1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

ARTHRITIS ADVISORY COMMITTEE

DAY I

Wednesday, June 2, 2004

8:00 a.m.

ACS Conference Room

5630 Fishers Lane

Rockville, Maryland

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PARTICIPANTS

Allan Gibofsky, M.D., J.D. Chair

Jayne E. Peterson, R.Ph., J.D., Executive Secretary

MEMBERS:

Jennifer J. Anderson, Ph.D.

Joan M. Bathon, M.D.

Dennis W. Boulware, M.D.

John J. Cush, M.D.

J. Michael Finley, D.O.

Steven G. Geis, Ph.D., M.D., Industry

Representative

Gary Stuart Hoffman, M.D.

Wendy W. McBriar, R.N., M.S., C.H.E.S.,

Consumer Representative

SPECIAL GOVERNMENT EMPLOYEE CONSULTANTS (VOTING):

H. James Williams, M.D.

Brian F. Mandell, M.D., Ph.D.

David T. Felson, M.D., M.P.H.

GOVERNMENT EMPLOYEE PARTICIPANT (VOTING):

Marc C. Hochberg, M.D., M.P.H.

GOVERNMENT EMPLOYEE SPEAKER (NON-VOTING):

Robert Terkeltaub, M.D.

FDA

Brian Harvey, M.D., Ph.D.

Sharon Hertz, M.D.

James Witter, M.D., Ph.D.

Lourdes Villalba, M.D.

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C O N T E N T S

Call to Order, Opening Remarks, Introductions,

Allan Gibofsky, M.D., J.D. 5

Conflict of Interest Statement,

Jayne E. Peterson, R.Ph., J.D. 8

Welcome, Brian E. Harvey, M.D., Ph.D., Acting

Director, DAAODP, FDA 12

Uric Acid and Gout, James P. Witter, M.D., Ph.D.,

Medical Team Leader, DAAODP, FDA 16

Gout: An Evolving Problem at a Therapeutic

Crossroads, Robert A. Terkeltaub, M.D., Chief,

VAMC Rheumatology Section, Professor of Medicine

in Residence, University of California,

San Diego 38

Cardiome Pharma, Inc. Presentation:

Introduction, Alan Moore, Ph.D., Executive Vice

President, Clinical Development and Regulatory

Affairs 82

Gout: a Serious Progressive Disease,

Ralph Snyderman, M.D., Duke University

Health System 88

Oxypurinol Efficacy and Safety, Garth Dickinson,

M.D., University of Ottawa 96

OXPL213 Analysis, Robert W. Makuch, Ph.D.,

Yale University 106

Unmet Medical Need/Clinical Experience and

Post-Approval Issues, Leonard Calabrese, D.O.,

Cleveland Clinic Foundation 115

Oxypurinol for Symptomatic Gout in

Allopurinol-Intolerant Patients,

Lourdes Villalba, M.D., Medical Officer,DAAODP, FDA 139

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C O N T E N T S (Continued)

Open Public Hearing:

Edward G. Mihalo 175

Nancy Joseph-Ridge, M.D. 179

Jane T. Osterhaus, Ph.D. 184

Zeb Horowitz, M.D. 188

Walter J. Clifford Statement 193

(Read by Edward G. Mihalo)

Allyn Hamilton 198

Committee Discussions and Questions 200

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P R O C E E D I N G S

Call to Order, Opening Remarks, Introductions

DR. GIBOFSKY: Good morning and welcome to

the first of a two-day meeting of the FDA Arthritis

Advisory Committee. My name is Allan Gibofsky,

from Cornell University Medical College, and it is

my privilege and honor to serve as chair of the

committee.

I would like to begin by welcoming

everyone here, our colleagues, our visitors and our

guests from the public to the first of two days of

what I know will be a very spirited and interesting

discussion focusing on an old disease and new

implications for its therapy in the public good.

I would like to begin by asking the

members of the table to please identify themselves

for the record and for the public who are observing

us, beginning on my far right, Dr. Geis.

DR. GEIS: I am Dr. Steve Geis. I am the

industry representative on the committee. I am a

now retired member of the community and previously

worked in the pharmaceutical industry.

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DR. FINLEY: I am Michael Finley. I am

Associate Professor of Medicine at Western

University College of Osteopathic Medicine, Pacific

and Pomona, California. I am a member of the

committee and a rheumatologist.

DR. CUSH: Jack Cush. I am a

rheumatologist from Presbyterian Hospital in

Dallas.

MS. MCBRIAR: Wendy McBriar, Director of

Arthritis Services at Virtual Health in New Jersey,

consumer rep.

DR. BOULWARE: Dennis Boulware, Professor

of Medicine, University of Alabama at Birmingham,

and I an a rheumatologist.

DR. BATHON: Joan Bathon. I am a

Professor of Medicine at Johns Hopkins University

and a rheumatologist.

DR. MANDELL: Brian Mandell, Vice Chairman

of Medicine at the Cleveland Clinic, Department of

Rheumatology.

DR. WILLIAMS: Jim Williams,

rheumatologist at the University of Utah.

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MS. PETERSON: I am Jayne Peterson. I am

the Acting Executive Secretary of the Advisory

Committee meeting today.

DR. GIBOFSKY: Allan Gibofsky, Professor

of Medicine and Public Health Cornell University

and a rheumatologist.

DR. ANDERSON: Jennifer Anderson, Research

Professor Emeritus of Biostatistics at Boston

University School of Public Health.

DR. HOFFMAN: Gary Hoffman, Cleveland

clinic, rheumatology, Professor of Medicine and

Chairman of Rheumatology.

DR. FELSON: David Felson, Professor of

Medicine at Boston University School of Medicine

and a rheumatologist.

DR. VILLALBA: Lourdes Villalba. I am a

medical officer in the Division of Anti-Inflammatory,

Analgesic and Ophthalmic Drug

Products and I a rheumatologist.

DR. WITTER: Good morning. Jim Witter,

from the FDA.

DR. HERTZ: Good morning. Sharon Hertz, I

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am Deputy Director for this Division of Anti-Inflammatory

and Analgesic Drug Products.

DR. HARVEY: I am Brian Harvey. I am the

Deputy Director of the Office of Drug Evaluation V,

and it is my pleasure to be the Acting Division

Director for this Division.

DR. GIBOFSKY: Thank you, all. Now I

would like to call on Jane Peterson, our Acting

Executive Secretary, to review the conflict of

interest statement. Jayne?

Conflict of Interest Statement

MS. PETERSON: Thank you. I am going to

read the conflict of interest statement now. The

following announcement addresses the issue of

conflict of interest with respect 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 and

information provided by the participants, the

agency has determined that all reported interests

in firms regulated by the Center for Drug

Evaluation and Research present no potential for a

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conflict of interest at this meeting, with the

following exceptions:

Dr. Brian Mandell has been granted a

waiver under 18 USC Section 208(b)(3) for

consulting with a competitor on a general issue.

