the maintenance

regimen.

So, increasingly, other drugs are coming

into the forefront and many of these have

interactions. So, I would certainly encourage the

sponsor to explore this issue in further

postmarketing studies.

DR. BRAUNSTEIN: Dr. Kopp?

DR. KOPP: Yes. I would say yes as well.

With regard to special populations, I urge the

sponsor to look at another Asian-origin population,

Native Americans. I was very happy to see that

there is a large ongoing trial in ESRD. I think

you have 2500 patients. I think that will be

important to define what the safe upper limits of

dosing would be.

I echo Dr. Neylan\'s comments about other

drugs, particularly tacrolimus FK since it is so

closely related to cyclosporine and also serolimus

and knowing more about those interactions.

DR. BRAUNSTEIN: Thank you.

We will go on to IIB, safety in regards to

renal effects, the clinical laboratory monitoring

in the Crestor development program exposed a

heretofore unknown effect of a statin to cause mild

proteinuria sometimes associated with microscopic

hematuria and mild renal impairment and increased

creatinine. This effect appears dose-related in

frequency and perhaps severity and reversible on

discontinuation of therapy or on lowering the dose

of the drug.

Then there are three questions and a

comment; a., has the risk of adverse renal effects

of rosuvastatin been adequately evaluated over the

proposed dose range? b., what further

investigations are needed, if any, of this novel

drug effect? c., is comment on the data presented

suggesting that this may be a statin class effect

and d., is monitoring of renal function recommended

for this drug or potentially for all statins.

So I will take a crack at these four and

then pass it on to Dr. Woolf. Has the risk of

adverse renal effects of rosuvastatin been

adequately evaluated over the proposed dose range?

I think it has been evaluated and defined that

there is a problem, so I think that the risk has

been defined.

Certainly, I am very happy to see that

almost 900 individuals were on the drug for 96

months. That is very reassuring that it is not

going to be a major disaster. So I think it has

been adequately defined.

b., what further investigations are

needed, if any, of this novel drug effect? I think

that this should be examined prospectively in

regards to trying to figure out what populations

are susceptible to this, if there is any group of

individuals that may develop this because of

increased susceptibility? Are there medications

that these patients are taking, herbs, vitamins,

nonsteroidals, some of the other medications that

may affect tubular function that, in association

with this particular very potent statin, may lead

to proteinuria and possibly hematuria?

Defining what the hematuria is due to. I

think that we have had a beautiful discussion by

Dr. Lewis and also by Dr. Kopp concerning the fact

that, in many cases of hematuria, we don\'t know

what the structural defect is that causes the

hematuria. But I think that we should still be

looking for that. So I do think that there are

some further investigations that should be done in

a prospective fashion now that the knowledge is

there that this is a potential effect of the drug.

Comment on the data presented suggesting

that this may be a statin class effect. I think

that it very likely may be and I say that because I

am impressed with a couple of pieces of data that

were presented. Number one, the lipophilic study

showing that this is more likely to get into the

renal tubules than most of the other statins that

are on the market except for pravastatin which is a

weaker drug.

So this is more likely to get to the

tubules and get into the tubules. Also it is a

very potent drug, as has been shown by the in vitro

data. I was also impressed with the melanic acid

addition experiment in vitro that this can overcome

the tubular readsorption problem induced by the

drug suggesting that, really, what we are seeing is

a drug that is taken up by the tubules much easier

than many of the other drugs and is a very potent

inhibitor of the HMG Co-enzyme-A system.

Therefore, if one is able to get a

sufficient quantity of a very potent statin into

the tubules, I think it is likely that one will see

the same type of effect.

So, although I am just commenting on this

because it does say comment, I think that it

probably will turn out to be a statin effect from

very potent statins that get in the tubules.

Is monitoring of renal function

recommended for this drug or potentially for all

statins? I don\'t think monitoring for potentially

all existing statins in the market is necessary

because we have a lot of a experience with that, so

I don\'t think that one has to go back to that

group. For future statins, obviously, the renal

effects need to be looked at.

For this particular statin, I do think

that monitoring should be recommended for doses of

40 milligrams because of the proteinuria and the

hematuria and not knowing really what the long

long-term problems associate with that might be.

So I do think that it reasonable.

Now, I might say also that it is in this

group of patients who are getting the statins that

many of them will have comorbid conditions that

require renal-function monitoring anyway,

hypertension, diabetes, for instance. But I do

think that there should be a clear statement in the

labeling that individuals who receive 40 milligrams

of rosuvastatin should have periodic monitoring of

at least urinalysis for proteinuria and hematuria.

Dr. Woolf?

