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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