He receives less than \$10,001 a year. Dr. Allan

Gibofsky has been granted a waiver under 208(b)(3)

for consulting and speaking for a firm that has an

interest in a competitor. He consults and speaks

on matters unrelated to those being discussed at

this meeting. He receives less than \$10,001 a year

for consulting and greater than \$10,000 a year for

speaking. Dr. John Cush has been granted a

208(b)(3) waiver for consulting and speaking for a

competitor on unrelated matters. He receives less

than \$10,001 a year for consulting and less than

\$5,001 a year for speaking. Dr. David Felson has

been granted a 208(b)(3) waiver because a colleague

has a research grant from a competitor to study

gout in general. The grant is less than \$100,000 a

year. Wendy McBriar has been granted a 201(b)(3)

waiver for consulting with a competitor on an

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unrelated matter. She receives less than \$10,001 a

year.

Dr. Robert Terkeltaub has been granted a

limited (208)(b)(1) waiver for consulting with two

competitors. He consults on unrelated matters for

one and on an unrelated matter for the other. He

receives less than \$10,001 a year from each firm.

He also speaks for a competitor on gout and

receives less than \$5,001 a year. Under the terms

of the limited waiver, Dr. Terkeltaub will be

permitted to make a presentation to the committee

and to answer any questions related to his

presentation, however, he is excluded from

participating in the committee\'s discussions.

Lastly, Dr. Marc Hochberg has been granted

a 208(b)(1) waiver for his consulting with two

competitor son unrelated matters. He receives less

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

A copy of these waiver statements may be

obtained by submitting a written request to the

agency\'s Freed of Information Office, Room 12A-30

of the Parklawn Building.

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Lastly, we would also like to note for the

record that Dr. Steven Geis is participating in

this meeting as an industry representative, acting

on behalf of regulated industry.

In the event that the discussions involve

any other products or firms not already on the

agenda for which FDA participants have 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 product they may wish to comment upon. Thank

you. Dr. Gibofsky?

DR. GIBOFSKY: Thank you, Miss Peterson.

We are going to have a very full agenda today with

a number of distinguished speakers making

fascinating presentations. I would also like to

ask our colleagues in the audience to remember that

we do have a time schedule for the open public

hearing at which time, if any of them would like to

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offer any comments on the presentations, they can

feel free to do so. Please schedule them through

the Acting Executive Secretary or through a member

of the FDA staff as we go into our deliberative and

discussion period.

At this point I would like to introduce

once again Dr. Harvey, the Acting Director of the

DAAODP, who will offer us some welcoming remarks

and introduce the first speaker of the program.

Dr. Harvey?

Welcome

DR. HARVEY: Great! Thank you very much

and thank you all for being here. I would like to

say that I am pleased that under my watch the work

of many people, over many years, is coming together

for this two-day panel on the treatment of gout,

both acute and chronic. Of course, you all have

the agenda here and we will be getting to that in

just a second.

I would like to say it is my pleasure to

be the Acting Director of this Division. I am

currently at the Office level as well in the Office

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of Drug Evaluation V. I took over back in November

from Lee Simon so I have some big shoes to fill.

This past fall, when I told my wife that Dr. Simon

was leaving and, I said, going to a better place,

she said, \"oh my goodness, is he sick? Did he

die?\" \"No,\" I said, \"he\'s going back to Harvard.\"

But I am glad to be here.

As we look over the agenda and we see that

we are dealing both with the issues of acute and

chronic gout, in my current position I have the

opportunity, as an outside activity, to still see

patients on weekends as an in-hospital medicine

physician. This past weekend\--you know, federal

holiday, what better way to spend it than working

in a hospital! I actually did see a patient with

an acute attack of gout. I won\'t go into any

details. I don\'t want to violate HCFA, but it

amazed me that in the twenty years since I have

been in medical school the treatment options that

we have for this patient, just past Monday, really

have not changed much. You know, we have the same

basic medications that we had back when I was in

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medical school in the \'80s.

So, I think we really have an opportunity

to here to chart the future and we have the

expertise. We have all the important groups

represented and I think we can really do a lot to

sort of outline future clinical trial designs and

sort of a broad overview but also in some nuts and

bolts ways on the future of clinical trial designs

for both the acute treatment as well as chronic

treatment of gout.

In thinking about it, as part of the

mission statement of the FDA under the FDA

Modernization Act of 1997, affectionately known as

FDAMA, it actually outlines what our mission is,

and it is not only to protect the patients but it

is also to promote patient health, to paraphrase.

I think the two days of this panel meeting really

represent what that is all about.

So, at this time I would like to thank the

committee members, both the permanent members and

the consultants. I would like to thank the

presenters. I would like to thank the industry

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representative and the patient representative for

their perspectives on things. Of course, I mean,

the reason we are all here is because of the

patients. I would like to thank those in the

audience for your attendance today because getting

information out, education, patient awareness,

public awareness is also an important part of that

puzzle as well. So, for those who are going to be

presenting at the open public hearing and those who

are in the audience listening, I think we are all

playing important roles and I would like to thank

you all for being here.

Actually, at this point I would like to

introduce the first presenter, Dr. Jim Witter who

is one of our senior medical officers in the

Division and a team leader. He is going to give

his presentation on uric acid and gout. Dr.

Witter?

DR. GIBOFSKY: While Dr. Witter is coming

to the podium, could I ask the member of the panel

who just joined us to identify himself and

introduce himself for the record, please?

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DR. HOCHBERG: Marc Hochberg, University

of Maryland, Baltimore and the Maryland Veterans

Affairs Healthcare System.

DR. GIBOFSKY: Thank you, Dr. Hochberg.

Dr. Witter?

Uric Acid and Gout

DR. WITTER: Good morning. Thank you for

being here today, taking time out of your busy

schedules to help us with the topic today and

tomorrow, which is an area that is often ignored in

terms of public health, as Dr. Harvey has just

alluded to.

So, what we want to do over the next two

days is to really tap the resources that we have

here and gather input regarding issues that we

should consider as we think about clinical trials

intended to support the development and approval

for drugs that treat gout and/or hyperuricemia.

We will be focusing over the next two days

on both the acute situations and chronic

situations, somewhat of an artificial divide but we

thought it was necessary and was most effective to

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do it that way. My comments will be particularly

towards a chronic setting.

So gout, what is the problem? Well, as I

indicated earlier, it is an important unmet medical

need because it causes both acute and chronic pain.

In certain settings, in certain situations it can

also cause joint and renal damage. There is an

increasing incidence and severity that has been

noted in the literature over the past few years.

Estimates, for example, have it at a little over 8

persons per 100,000 in the U.S. that are affected,

with a male to female ratio of approximately 1:6.

This increase has been commented on, that it is not

related to the overall use of diuretics which is

becoming more prevalent in the population as well.

It appears as though gout is presenting

itself at earlier age. This is particularly true

for males. In females the increase seems to be

mostly in the postmenopausal period. There also

appear to be, and I think we will hear about this

shortly, increases related to obesity, tying into

what has been called the insulin resistance

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syndrome which, again, is something that we will be

hearing more about in a second.

Also as Dr. Harvey had indicated, there

are really not a lot of treatment options that are

available currently. So, one of the outcomes we

are hoping for from this meeting will be that in

the future there will, in fact, be more options.