DR. WOOLF: This is the area that bothered

me when I read the briefing documents and my

concerns have been partially allayed but not

clearly so. The answer to a. is I don\'t think my

concerns really have been adequately evaluated. I

don\'t think that a dipstick urine for protein or

blood is adequate and the number of patients who

actually got formal urinary protein evaluations

and, as we heard, virtually nobody got studies of

sediment I think is an oversight.

In fact, I am kind of surprised that this

wasn\'t picked up earlier so that it couldn\'t have

been investigated in the trials that were finishing

up toward the end of the evaluation process,

particularly those that were started in response to

the FDA\'s comments in 2001.

What further investigations I think we do

need to look at the urine sediment for people who

do have hematuria. Simply that it is unexplained

is not acceptable. It may be unexplained and

benign and it may be unexplained and, five years

from now, have some serious consequences. I think

we need to know which it is.

The statin class effect, no matter how you

slice it and dice it, the 40-milligram dose of

rosuvastatin seems to have a greater issues than

any of the other doses of the statins that were

studied clinically. The in vitro data, I think, is

very intriguing and very interesting and very

plausible but, as far as I know, humans don\'t have

possum cells. So, perhaps, we need to look at

people rather than in vitro data.

So I think that is very interesting. It

gives a nice plausible explanation, but I don\'t

think it is adequate. So, in light of a., b., and

c., I think that clearly the 40-milligram dose

needs to be monitored both in terms of something

more than a dipstick urine for renal toxicity.

DR. BRAUNSTEIN: What would you suggest?

DR. WOOLF: I think that some studies

actually have to have formal urinalysis and urinary

protein in measurements formally normalized to

creatinine and then, if one wants to look at

breaking down the classes of protein, remember that

I think 22 of the 57 patients where it was looked

at actually had a glomerular component, seven or so

with glomerular and there was another eight or so

mixed. I may have those numbers backwards but, by

no means, was it simply tubular dysfunction.

DR. BRAUNSTEIN: That was the baseline.

DR. WOOLF: No; that was the 40-milligram

dose.

DR. BRAUNSTEIN: Was it?

DR. WOOLF: Yes.

DR. ORLOFF: Clarification, Dr. Woolf.

DR. WOOLF: Yes.

DR. ORLOFF: It sounded like you were

calling for monitoring in ongoing trials as opposed

to making a comment on whether and how monitoring

should be conducted in, for example, open-market

use.

DR. WOOLF: That is a very good point,

which you didn\'t ask us to clarify. But, for sure,

it ought to be in monitoring of ongoing trials. I

mean, that would be mandatory. I would like to see

urine analyses and formal protein measurements or

at least spot with creatinine corrections on

patients on 40 milligrams at some interval. I

agree with our chairman that these are people

likely to have comorbid processes and it may be

difficult to sort out what is causing what. But

that doesn\'t mean we shouldn\'t look.

DR. BRAUNSTEIN: Dr. Hennekens?

DR. HENNEKENS: As I look at the 5 to

40-milligram range of doses, I feel the benefits on

LDL, HDL and triglycerides is striking and the

hazards on the liver as measured by ALT and the

muscles as measured by CK are generally reassuring

such that they appear to be as good or even more

favorable in some cases than the other marketed

statins.

The big issue I grappled with here is that

the 20-milligram dose, in my view, is associated

with a 0.7 percent rate of proteinuria. This is a

low absolute rate but, in my view, it is far higher

than the other marketed statins and it is

compounded by the fact that when the dose is

increased to 40 milligrams, it is up to 1.2

percent.

On its own, I am not concerned about it as

part of a development program. However, I am

concerned about what impact this will have when

millions of people take 40 milligrams of this drug

for five to ten years. I am not certain this will

be a reversible tubular defect\--not that it won\'t.

I am just not certain. I just don\'t know.

I would say that the data that I saw

suggests diminution, not complete reversibility, of

the effect. I would also like to see perhaps more

elucidation of this issue ranging from basic

research to understand the mechanisms better to

clinical studies to quantitate the magnitude and

clinical significance of the problem. My concerns

here do relate specifically to the 40-milligram

dose. So I would perhaps want to see more cogent

data beyond just monitoring the trials which have a

relatively low sample size of people on the

40-milligram dose to basically better understand

and quantitate the problem before deciding on a

solution that may or may not be adequate.

DR. BRAUNSTEIN: So, if I understand your

responses to the questions, a., has the risk of

adverse renal effects of rosuvastatin been

adequately evaluated over the proposed dose range.

Do you think it has been adequately defined?

DR. WOOLF: Well, the risk has been

adequately evaluated in the sense that I now

believe there is a risk at the 40-milligram dose.

DR. BRAUNSTEIN: And the further

investigations, you noted. You didn\'t know whether

you thought that this was statin class effect.

DR. WOOLF: I did say, in my reading of

the data, I would say that it seems to be not

necessarily peculiar to this drug but peculiar to

the dose of the drug, 40 milligrams and above, not

to this drug, even.