But to list them, we have for example non-steroidal

anti-inflammatory drugs which, as you know, word at

the level of prostaglandins. We have colchicine

which work at the level of microtubules. This is

available both as an oral and as an intravenous

agent. We have allopurinol which works at the

level as an inhibitor of xanthine oxidase. We also

have probenecid which works at the level of the

renal tubule.

As we then transition from a clinical

trial to look at the data that comes in-house, what

we are interested in ultimately is to write a

label. I would like to spend a little time on

discussing that. Label claims have various legal

and regulatory uses but their primary purpose is to

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inform healthcare providers and patients about the

document that is underlined, both the documented

benefits and risks associated with the product.

These claims are intended to then describe the

clinical benefit and, in fact, once these are

approved, the sponsor can actually promote such

claims. What we hope for in any situation is that

we have as accurate as possible label because this

allows for effective risk management down the road.

We do not at the present time have a

specific guidance document for gout. We do for

many other areas, as you are aware. But if we did,

what should we be thinking through in terms of if

we tried to standardize the language in the labels

for chronic use, for example? Some of the options

may be for treatment of hyperuricemia associated

with gouty flares, gouty arthritis, tophi or renal

calculi.

On the other hand, in an acute situation

or for prophylactic use the label might say for the

short-term treatment of uric acid-induced gout.

I will just take a second to remind

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ourselves then what is some of the language that is

currently available for the various agents that are

approved: Indocin, one of the oldest of the

medicines maybe that is out there. The label under

the indication sections says this is effective in

active stages of acute gouty arthritis.

Benemid or probenecid reads for the

treatment of hyperuricemia associated with gout and

gouty arthritis.

Zyloprim or allopurinol reads the

management of pats with sings and symptoms of

primary and secondary gout, and has in parentheses,

acute attacks, tophi, joint destruction, uric acid

lithiasis, and/or nephropathy. It also notes in

rather bold letters, although I haven\'t bolded it

here, that this is not an innocuous drug and it is

not for asymptomatic hyperuricemia, a topic that I

am sure we will get into today.

As mentioned, also we have colchicine.

This is probably the oldest drug. I believe it was

DESI; it didn\'t go through a formal NDA approval.

It has in its language for the treatment of gout,

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relieving pain of acute attacks or as interval

therapy to prevent acute attacks of gout.

It is almost summertime so I thought it

would be appropriate to talk about the activities

that go on. In the older days of this field it

became clear that the gold standard in terms of

looking at this problem was something that has been

called the urate pool. So, I thought I would just

describe that and discuss that for a second as it

may apply to our situation here today.

In this cartoon we have a mechanism to

fill this pool, and that is the diet. We have a

mechanism to also drain this pool through the

urine. These can be impacted in various ways which

we will be discussing over the next couple of days.

But let\'s take it that we have the pool at a

certain level. What I have drawn here is kind of a

wave which represents the serum uric acid level.

It is intended to be a little bit bumpy because it

is not necessarily static. As every pool does, it

tells you how deep it is. So, I have given you

some numbers here of 10 mg/dl and 6 mg/dl.

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Now, when we have a situation that is

appropriate under perhaps, you know, steady state

conditions\--and this is really a poor man\'s version

of modeling. We have Dr. Meyer Katzper here in the

audience who can talk to you more if you are

interested in modeling and approaching this

situation through modeling, but we have an

equilibrium, let\'s say, with two other compartments

of this pool, the joint and a tophus. It may be

then that under situations of equivalence or when

things are equilibrated that there is a dynamic

interplay between these two, with exchanging in

both ways. But when the uric acid level then

rises, we have a situation that the joint, for

example, fills more rapidly and we have then an

acute attack. As you can see, I have drawn the

arrow going back to the pool to maintain again this

equilibrium.

With a tophus it may not be exactly the

same situation. There may be mechanisms that can

allow this to form but there may not be as

effective mechanisms to allow it to be resorbed,

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and that may be an issue that become important

clinically, especially in clinical trials.

So, as our little friend here is

encouraging us to do, let\'s jump in. In terms of

what we are trying to get at today, it is the issue

of clinical trials and how we should go about

thinking about them. One of the basic and first

questions we would want to ask then, particularly

in a chronic situation, is about the baseline serum

uric acid level.

It is interesting in the sense that the

prevalence of gout has been estimated to be 30

percent when the serum uric acid is 10 mg/dl, but

only 0.6 percent when it is 7 mg/dl and, yet, there

still is in general a poor correlation of serum

uric acid to gouty flares. So, this is something

that we would like you to comment on.

Also, the issue of prior flares at what we

call a target joint, the issue of the number of

flares that have occurred at this joint in order to

get somebody enrolled in a trial, the severity of

the flares at that joint and then how should these

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be diagnosed? Should we require that these all be

diagnosed by crystal analysis for example? Is it

sufficient that a physician makes a diagnosis? Or,

is it even sufficient that the patient self-reports? We

would like your comment on these

topics.

With relationship to tophi, we would like

some comment about how we go about distinguishing,

for example, from nodules that might occur in RA or

nodes that might occur in OA, and the relationship

of size in terms of entry into clinical trial.

Renal status is also something that we

will be talking about over the next couple of days.

So, we would like you to think about the issue of

chronic renal insufficiency and how that should be

factored into any trials.

Regarding exclusion criteria then,

particularly for a chronic situation, we want to

make sure that at a minimum we exclude other

crystal-induced diseases, or that we make sure that

there are no other inflammatory diseases or

infections enrolled. We would like you to consider

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what we should do with renal status, particularly

with use of diuretics; with the issue of co-morbid

diseases, as I mentioned earlier about obesity; and

any thoughts you may have on special populations

such as a transplant population or those with

genetic defects. The latter is probably applies

more to a younger population, as you are all aware.

In terms of efficacy issues then, we would

like some discussion on endpoints and the duration

of these endpoints. One of the questions that we

are going to be discussing today at length, I would

hope, is the issue of whether or not serum uric

acid is a valid surrogate or not. I will be

discussing more about surrogacy in a second.

We also would like to have comment about

the number of gouty attacks, particularly early on

in a chronic study\--how much, how long should we

exclude these kinds of events from the analysis?

If the endpoint happens to be tophi, should we be

thinking in terms of the size or the number?

In other areas of medicine we have given a

lot of thought to the concept of disability and

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quality of life domains so we would like you to

share any thoughts you may have in this area as

well.

Then in terms of duration, how much, how

long should each area of the various trials be?

For example, if one is looking at the endpoint of

serum uric acid, is a trial of 6-12 month duration

sufficient? Whereas, if you are looking at tophi,

if that is the endpoint, do we need to have

something more in the range of 1-2 years?

As I indicated earlier, I would just like

to talk for a bit about what a surrogate is so that

we are on the same page, so to speak, as we go

forward with this area. If you look in the Code of

Federal Regulations under 314.510, Subpart H and it

has been dubbed affectionately the surrogate

approval, it reads as follows: FDA may grant

marketing approval for a new drug product on the

basis of adequate and well-controlled clinical

trials establishing that the drug product has an

effect on a surrogate endpoint that is reasonably

likely, based on epidemiologic, therapeutic,

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pathophysiologic, or other evidence, to predict

clinical benefit or on the basis of an effect on a

clinical endpoint other than survival or

irreversible mortality.

Now, to dig down and drill down just a

little bit more, a definition that we use for a

surrogate endpoint is a surrogate endpoint of a

clinical trial is a laboratory measurement or a

physical sign used as a substitute for a clinically

meaningful endpoint that measures directly how a

patient feels, functions or survives. The idea of

a surrogate then is that changes induced by any

therapy on a surrogate endpoint are expected to

reflect changes in this clinically meaningful

endpoint.

There are some caveats to the Subpart H

approval process. One of those, for example, is

that there is a requirement that the applicant will

study the drug further to verify and describe its

clinical benefit where there is, in fact,

uncertainty of the relationships of the surrogate

to the clinical endpoint, or the observed clinical

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benefit to the ultimate clinical outcome. It is

assumed, for example, that post-marketing studies

will usually be under way, that they will be

adequate and well controlled, and that they must be

carried out with due diligence.

Continuing with caveats a bit later in the

CFR, it notes that the FDA may withdraw approval

following a hearing if some of the following apply:

that a post-marketing clinical study, in fact,

fails to verify the clinical benefit; that the

applicant fails to perform the required post-marketing study

with due diligence; that

promotional materials are false or misleading; or

other evidence demonstrates that the drug product

is not shown to be safe or effective under its

conditions of use.

So, to give you some idea of surrogates

are currently are from an FDA perspective, I have

just listed some here\--blood pressure lowering;

this should say lipid lowering, not lipid lowering

agents; the use of blood sugar levels; bone mineral

density levels and the HIV load. These are some

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examples of currently accepted surrogate endpoints.

So, let me restate my question earlier

then in relationship to serum uric acid levels and

re-ask the question, are these both valid surrogate

endpoints? What I mean by that is when you look

at, for example, a change of serum uric acid

concentration\--let\'s say you go from 10 to 8, is

that a valid surrogate endpoint? Or, is it a valid

surrogate endpoint when one approaches and attains

a selected endpoint, such as 5 mg/dl or 6 mg/dl?

So, we would like some discussion on that point

because it is a very important distinction.

Then, in terms of serum uric acid, we also

would like some discussion about the issue of

precision and, reflecting back to the pool idea,

that is, serum uric acid estimates can change, can

vary, so should we have multiple values done at

multiple times to make sure that we are getting the

best estimates of what is going on?

Looking again at the issue of targeted

versus non-targeted joints, should they be

evaluated together or separately? We would like

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some discussion on that.

Then, if tophus happens to be one of the

endpoints in the trial, what is the best way to go

about looking at that? Is it with some kind of

imaging modality such as an MRI, or is a manual

method sufficient? And, should it be a percent

resolution or should it be a complete resolution?

Some of the design and statistical issues

that we would like comment on are the issue of the

initial titration to minimize flares. I think we

are all aware that in the early period this is a

problem so we would like your comment on this. We

would like you to comment also on the issue of a

placebo control. Should this be, for example,

during some or all of the trial? It gives us the

advantage of looking at superiority to placebo

issues to help us understand the effect sizes for

example. Or, should we be thinking more about an

active control or standard of care control?

Then we could enter into issues of non-inferiority

and that would engender a discussion of

how different can the test compound be from the

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controlling agent. Obviously, the selection of any

kind of active control depends on the drug under

development. If you are looking at something that

works at the level of the kidney, that is different

than if you are looking at an enzyme inhibitor.

We would also like some comment on the

dose ranging that we should be looking at to

achieve various target serum uric acids, and any

comments you may have on the approach. Should we

have, for example, a means approach or a responder

approach, the latter being very important and used

a lot for example in rheumatoid arthritis? Then,

any comment you may have on this concept which is

evolving of a minimal important difference to get

some idea, again, of the clinical benefit.

Co-medications and diet issues,

particularly in a chronic situation, can be very

important and we would like your thoughts about

this. For example, use of low dose aspirin can

have an effect on renal clearance; the use of

colchicine; and then the concomitant use of NSAIDs

or COX-2 agents.

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We would also like you to comment on the

issue of alcohol use and how we should approach

that. For example, is a patient diary a way to go

about that? Then, any thoughts you may have on

restrictions of diet to standardize.

So, the issue always, particularly for

approval, is, you know, how safe is safe? I think

it is particularly important for this topic today

in particular because generally when one goes and

decides that something is going to be employed to

lower uric acid levels, this is for the most part a

lifelong decision. So, the issue we would like you

to discuss today is whether this necessarily has to

be a daily long-term use or can it be intermittent,

and should we approach that.

We would like you to discuss the issues of

co-medications, as I just discussed, for either

gout prophylaxis or treatment. For example, is

there a possibility that a myopathic result could

be worsened if somebody is taking colchicine? We

would like any thoughts you have on special

populations. I had mentioned earlier the issue of

33

chronic renal insufficiency.

Then, comments about whether ICH

guidelines are adequate in this setting. To remind

you what that is, some minimum requirements in

terms of patient exposure that we look for when an

NDA comes in or BLA. In terms of patients then, it

looks something to the range of 300-600 patients

for 6 months, 100 patients for a year and 1500

total. We are generally interested in what will

ultimately be the highest dose.

So, the better that we have clinical

trials designed, the better that we have

information in these clinical trials, the better

decisions can be made at various different levels.

For example, at FDA we evaluate the risks and

benefits for a population. You can see in this

cartoon that the benefits seem to outweigh the

risks. The healthcare provider though also takes

that same information as is translated in the label

and makes a decision for a patient and, again, in

this cartoon it looks as though the benefits are

winning. Then the patient, importantly the most

34

important factor in anything, evaluates the

benefits and risks in terms of their personal

values. In this case, it looks like maybe this

person hasn\'t quite made up their mind but maybe it

isn\'t to their benefit.

So, there is lots to discuss today and

tomorrow and we are looking forward to it. Thank

you.

DR. GIBOFSKY: Thank you, Dr. Witter. One

quick question, if I may, can you give us examples

of agents that have been approved under Subpart H

and also agents that have been withdrawn by the

agency under Subpart H?

DR. HARVEY: Hi, I will jump in\--Brian

Harvey. The easy question is that to my knowledge

nothing has been withdrawn under Subpart H. There

was actually a public hearing a few years back,

under the auspices I think of the oncology group,

where they actually discussed\--Dr. Pasteur? There

was a panel meeting, advisory panel, where these

various issues were discussed and that is a matter

of the public record of what things have been

35

approved under Subpart H, what has been done post-market and

what, if any, actions have been taken by

the agency. So, that is all available publicly

but, to my knowledge, nothing has been withdrawn

under Subpart H.

DR. GIBOFSKY: Dr. Hochberg?

DR. HOCHBERG: Yes, regarding the slide on

current state surrogates, specifically with regard

to bone marrow density just a question, my

understanding is that for a new drug to be approved

it has to demonstrate fracture risk reduction, but

for a new form of a preparation, for instance, of

an already approved drug it can be approved with

comparability with regard to bone marrow density.

Is that correct, or am I incorrect?