DR. BRAUNSTEIN: You would favor

monitoring at the 40-milligram dose.

DR. WOOLF: I think I am saying that, on

the one hand, monitoring may be too much but, on

the other hand, it may be too little. I am still

not basically getting my hands around both the

mechanisms as well as the magnitude of the issue.

So, in some ways, if there were a way to try to

suspend monitoring as a solution for this because

it may turn out, with further evaluation, that this

is less of a problem than it appears and,

therefore, monitoring wouldn\'t be necessary.

On the other hand, if further data support

the magnitude of the problems would be greater,

than monitoring might not be enough. So I am just

not sure.

DR. FOLLMAN: I broadly agree with what

Charlie mentioned. In terms of part a., has the

risk of adverse events been adequately evaluated,

for the other safety parameters over the range of 5

to 40 milligrams, I think we have a flat-dose

response curve and there is not a concern about

muscle toxicity or liver toxicity.

Here, though, in terms of the kidney, we

have a concern at the 40-milligram dose. The real

issue, I think\--and so this is unlike the other

safety parameters. The 40-milligram dose is, I

think, the thing we are all focusing on, has it

been adequately characterized.

Your point about the risk is, I thought,

well put that we are aware now of a risk that we

didn\'t know about before. This had not occurred in

the other statins. The real issue to me is whether

we have enough information to feel comfortable that

there won\'t be clinical events related to the

kidney once it is licensed.

That is something we don\'t really know

now. The only way to get knowledge about that is

to do large studies. Charlie mentioned that this

is a relatively rare event probably and the only

way we are going to get information on it is to

study it in a lot of people.

So, to finish up, I guess, Part a., the

risk has been adequately characterized in terms of

these laboratory parameters. The clinical sequelae

we don\'t know yet. So, for part b., what further

investigations might be needed, I think the large

clinical-trials program that they have mentioned

earlier today, probably over 20,000 people that

they are going to be studying, would be good for a

step in that direction, I think, maybe the only

step that needs to be done in terms of monitoring

clinical consequences for this problem.

In terms of Part c., whether this is a

statin class effect, when I read this, I thought, I

don\'t really know one way or the other. But I also

thought it didn\'t really matter because we don\'t

see any evidence of this in any of the other

statins. This is only brought to our attention

because of the high dose. So, whether or not it is

a statin class effect doesn\'t matter to me. We

see it here at 40 milligrams, to some extent, and

certainly at 80 milligrams. That is what we need

to focus on, whether we have clinical events, an

increased rate of clinical events for this.

Then, finally, I would agree that

monitoring of renal function is probably needed if

we are going to approve this study. Eventually, it

might turn out with more information. We know that

it is unnecessary. Charlie was saying he just

didn\'t know at this point and I agree, we don\'t

know. So, to be on the safe side, we should

monitor now. Eventually, it might be viewed that

it is unnecessary in some populations or maybe

across the board.

DR. BRAUNSTEIN: Dr. Watts?

DR. WATTS: I don\'t think the adverse

renal effect has been explored adequately at the

higher dose. I agree with Dean. I don\'t know

whether this is a class effect and I don\'t know

that it matters. If it is a class effect, it seems

to be related to the potency of the drug and the

low lipophilicity. So it doesn\'t seem to apply to

the other statins that are in clinical use.

If I were taking this drug in a

40-milligram dose or if I were using it in my

clinic, I would want a baseline serum creatinine

and a baseline urinalysis. Periodically, I would

want a dipstick urinalysis and, if I saw 2-plus

protein or 1-plus blood or both, then I would at

least repeat that urinalysis. If those findings

were there on repeat, then I would want to quantify

my urinary protein and renal function.

So, in clinical practice, until there is

more data for safety, I would recommend monitoring.

I don\'t know that it needs to be monitored with

quantitative urinary protein because the dipstick

seems to be sufficiently sensitive to let you know

where there might be a problem.

I think there is probably some data in the

existing dataset that would help us. I asked about

the time of the appearance of this. It looks like

there were several hundred patients who had

proteinuria, several hundred patients who had

hematuria, and I am not convinced that the sponsor

has looked adequately at the existing data to

convince me that this is a transient phenomenon

versus a fluctuating phenomenon and that

longer-term use might show that there is a problem.

I think that, in the ongoing large trials,

it should be possible to answer that question and

also do more detailed analysis to find out if there

are other changes in tubular function that emerge

in patients who show proteinuria. I think that it

may turn out to be very reassuring data from the

existing set and from the ongoing trials, but,

until we have that reassurance, I think patients on

the high dose should be monitored.

DR. BRAUNSTEIN: Dr. Wierman?

DR. WIERMAN: I agree with the comments

that Dr. Watts just made. Perhaps, unlike some of

the other members, I think that additional research

does need to be done at the basic level because I

think, if we understand the mechanism of how this

agent is working at the tubule, you may be able to

predict which patients might be at risk and what

drug-drug interactions it may occur in.

So I think that, as well as the careful

monitoring of patients initially as the drug gets

approved and in ongoing studies, I think further

basic studies to understand the molecular

mechanisms may provide the insight then to target

patients and to use the drug most safely.

DR. BRAUNSTEIN: Dr. Levitsky.

DR. LEVITSKY: I agree that the risk of

adverse renal events has been adequately evaluated

up to the highest dose range, the 40-milligram dose

range, at which point I think that further

evaluation is necessary and those further evaluates

should consist of the large-scale clinical

surveillance studies that are under way as well as

further in vitro studies.

The in vitro studies that were presented

are convincing for some sort of statin class effect

but the human studies do not yet support this, so

they need to be carried further. I am concerned

that this is an important issue because, no matter

what dosage range is suggested by

the FDA, many of the other drugs in this class may

well be used outside those dosage ranges so,

knowing this is a class effect is an important

thing for physicians, particularly specialists,

using these agents.

Then, finally, I certainly would recommend

monitoring of renal function as was suggested

before in patients on the highest dose of these

drugs.

DR. BRAUNSTEIN: Dr. Neylan?

DR. NEYLAN: I agree that the approximate

low-level risk of renal dysfunction has been

characterized, although I do believe that there is

much, as the previous panel members have suggested,

that can be done to further understand, both at the

level of prospective clinical trials, postmarketing

surveillance and, of course, further preclinical

data.

As far as the types of further

investigations, I am certainly intrigued by the

hypothesis put forth by the sponsors as to a

mechanism for changes in tubular handling of

protein. I struggle, though, to make that model

answer all the questions regarding the renal

picture as a whole and especially hematuria which I

guess I have sort of latched onto especially today.

So I would encourage other looks, other

relevant models, to look at the possibility both at

the tubular epithelial level and other parts of the

kidney that there is not some evidence for ongoing

increased turnover or inflammatory process.

Is this data suggestive of a class effect?

My gut feeling tells me yes, although I certainly

do not think there is enough here to warrant

stating that or carving it in stone. I do think it

is very important to understand this. As Dr.

Levitsky says, the use of all these agents will be

broadly applied and used increasingly in the coming

years and especially given the potential

interactions and different handlings within special

populations. Despite current dose ceilings for

these other agents, we are likely to see a wide

variety of increased exposures and I think it

behooves the community to be on the lookout for

this and for all of us to better understand if

there is, indeed, a class effect or not.

Finally, monitoring, should it be

recommended? My bias as a nephrologist is that, in

this population of patients, in general, renal

function in older patients with multiple

comorbidities for cardiovascular disease and

nephrosclerotic disease do warrant periodic

monitoring if only once a year for serum

creatinines and urinalyses. I agree with Nelson\'s

observation that, were I starting this in the

clinic, and now as I think about it for other

statins, obtaining a baseline urinalysis and a

serum creatinine seems a very modest and quite

acceptable start for this.

DR. BRAUNSTEIN: Thank you.

Dr. Kopp?

DR. KOPP: For Question a., I think the

studies to date have been adequate but could be

improved. I will touch upon some of the themes

that we have heard about already. Is this a

functional defect? I think that is possible but I

am not sure that that is all that is going on. Is

there a structural problem? I gather we have had

just one renal biopsy available in somebody who has

both proteinuria but not renal failure and is this

progressive as we follow patients out three and

four and five years.

Again, two issues that were talked about,

how do we understand the glomerular proteinuria

that apparently is present in about a third of the

patients, either pure glomerular or mixed, a third

of the patients with proteinuria that we were told

about and how do we understand hematuria. Is it

functional, as Dr. Lewis mentioned can happen, or

is it something else?

In terms of further investigations, I

think animal studies might add something here. We

heard that a variety of statins cause

epithelial-cell damage but maybe we can learn

something more. Maybe we can better understand is

there a glomerular-disease element as well using

that model.

In terms of human investigations, I think

I would like to see continued follow up on patients

beyond 96 weeks and I would argue that we should be

doing more renal biopsies in those patients who

have unexplained proteinuria possibly as part of a

research protocol rather than from pure clinical

indications to try to increase that n of 1 and get

a sense of are there patients who do have

tubular-cell atrophy and so forth at a relatively

early stage before they have a rise in creatinine.

In terms of a class effect, like, I think,

like everyone here, it is possibly true that it is

a class effect and it is also possible that

rosuvastatin has an additional action and I think

it is very hard to sort those two out.