DR. HARVEY: Well, I think the specifics

of what other divisions do in their risk/benefit

analysis\--I would refer you to the various guidance

documents and policy documents in those specific

areas, and it is an evolving field and, of course,

those various divisions go to their expert panels

for input as well. So, we are sort of on a

36

parallel track with them. They may be a little bit

ahead, but I think some of those technical nuances

really all are on the FDA web.

But you raise some valid points and during

your discussion there may be some parallels and

sometimes those parallels are valid and sometimes

they are not. Of course, today\'s discussion will

be a general discussion about those gout issues but

with the specifics of gout that may supersede some

of the other areas as well.

DR. GIBOFSKY: Thank you, Dr. Harvey. Are

there any other questions from the panel about the

methodology? We will talk about pathophysiology

throughout the rest of the day. Dr. Geis?

DR. GEIS: Just quickly, is there any

history of a drug being approved based solely on a

surrogate marker without the sponsor collecting any

clinical relevant data?

DR. HARVEY: Brian Harvey, I will keep

jumping in because these really are big picture

questions you are asking and not really specific

for the gout issue. But I think we are all well

37

aware of the public record in the area of HIV

disease and how the approval of drugs in that area

have really been tied not only to clinical outcomes

but also the surrogate of viral load. Of course,

significance is always in the eye of the beholder,

but there really is a huge body of information out

there in the public record on those various areas.

We can look to HIV treatments as one area.

Oncological project is another where they have sort

of led the field of pharmaceutical development

using these surrogate endpoints. Of course, as you

know, there is a huge body of clinical literature

as well as a lot of FDA information, both in

formalized guidance as well as public record from

previous panels. So, it is a good question. I

think it is a good guiding principle but, as

always, significance is in the eye of the beholder.

DR. GIBOFSKY: Thank you, Dr. Harvey. At

this point, if there are no other questions from

the panel regarding Dr. Witter\'s presentation, I

would like to call up Dr. Robert Terkeltaub, who is

Chief of the Veterans Administration Rheumatology

38

Section and Professor of Medicine in Residence at

University of California, San Diego, who will

address us on gout as an evolving problem at a

therapeutic crossroads. Dr. Terkeltaub?

Gout: An Evolving Problem at a

Therapeutic Crossroads

DR. TERKELTAUB: I want to thank Jim for

inviting me and also to thank Brian for providing a

note to my chief of service so I could be excused

from my medical duties. It is a nice break from

that particular service right now.

I am really honored to be here. I am

going to talk about a problem that I have worked on

for many years and that I feel very strongly about

as a major public health problem. Basically, we

are dealing with the prototypical crystal

deposition disease. What you are seeing here, of

course, is an aggressive tophus deposited in the

toe that is destroying underlying connective

tissue.

The issue is partly of the normal

metabolism of uric acid, the normal product of

39

purine metabolism. I am not going to belabor you

with all the steps involved in purine metabolism

but basically xanthine oxidase at the end stages of

purine metabolism generates uric acid and,

obviously, this has been a fruitful drug target and

allopurinol targets this particular enzyme.

We are dealing with a question of balance

and human uric acid balance is pretty precarious

because the size of the total miscible uric pool in

the typical male is a gram to 1200 mg. Our

production and intake of purines balances with our

elimination of purines on a daily basis. So, the

size of what flushes through a uric pool is about

the same size as the uric pool. So, you can see

that either excess purine production or even small

decreases in uric acid elimination will produce

hyperuricemia over time.

Basically, we are dealing with a disease

in which hyperuricemia is only one manifestation.

We have an increase in the total body urate pool

and ultimately the deposition of monosodium urate

crystals and clinical expression in these various

40

forms, including not only arthritic manifestations

but also urolithiasis with not only uric acid but

also calcium oxalate in some patients, and a rare

problem these days in the form of interstitial

nephropathy, most likely because of better control

of not only hypertension but also hyperuricemia.

So, we have a disease in which the

etiology is very well understood vis-a-vis the

monosodium urate crystal being pro-inflammatory,

depositing tophi, and we understand purine

metabolism very well. We have a disease in which

diagnosis and therapy are well developed but often

poorly applied, which is an issue which hasn\'t yet

been discussed but can be, and we have a common

disease in which we have approximately 3-5 million

affected subjects in the United States alone. We

have a high prevalence in certain minority groups

of a disease that is growing in numbers, and a

disease that is evolving clinically due to not only

socioeconomic factors but also iatrogenic factors

that must be considered. So, we have a major

public health problem.

41

If you look at the raw numbers, if you are

dealing with the NIH-IS survey and self-reported

prevalence, you are dealing nearly with a doubling

of the self-reported prevalence of gout between

1969 and 1996. If you are looking at the annual

case incidence in this study from Rochester, you

are dealing with approximately a 50 percent

increase. Now, these epidemiologic data are

subject to limitations in a disease that is

episodic, that is recurrent but, anyway, it appears

from the numbers that the disease is more common.

The reasons for this are complex. One is

almost certainly the increased of longevity of the

population. Sustained serum uric acid elevation

over time times longer time is going to lead to

more gout, in our view. An increase in the

prevalence of hypertension, increased use of

diuretic and aspirin therapy\--and I will show you

our own evidence but basically the epidemiologic

evidence in certain studies argues that increased

diuretic use is a risk factor for more gout.

Dietary trends\--increased obesity and

42

metabolic syndrome, demographic trends in the

United States, improved survival from coronary-artery

disease, congestive heart failure and

diabetes mellitus, and many of the patients who

have stents wouldn\'t be around to get gout in this

day and age, and basically increased end-stage

renal disease and increased survival from this, and

increased transplants as well as the limitations in

the current generation of anti-hyperuricemic drugs.

So, what are the numbers here? If we look

at hypertension alone, there has clearly been more

than a 10 percent rise over the 1990s. If we look

at hypertension treatment patterns, there has been

a major change. I wanted to cite the ALLHAT study

which is a study that was done on 42,000 subjects

in the United States and compared outcomes,

including non-fatal MI and also stroke and CHF, and

the results were interpreted to support the use of

inexpensive thiazides relative to ACE inhibitors,

calcium channel blockers, alpha-adrenergic blockers

for the treatment of mild to moderate hypertension.

So, this study has been quite influential.

43

For example, in my own healthcare system,

the VA, VISN-22 which is the desert Southwest VA,

we have reviewed a population of approximately a

quarter of a million and we have a very special

group of patients, obviously, about 90 percent

male. We are dealing also with about 40 percent of

the population in our VISN-22 population being 65

years of age or older. But in this 5-year period

that was reviewed, very generously by a pharmacist,

aspirin use was up approximately 10 percent.

Furosemide use was up approximately 4.7 percent and

hydrochlorothiazide use in the cost conscious VA

system was up 74 percent. Allopurinol was up 12

percent during this time period. This is in line

with national prescribing figures for allopurinol,

as I understand them. So, we are dealing with a

situation where the hydrochlorothiazide use is

exploding in the very cost conscious environment of

the VA and most likely cost conscious environments

elsewhere, which means almost everywhere.

I saw the movie \"Supersize\" this weekend

and I was very happy to see that hyperuricemia and

44

gout made it onto the radar screen of that movie.

Basically, Time magazine has covered this topic in

depth and this week\'s cover issue is on obesity as

well. We are very clear on the fact that obesity

is a big problem in America and increased body mass

index alone is associated with hyperuricemia but

insulin resistance clearly compounds the problem.

The principal features of the metabolic

syndrome are legion and they include hyperuricemia.

Basically, what we are dealing with is a number of

renal effects pure to insulin resistance alone and

then compounded by hypertension. But basically

hyperuricemia stimulates increased renal sodium

reabsorption and uric reabsorption as well. There

is an additional mild effect in renal ammonium

excretion associated with insulin resistance that

promotes an acid milieu. Basically, we realize

that the relative risk of urolithiasis in men who

carry a diagnosis of gout is at least 2. So, the

problems of insulin resistance certainly compound

hyperuricemia, and up to 20 percent of patients

with gout have a history of kidney stones and this

45

may also contribute to morbidity with gout.

So, what we are dealing with along the

lines of epidemiology is a problem that goes up

with aging. The age-adjusted prevalence of

metabolic syndrome rises steadily so that up to 35-40

percent of individuals greater than age 70 meet

the criteria for metabolic syndrome. You can see

when you look along ethnic lines and if you look at

men and women that the most rapidly growing ethnic

subpopulation, Hispanic subpopulation has the

highest age-adjusted prevalence of metabolic

syndrome.

Basically, what are the diet and alcohol

related trends that may be influencing the

incidence of gout? Choi has done a very impressive

large study in male health professionals aged 40-75, almost

50,000 people followed up for 12 years,

and 730 of these people developed new gout in this

time frame. So, these were people who did not have

gout at the beginning of the study. The relative

risk of incident gout was 1.41 in the highest

quintile for meat consumption; 1.51 for seafood;

46

and then almost half for dairy product consumption,

low fat dairy products; and any form of alcohol,

2.53. But when it was broken down to beer, 1.75

for 5 beers a week to 1 beer daily; 2.51 for 2 or

more beers daily; and then spirits, 1.15; and wine,

1.04.

Now, you know, I view these data for dairy

products as maybe reflecting ascertainment bias

given that the people in the highest quintiles for

dairy product consumption in this study who had the

low incident gout risk were consuming 2 glasses of

skim milk per day or consuming a fair amount of

non-fat yoghurt per day and there has to be a

difference between people who drink a lot of skim

milk and other people.

Basically in terms of the multivariate

analysis, these differences were not immediately

obvious when hypertension diuretic use was factored

in and I think people recognize that there has to

be a difference between a beer drinker and a wine

drinker. So, I think there is also room for

interpretation of ascertainment bias in these data,

47

but these are very compelling studies that are

going to have to be addressed.

Basically, we have another issue in that

several popular diets that are high in fat and also

high in meat and seafood consumption and low in

carbohydrates have the potential to promote

hyperuricemia by ketosis and high meat and seafood

intake. I won\'t mention these diets by name

because I don\'t have to, everybody knows the names,

and people realize that there is a low carb frenzy

in this country that also has very high economic

impact.

The economic impact also is something that

is reflected in beer intake. If you look at the

alcohol consumption numbers in the United States,

alcohol consumption actually has been somewhat flat

or slightly declining over the last 20 years,

however, beer consumption\--and beer of course

contains the very readily absorbed di-tetra purine

guanosine\--beer consumption is the segment of the

alcohol market that has risen steadily. This is

the very hot-selling lite beer de jour, Michelob

48

Ultra, but basically what we are dealing with is

lite beer and low carb beers have markedly

increased in their market share and in their

overall consumption in this country and have been

promoted as health-conscious options. They

certainly are a bit lower in carbohydrates but they

are not lower in guanosine content. So, this is a

factor in terms of the public health problem that

has to be considered as well if one takes into

consideration the data on incident gout that I

mentioned.

The other issue in terms of the

epidemiology of this disease is that the classic

profile of a gout patient, including several people

in this room, I am sure, is illustrated here. We

are dealing with a disease in which the classic

profile is changing. There are many more females

that are involved and there appears to be a rise in

the 70-80 age group as well.

Gout in older women is increasing in

prevalence partly because of increased longevity.

That is the assumption, but also it is linked to

49

very common use of thiazide diuretics and currently

the numbers are that more than 25 percent of

individuals greater than the age of 65 are using

diuretics, mainly thiazides, and also linked to

chronic renal insufficiency and congestive heart

failure. Attending on internal medicine this

month, we realize that about 20 percent of our

admissions at the VA are for congestive heart

failure exacerbations. So, we are seeing a lot of

gout and CHF and a lot of gout in older women with

CHF at the University of California, San Diego and

at the VA in San Diego.

Will decreased use of estrogens ultimately

raise uric acid and gout prevalence? Estrogens are

uricosuric and estrogens are becoming somewhat more

out of favor given the recent data in press, and

there is a question about whether serum uric acid

and gout prevalence will rise in women because of

the anticipated decrease in the use of estrogens.

Also, gout in women can be different

clinically and this has to be factored into the

design and interpretation of clinical trials. As

50

opposed to the classic podagra, the gout in women

can masquerade as inflammatory hand osteoarthritis.

Uric crystals love to deposit in osteoarthritic

joints, most likely because of solubility issues

with respect to altered matrix integrity in the

osteoarthritic joint. Gout, presenting as tophi is

a common presentation in older women with

tophaceous gout.

What about renal insufficiency? Renal

insufficiency promotes hyperuricemia and gout

clearly, and makes management of hyperuricemia and

gouty arthritis substantially more difficult. What

about the numbers? Well, we know that in 1987

there were 156 new cases per million of end-stage

renal disease. In 1997 there were 303 new cases

per million. And the prevalence of end-stage renal

disease is 4-5 times higher in African Americans

and in the elderly.

In terms of transplants, the number of

transplants has nearly doubled also in the same

time frame, partly because of improved transplant

donor networks and protocols. In addition to renal

51

transplants, we see more heart, liver and pancreas

transplants as well. We realize that transplants

and cyclosporine-induced gout is an emerging

problem in gout. In terms of cyclosporine-induced

gout in the setting of major organ transplantation,

hyperuricemia is present in more than 80 percent of

the cyclosporine-treated patients in this setting.

Mean serum urate levels are often spectacularly

high and the gout prevalence is between 8-13

percent by 3 years, typically more than 10 percent,

and a lot of this depends also on the cyclosporine

dosing which often is higher for the cardiac

transplant patients.

So, what is going to happen with

transplant-associated gout, associated with

cyclosporine use clinically is that we see rapidly

expanding tophi refractory to therapy. There may

be some sort of extrarenal cyclosporine effect that

may affect urate solubility. This appears to be

beyond the pale in terms of the rapid expansion of

tophi relative to the urate levels, and the

arthritis may be refractory to steroids and other

52

anti-inflammatory therapeutics. We often see

patients with transplants who are on 10 mg, 15 mg

of prednisone a day and still come in with

polyarticular gout. Cyclosporine, of course, is

nephropathic and induces chronic renal

insufficiency, and cyclosporine and chronic renal

insufficiency can contribute to serious adverse

drug interactions. One of these is called

colchicine myopathy which may present very quickly

after oral colchicine initiation in this setting.