In terms of monitoring, I would first say

that, yes, for 40 milligrams but I would also say

that there are patients who may only be getting 5

milligrams. But if they are getting cyclosporine

and their AUC is seven-fold elevated, they may have

drug levels comparable to 40 milligrams. So I

think the package label ought to say something

about patients at a high risk for toxicity either

because of a change in the AUC, the PK, or,

alternatively because of a second agent that might

be additive or even synergistic in terms of tubular

toxicity. We will have to leave it up to the

clinician to use good judgment about how to

interpret increased risk.

Like the others, I would like to see, at a

minimum, a creatinine and an urinalysis. I would

argue a protein-to-creatinine ratio, particularly

in this population that we talked about with

diabetes and hypertension is pretty much standard

of care and then periodically\--and I don\'t know

what the right period is; would it be every six

months or every year\--to repeat at least the

urinalysis or the protein-to-creatinine ratio.

DR. BRAUNSTEIN: Thank you.

Dr. Carpenter?

DR. CARPENTER: With respect to a., I

think yes, the studies presented have been adequate

to define the risk of the renal issues that we have

been discussing. However, we have not defined the

lesion. I think that is where our level of

uncomfortableness is here, that we know something

is going on but we don\'t really have a good handle

on precisely what it is. Thus further

investigations, I think, would be most useful and I

particularly appreciate the animal studies effect.

I think at this point the data done in the

OK cells suggesting that this is a statin class

effect can only be taken at this point as a

suggestion. It is interesting but this may be

something that is true across statins but is

perhaps even unrelated to the global renal effects

that we are seeing.

The point that could be inserted here,

too, is the 40-milligram dose does seem to be that

which, as others have mentioned, is where we are

most concerned. That would lead into the

monitoring question and I would address this at two

levels; first, monitoring with respect to clinical

use. I would agree with Dr. Watts\' suggestion that

preliminary investigations of creatinine levels as

well as subsequent dipstick urinalyses would

probably address that and particularly at the

40-milligram dose level.

As I recall, although the numbers of

patients in the 40-milligram categories were

actually quite good because of the inclusion of the

back-titration subjects, there were probably lower

numbers in the 20-milligram dose than in any other

dosage category so I still have some reservation

about eliminating monitoring in that category

simply because of the limitations of the numbers.

Finally, at a second level of monitoring,

as the sponsors indicated they were already doing,

I think it is a great idea, in continued trials, to

examine fresh urine sediment as another approach to

trying to define what the lesion is.

DR. BRAUNSTEIN: Thank you.

We will move on to the third issue which

concerns dosing recommendations. We will take all

of these as we go around as a group. No. 1, are

the data adequate to support the 5, 10 or

20-milligram doses as a safe start dose. 2, are

the safety data adequate to support a maximum dose

of 40 milligrams a day. To a certain extent, we

have already discussed this but I think it is

worthwhile saying yes or no.

3, does the committee recommend a range of

start dosages\--that is 5 to 20 milligrams\--in which

an individual may be initiated on therapy based on

CHD risk, baseline LDL cholesterol levels and

target LDL cholesterol or, alternatively, should

there be a fixed start dose of 10 milligrams

recommended for the general population with 5 and

20 milligrams reserved for special circumstances as

proposed by the sponsor.

Dr. Woolf, will you handle those?

DR. WOOLF: I\'ll try. I think that we

have beaten No. 1 to death. It is more than

adequate data that these are safety dose. The

40-milligram dose is a very valuable addition to an

armamentarium that desperately needs some

augmentation at higher efficacy. So, with data we

have, despite what I said before, I think that, in

this population, I would rather run the risk of

some unexplained proteinuria than cardiovascular

disease. So the answer to that is yes.

The answer to 3\--

DR. WOOLF: 3 and 4 are together\--is

somewhat difficult. Those of us who have been

around long enough remember that we were told we

needed to titrate statins. That is what we were

brought up with and that is what the general

physician in primary practice was told. And the

company, the industry, did a very good job of that.

So now the industry is trying to say, well, we made

a mistake. We now know better. We should have a

fixed dose.

So we are betwixt and between. The

notion, then, of saying, well, yeah; 5 is

effective. 10 is more effective. So why don\'t you

start with 5. That gets us back to titration and

people are not going to get titrated. Even in good

studies done by cardiologists, done by

endocrinologists, who should know what they are

doing, it ain\'t happening.

So I would go along with starting with the

10-milligram dose to start in the non-high-risk

patients and back titrate down if I don\'t need to

rather than try to convince somebody to go up

because that is not going to happen. So I would

like to see the start dose at 10. The safety

profile seems to be comparable to 5, at least in

the several thousand patients that have been

presented to us.

I would reserve 20 and, perhaps, even 40

to start doses for people with high and ultrahigh

risk doses\--risk, rather.

DR. BRAUNSTEIN: Thank you.

We are actually going to go out of order

because Dr. Wierman has to leave. So I am going to

ask her to answer III and also to weigh in on IV

before you leave.