I have some good news. Cyclosporine and

gout will be a brief footnote in the long history

of gout. At the VA we looked at cyclosporine

prescriptions over the same time frame and we

looked at thiazide prescriptions and they were down

by approximately a third, and the prescriptions of

tacrolimus and sirolimus were way up in that time

frame. People are realizing that there are

alternatives with less hyperuricemic toxicity but

also principally less nephropathic toxicity. These

are being currently optimized for transplant

medicine and the cyclosporine alternatives include

53

tacrolimus. Another inhibitor of calcineurin like

cyclosporine, however, is marginally better for

hyperuricemia as well as hypertension and

nephropathy in my view, in reviewing the

literature, as well as sirolimus and mycophenolate.

Combination regimens with lower dose cyclosporines,

such as 25 mg twice a day of cyclosporine

microemulsion are clinically efficacious.

Eventually, clearly, advances in therapeutic new

intolerance will render cyclosporine fully obsolete

and we will get rid of any iatrogenic issue.

So, what we have here is the situation of

increased gout prevalence and increased clinical

complexity of gout in the United States. It is

very hard to measure gout clinical complexity but

from talking to my colleagues everywhere, people

generally agree that gout is more difficult to

manage; there is more tophaceous gout and the

problem of gout and chronic renal insufficiency

makes the disease more complex. This has clearly

evolved over the last 20 years and has accelerated

over the last 10 years. What we have is a \"perfect

54

storm\" so we have to try to deal with the numbers.

The IMS data for the rise in allopurinol-treated

patients is impressive. It is 25 percent

in this time frame. Basically, it is not because

of improved medical education, I am pretty certain.

The other problem is that refractory

tophaceous disease has not disappeared and appears

to be making a comeback, as I have mentioned.

Refractory gout is painful, destructive and

incapacitating, as you can see by these erosive

changes illustrated here. Joint erosions can

progress even with effective therapy that lowers

serum urate. Once you deposit urate crystals in a

joint, the crystals are very pro-inflammatory and

can promote matrix metalloprotease expression and

nitric oxide production and promote cartilage

destruction and connective tissue destruction. So,

we have to deal with this issue.

There are some larger issues here.

Sustained hyperuricemia, even in a very predisposed

population such as in Kinma, in Taiwan is

associated with incident gout in only 20 percent by

55

5 years, and we need to determine what factors,

other than serum urate, account for the clinical

crystal deposition as gout, and what are the

natural urate crystallization regulators. Can they

be harnessed in therapy? In the meantime, we are

dealing with measures to reduce inflammation and

reduce serum urate.

The extent of effectiveness of the non-

pharmacologic mechanisms directed to urate

metabolism, such as diet, alcohol, lifestyle and

anti-hypertension therapy, are not exactly clear,

to be kind. Clearly, the existing generation of

anti-hyperuricemics is antiquated and needs

improvement.

What about diet because we are the FDA

and, you know, this is the Food and Drug

Administration? What about diet? Traditional low

purine diets that have been used in the past more

commonly are unpalatable and they only reduce serum

urate by up to 1 mg/dl or 15 percent about the max.

What about roles of other diets? There is a

customized 40/30/30 diet with caloric reduction.

56

It was a small open study with 13 patients. These

were all overweight or obese men with gout. When

you tailor a weight reduction diet for insulin

resistance and look at 16 weeks and achieve a lot

of weight loss\--at 16 weeks you are achieving about

1 lb per week weight loss, which is pretty

impressive\--urate levels decrease by 18 percent

with a 40/30/30 carb/protein/fat scheme. Caloric

restriction is the key here, but also replacing

refined carbohydrates with complex ones and

replacing saturated fat with monounsaturates and

olive oil, nuts and seafood. So, this argues that

some diets that are the same overall scheme as some

of the popular best-selling book low carb diets may

actually be okay for gout. So, not all low carb

diets may be adverse. The effects of diet and

alcohol modification on hyperuricemia and on gouty

arthritis itself need a careful controlled long-term study,

including the very popular low carb

diets right now which really have not been studied

at all in a controlled way, although there is a

hell of a lot of publicity on the Internet about

57

gout being worsened by several low carb diets.

In terms of the uric acid lowering

pharmaceuticals that are currently in use,

allopurinol, in terms of serum uric acid lowering

therapeutics, is dominating of course the use in

the U.S. market. Oxypurinol has been available on

a compassionate use basis and, of course, is a

major active metabolite of allopurinol.

Allopurinol has limitations and that is

why I think we are assembled here in part. Rash in

approximately 2 percent of subjects; intolerance,

and we will go over what defines intolerance, in up

to 10 percent of subjects. Major allopurinol

hypersensitivity is rare, approximately 100 cases

reported, but has a 20 percent mortality rate.

Oxypurinol cross-reactivity puts some limits on

alternative use. Then tophus reduction with

allopurinol is often slow so that raises another

bunch of issues because the optimum dosing of

allopurinol relative to label and relative to the

published guidelines for avoiding allopurinol

hypersensitivity syndrome is controversial. The

58

optimum dosing of allopurinol is particularly

controversial with chronic renal insufficiency.

If you look at drugs that are used to

promote uricosuria, probenecid is the most common

one used in the United States.

Sulfinpyrazone use is problematic.

Sulfinpyrazone is related to phenylbutazone and can

cause some of the same problems that phenylbutazone

causes hematologically at the level of the GI tract

and also the anti-platelet effect of sulfinpyrazone

can lead to adverse drug interactions.

Benzbromarone is not FDA approved and

hepatotoxicity can be serious with this drug and

has led to withdrawal from the marketplace in

France, as an example.

Losartan and fenofibrate are among drugs\--every

two or three years there is some other drug

that is discovered to be mildly uricosuric. The

current ones are losartan and fenofibrate which

have relatively weak effects and questionable

extent of synergy with current drugs but can get in

the way in terms of clinical trial evaluation. We

59

are dealing with drugs that typically will reduce

serum urate on their own by 8-10 percent and up to

15 percent or 20 percent.

Can we develop pharmacogenomic approaches

to optimize uric lowering therapy based on

spectacular recent science in terms of

understanding renal urate handling? The classic

disorder of renal urate excretion in primary gout

is such that if you look at the gouty patients\'

urinary uric acid relative to their plasma uric

acid at a level of, let\'s say, 8 mg percent of

plasma uric acid, the patients with gout will have

approximately half as much urinary uric acid put

out. Given that three-quarters of patients are

under-excreters, this is quite significant.

Basically, the most compelling development

in this field is the identification of this

molecule, URAT1, as the major mediator of proximal

tubule urate reabsorption in the kidney. URAT1 is

a member of the organic anion transporter family.

It has this multiple pass transmembrane protein

structure and it functions as an anion exchanger,

60

more active for organic anions than for inorganic

anions. It is thought that the anions in the

intracellular side of the proximal tubule cells are

triggering urate reabsorption by this exchange

mechanism. I only conceptualize that it goes

through the middle of this molecule. We are not

sure if that is the case.