DR. WIERMAN: My answers are for III-1,

yes; I think the data are adequate to support the

doses, the safe-start doses, any of the start dose

and to support the maximum of 40 milligrams daily.

I go back and forth on whether or not we

should recommend the 10 versus the fluctuating

dose. I am swayed by the arguments that say that

people don\'t switch the doses once they start and I

think we should do a better job as clinicians and

educators of dosing down as well as dosing up. So

I would favor the 10 start dose. I guess that is

the end of that. The overall answer for the

recommendation to IV, I vote yes.

DR. BRAUNSTEIN: Thank you.

We will go back to Dr. Hennekens.

DR. HENNEKENS: Question 1, I think the

answer is yes. Question 2, the answer is yes with

the caveats we have discussed. With regard to Nos.

3 and 4, I feel that the same distinguished

panelists who published on the low percentage of

people achieving goals also in their publications

is the large number of patients who would benefit

from statin therapy and who were not treated at

all. So my own view of these questions, 3 and 4,

would be that whatever the sponsors and agency

finally decide are going to do the most good for

the most people by getting more people on statin

therapy would be the best strategy to achieve.

DR. BRAUNSTEIN: Thank you.

Dr. Follman?

DR. FOLLMAN: For the first question, I

would say yes, they are fine start doses. The

second question, has 40 milligrams daily be

justified; I would say probably provided we are

monitoring that and the ongoing studies don\'t show

anything alarming. And I favor a 10-milligram

start dose for the reasons Dr. Woolf mentioned. I

think, for whatever reason, if we titrate, if there

is more titration involved at the end of the day,

there will be fewer people achieving goals.

So, if we have a 10-milligram start dose,

I think we will have better health in the people

who are getting the statin.

DR. BRAUNSTEIN: Thank you.

Dr. Watts?

DR. WATTS: The answer to 1 is yes. The

answer to 2 is yes. I like the Hennekens Principle

for the start dose. I think cost should also be

considered here if the 5-milligram tablet would be

half the price of the 10-milligram tablet, then

maybe that would weigh in for a lower dose. But

the practical issues of titration not happening are

also there.

I think, certainly, the 20 and

40-milligram start doses should be start doses only

for high-risk populations.

DR. BRAUNSTEIN: Dr. Levitsky?

DR. LEVITSKY: 1 is yes. 2 is yes. 3

requires a digression which is that, as a

pediatrician, I have watched with bemusement over

the years as internists finally came to the

conclusion that 90-year-old 90-pound ladies were

not the same as 300-pound 30-year-old guys when it

came to drug doses.

You guys are moving in the right

direction, But I am worried at the idea that you

all still can\'t titrate a dose based upon response.

I would like to have 5-milligram doses because

there are so many drugs now that we don\'t have

adequate dosing for because you all who make up

larger parts of the population don\'t need them.

So I really would like to have a titration

ability but I will defer to you. You are going to

be using these drugs more than we will. It looks

as if the 5 is going to be something you have to

call the company and get special permission for,

not something that is going to be available in

every CVS.

DR. BRAUNSTEIN: We are getting a lot of

head-shaking that says no.

Dr. Neylan?

DR. NEYLAN: They may score the tablet, of

course. Yes to the first, yes to the second and to

3, 4, I would sort of split the difference and say,

\"Suggested 10-milligram start dose (5 to 20),\" so

start off with the suggestion of the fixed start

but in the dosing section give some rationale for

why there might be some flexibility.

DR. BRAUNSTEIN: Thank you.

Dr. Kopp?

DR. KOPP: I say yes to 1 and yes to 2.

And, for the others, it is too complicated for me.

I pass.

DR. BRAUNSTEIN: Dr. Carpenter?

DR. CARPENTER: I say yes to 1. On

Question 2, I think there is concern enough at the

40-milligram dose when attempting the impossible

risk-benefit analysis of the standard variety

low-risk patient that, at that high level, the

increment over the 20-milligram dose seems minimal,

yet the risk may increase substantially so that, in

the nonhomozygous

familial-hypercholesterolemia-dose subjects, there

may be some question about the max dose there.

I think, otherwise, the safety data is

reasonable and the risk-benefit analysis in the

severe patients is also reasonable. With respect

to 3 and 4, I like the \"split the difference\"

approach suggested by Dr. Neylan. I had a

question reflecting Dr. Levitsky\'s comments as to

the youngest patient that has been treated with

these drugs and, despite the fact that the market

is obviously limited in pediatrics, in the future,

with obesity running rampant, this may change.

I just wondered if there was any data from

the sponsor on pediatric utilization here.

DR. BLASETTO: The data that we had in the

homozygous familial hypercholesterolemia, we did

allow patients in below the age of 18 and we

actually studied 80 of those patients in homozygous

FH.

\[Slide.\]

This is the result that we saw in LDL-C

reduction. We had a 20 percent reduction in LDL-C

in homozygous FH patients below the age of 18 and

up to the 40-milligram dose in a forced titrated

study at 26 percent mean LDL-C reduction which is

very favorable reduction in this severe homozygous

FH population of patients and below the age of 18.

DR. BRAUNSTEIN: Thank you.

I think the data are adequate to support

the doses of 5, 10 or 20 in various populations as

safe start doses. I do think that the safety data

has been adequate to support a maximum dose of 40

milligrams a day with all the caveats that have

been said.

In regards to whether to recommend a fixed

dose or titration, I am a bit torn here from the

standpoint that if one looks at the 5-milligram

dose, starting dose, there is a 43 percent

reduction in LDL cholesterol which is actually

greater than or equal to at least all the other

statins on the market and their starting dose. So

5 milligrams is at least equivalent.

Also, I like the idea of titrating based

on risk factors and target levels, especially in

the primary prevention population where, although

the slope of relationship between cardiovascular

events and mean LDL cholesterol levels is upward,

it is still certainly flat in comparison to

secondary prevention where I would advocate a

higher dose and getting a cholesterol down as far

as possible.

Nevertheless, I do think that, in order to

do the greatest good for the greatest number, if

you will, that a 10-milligram fixed dose is a

reasonable suggestion. I would also say that a

5-milligram starting dose is also a reasonable way

to go and to titrate up and to give the clinician

the ability to go either way. So either

5 milligram or 10 milligram and provide that 10

milligram does provide increased efficacy.

From a safety standpoint, the two are very

equivalent so I am not really worried about the

safety. So the risk-benefit ratio probably favors

the 10-milligram dose although we don\'t have data

on millions and millions of people for a score of

years or so. So saying that 10 milligrams is safer

than 5 milligrams is, as I said, based on somewhat

limited data but, thus far it does look that way.

So we will go to the final question which

is the overall recommendation. Before going to

that, we did not discuss today in any detail,

although the committee did receive the details

about isolated hypertriglyceridemia. First of all,

does the committee want to ask any questions about

that or do you feel that you are knowledgeable

enough, based on both the sponsor\'s material that

was sent out and the FDA\'s material that was sent

out to be able to include that in the overall

recommendations as it is stated here or do you want

additional information presented?

Does anybody want anything additional?

Dr. Levitsky?

DR. LEVITSKY: I read the sponsor\'s

statement and showed that it looked as if

triglyceridemia was somewhat improved but, if we

are going to include that, I would like to have

some further discussion, I think.

DR. BRAUNSTEIN: Okay. Can you briefly

summarize the isolated hypertriglyceridemia data?

DR. BLASETTO: Could I have the Type IIb

and IV, please, split.

\[Slide.\]

We performed a dose-ranging study in

patients with hypertriglyceridemia which included

patients with Type IIb and IV hypertriglyceridemia.

It was patients at randomization had triglycerides

between 300 and 800 milligrams per deciliter. This

is the response we saw. We did stratify the

patients by IIb and IV and the response in

triglyceride reduction in doses versus placebo, 5

to 40-milligram doses in the triglyceride

reduction.

So we saw reductions in triglycerides both

in IIbs and IVs. The Type IV patients had higher

baseline triglycerides expected had a large

reduction in triglycerides as would be expected.

DR. BRAUNSTEIN: FDA reviewers, do you

have any other comments about the triglyceride

data, especially the Type IV which is the pure

situation?

MS. MELE: I am just trying to remember

the results for this. I think what we saw were

when the HDL values were higher or lower, we were

getting higher and lower responses based on the

level of HDL. I was just trying to look that up.

When HDL was less than 39, we got a much

bigger response in triglycerides than when it was

higher than 39. So that was one thing we noticed.

The dose response, the biggest difference was

between 5 and 10 and then it started to level off

across 20, 40 and 80.

DR. BRAUNSTEIN: You note, in the medical

review, that the mean dose-response curve was flat

at doses about 10 milligrams.

MS. MELE: Right. That is about right.

DR. BRAUNSTEIN: But you did conclude that

it was efficacious for that indication.

MS. MELE: Yes. It just didn\'t get more

lowering when you went above\--you got a little bit

with 20 but certainly not with 40.

DR. BRAUNSTEIN: Is that a sufficient

summary? Great. Then let\'s go on to the final

question. We will start with Dr. Hennekens, the

overall recommendation. Do you recommend that

Crestor 5 to 40 milligrams be approved by FDA as an

adjunct to diet for the treatment of patients with

primary hypercholesterolemia and mixed dyslipidemia

and isolated triglyceridemia and for the treatment

of patients with homozygous familiar

hypercholesteremia as an adjunct to LDL apheresis

or if apheresis is not available?

DR. HENNEKENS: Yes.

DR. BRAUNSTEIN: Thank you.

DR. BRAUNSTEIN: Dr. Follman?

DR. FOLLMAN: Yes.

DR. BRAUNSTEIN: Dr. Watts?

DR. WATTS: Yes.

DR. BRAUNSTEIN: Dr. Levitsky?

DR. LEVITSKY: Yes.

DR. BRAUNSTEIN: Dr. Neylan?

DR. NEYLAN: Yes.

DR. BRAUNSTEIN: Dr. Kopp?

DR. KOPP: Yes.

DR. BRAUNSTEIN: Dr. Carpenter?

DR. CARPENTER: Yes.

DR. BRAUNSTEIN: I say yes.

Dr. Woolf?

DR. WOOLF: Yes, with a caveat and that is

there is no evidence that the 40-milligram dose is

any greater than 20 or perhaps even 10 for isolated

hypertriglyceridemia. I think that the range

should not be 5 to 40 but should be 5 to 10 or, at

most, 5 to 20.

DR. BRAUNSTEIN: Any other comments or

questions from the committee?

Summary

DR. BRAUNSTEIN: Let me just try to

briefly summarize what the committee\'s responses

have been. In regards to efficacy, the committee

unanimously felt that the sponsors had demonstrated

that Crestor was efficacious and sufficiently

efficacious all the way up to 40 milligrams to

warrant including a 40-milligram dose. So the

answer was unanimously yes.

In regards to mild toxicity, it was also

unanimously felt that the sponsor provided

sufficient evidence concerning the myotoxic

potential per LDL-lowering efficacy of rosuvastatin

and that is similar to that of currently marketed

statins.

In regards to the question of has the risk

of muscle toxicity associated with rosuvastatin

therapy been adequately evaluated in the

clinical-development program with respect to, among

others, numbers of patients, special populations,

drug-drug interaction. Basically, the answer there

was yes with some caveats; that is, if there needs

to be some more potential drug-drug interaction

evaluation in follow up.

In regards to renal effects, has the risk

of adverse renal effects if rosuvastatin been

adequately evaluated over the proposed dosage

range. The majority of the committee felt that it

had been adequately evaluated; that is, the risk

had been defined, that, unfortunately, the

mechanism has not been as well defined.

There was rather widespread encouragement

that further investigations are needed, both at the

basic and the clinical level and to look at some

animal models. I might mention that Dr. Orloff

indicated in a discussion that, perhaps, perfusion

of isolated tubules or perfusion of isolated

kidneys might provide some additional information

especially in comparison to the other statins

because one doesn\'t have some of the adsorption

issues.

As far as the data suggesting that this

may be a statin class effect, it is suggestive but

not proven. Is monitoring of renal function

recommended for this drug or potentially for all

statins? The committee really limited its concerns

to this drug and felt that, at the 40-milligram

dose, that clearly there should be some monitoring

of renal function, at a minimum, baseline

creatinine and urinalysis. There is a plea to

consider doing an albumin-creatinine ration in the

urine to start with and then periodic evaluation.

That evaluation has included creatinine and at

least a dipstick urinalysis if not a full

urinalysis all the way to doing periodic

albumin-creatinine determinations.

So we were certainly not unanimous on that

except that we were unanimous that at least a

40-milligram dose does warrant at this time further

evaluation after it is out on the market.

As far as dosing recommendations are

concerned, we agreed that 5, 10 and 20-milligram

doses were safe start doses in the various

populations that were described. Are the safety

data adequate to support a maximum dose of

40 milligrams a day? And the committee was

unanimous on that in the affirmative.

Does the committee recommend a fixed dose

versus titration? We were split on that. I think

most of us felt that the 10-milligram fixed dose is

a very reasonable compromise in getting physicians

to prescribe it, number one, getting patients to

take it without the hassle required for titration.

No. 3, that it is safe and the present data

indicates that it is as safe as the 5-milligram

dose.

So I think the majority of the committee,

although I think they would wish to see titration

ideally feel that a 10-milligram fixed dose is a

reasonable start. There is also the opinion of

several members of the committee that the clinician

should be given an option to start at 5 milligrams

as well as 10 milligrams and that the data be

provided in the package insert and with educational

sessions to discuss both the 5 and 10-milligram

start doses.

Finally, the overall recommendation was

unanimous that this should be approved.

With that, we will bring the session to

close. I thank the panel members, the FDA for a

wonderful analysis and certainly to the sponsors

for a beautiful presentation.

Thank you.

DR. ORLOFF: Let me add my thanks to all

involved, FDA reviewers, the sponsor and their

presenters and the committee for a great deal of

good work and worthwhile commentary. Thank you

very much.

\[Whereupon, at 3:30 p.m., the meeting was

adjourned.\]

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