URAT1 is to be contrasted with another

molecule, UAT, uric acid transporter, which is

actually a urate anion channeler and urate here is

thought to go through the middle of this membrane

protein, and this membrane protein is not a member

of the organic anion transport family. This is not

an exchange process. It is driven

electrochemically and is subject to regulation by a

number of mediators, including sugars, including

adenosine and including oxonic acid.

When one looks at what happens at the

level of the proximal tubule in the nephron, URAT1

sits on the luminal side and promotes urate

reabsorption, triggered by a number of organic

anions. Lactate includes some of the ketoacids

61

generated by burning fat with some of the popular

low carb diets, and includes metabolites of the

anti-tuberculous drug pyrazinamide and basically it

is inhibited at the luminal side by benzbromarone,

probenecid, losartan, sulfinpyrazone and actually

also high doses of salicylates. Urate reabsorption

into the circulation at the basolateral membrane is

mediated probably by UAT and by another member of

the organic anion transporter family.

It is important to remember that urate

movement at the proximal tubule is bidirectional so

there is a secretory pathway that probably has a

maximal capacity of about a quarter of that of the

reabsorption capacity in the proximal tubule.

There are potential mediators of this process that

are identified and we believe that UAT and a

sodium-dependent phosphate co-transporter and

another member of the OAT family carry out this

process.

So, we have a situation where the organic

anion transporter family, also known as the SLC-22

family, is highly regulated, and gender is one of

62

the factors that regulates expression of these

proteins, as well as aging, development,

hypertension, hyperuricemia itself, renal failure

and the effects of certain drugs. So, we have a

situation where we know that almost all the serum

urate is filtered; that there is bidirectional

urate movement at the proximal tubule,

predominantly reabsorption but also secretion; and

that reabsorption is finely tuned, probably by

other OAT family members but also possibly by the

sodium hydrogen ion anti-porter whose activity goes

up in metabolic syndrome and normally only 10

percent of the filter load is increased.

But there has been a very important

development pharmacogenomically in that subjects

who have defective URAT1 expression\--and these

subjects have a disorder that is known as

idiopathic familial renal hypouricemia and now it

is no longer idiopathic because it has been linked

to URAT1 mutations\--these subjects do not

significantly alter their uric clearance if they

are given probenecid, pyrazinamide or

63

benzbromarone. So, we realize that URAT1 is an

interesting pharmacogenomic issue and also a very

compelling specific drug target.

The problem though with uricosurics is

that the effectiveness of altered uricosurics is

limited by chronic renal insufficiency. There is

an element of uric over-production in 10-25 percent

of patients with primary gout and that imparts

urolithiasis risk, and there are other side effects

and drug interactions at play.

So, there has been a lot of interest in

the potential therapeutic role of uricase for

patients with gout. Uricase oxidizes uric acid to

a much more soluble compound, lantoin, generating

hydrogen peroxide. Basically, it is a critical

means in lower species to convert the relatively

insoluble uric acid to highly soluble lantoin. If

you look at the serum urate of a normal mouse, it

is 1 mg percent but the uricase knockout mouse,

generated by Kowski and his coworkers, developed

serum uric levels of 10 mg percent and get

uricosuric tubulopathy and will die unless they are

64

given a xanthine oxidase inhibitor.

So, uricase gene silencing in human beings

renders human uric balance quite precarious because

urate is insoluble in vitro at about 7 mg percent.

So, recombinant uricase is actually FDA approved

for short-term, single course use in pediatric

hematologic malignancies, and produces profound

acute urate lowering, typically 10-15 mg/dl down to

1-2 mg/dl, and has been effective in preliminary

studies short-term in gout patients. It has the

potential for accelerated tophus dissolution in

terms of months.

The issues with recombinant uricase are

that it is highly immunogenic, being

transcriptionally silent in human beings, which

limits both its safety and efficacy, and some of

the side effects seen over years of use of non-recombinant

uricase in Europe and recombinant

uricase worldwide have been respiratory distress

and anaphylaxis. Then the hydrogen peroxide

generation limits safety in specific patients.

There are concerns about cell transformation in

65

vitro because of the hydrogen peroxide generation,

and in vivo hemolysis in patients with G6PD

deficiency and hemoglobinemia have been reported.

In patients with tumor lysis syndrome,

obviously a complicated thing to treat,

neutropenia, sepsis, hypocalcemia and

hypophosphatemia all have been reported in a few

percent of patients treated with rasburicase for

tumor lysis syndrome and alkalinization of the

urine can promote these electrolyte disturbance, it

appears, in association with uricase use. The drug

is potentially lethal and is not orally

bioavailable, and clearly clinical trials of less

immunogenic forms are of interest and are in

progress for gout.

I would propose that the therapeutic niche

for concomitant uricase in gout to be limited term

treatment, with a long-lasting recombinant uricase

preparation of low antigenicity for the reduction

of macroscopic destructive tophus burden in highly

selected patients.

What about asymptomatic hyperuricemia in

66

vascular disease? This topic has received a lot of

press of late and it is important because there are

many more patients with asymptomatic hyperuricemia

than there are with gout. The press is from a fair

amount of really good literature that tells you

that serum urate levels correlate with untreated

blood pressure in children between the age of 6-18,

and that hyperuricemia is a very powerful predictor

of atherosclerosis and arterial occlusive events

and adverse outcome in primary vascular diseases.

A striking example is a 12-fold higher

cardiac death rate in stroke survivors at 5 years,

adjusted for renal function in those who are

hyperuricemic. And, I am not saying that we should

ignore such data. And, serum urate may be\--may be

and independent risk factor for atherosclerosis and

certain atherosclerotic vaso-occlusive

complications.

Basically, there is a large amount of

recent data that I have used, quite controversial,

that suggests direct linkage of hyperuricemia to

vascular smooth muscle dysfunction, increased

67

sodium reabsorption, hypertension, glomerulopathy,

cyclosporine nephropathy and chronic renal

insufficiency itself. The question has arisen is

markedly elevated normal serum urate in a human

being, such as the levels of 7, 8 that we see in a

human being, a beneficial or a harmful result of

evolutionary human uricase gene silencing?

Basically, if we are dealing with human

evolution, we realize that a key step was the

evolution of hominids to more upright posture and,

at about the same time uricase became silenced at

the transcriptional level in higher primates. What

has been done to address the issue of whether a

normal serum uric acid level of approximately 6 mg

percent or mildly elevated hyperuricemia, 7-8 mg

percent, in a human being may directly cause

vascular disease is to use a specific model where

oxonic acid, a uricase inhibitor, is given to rats.

The serum urate rises from approximately 1 mg

percent to 2-3 mg percent.

What happens in this model, which has been

developed primarily by Richard Johnson and

68

colleagues, is that the increased hyperuricemia

that is seen in this model correlates with

activation of the renin angiotensin system, more

sodium resorption, higher blood pressure, and there

is also some in vitro data that adding uric acid to

cultured cells will induce the proliferation of

these cells, induce COX-2, induce certain

chemokines and induce MAP kinase activation.

What are the flaws in interpreting this

model that we can bring up? One of the flaws is

that oxonic acid directly inhibits the function of

UAT which has an oxynate binding site. So, it has

the potential to promote intracellular retention of

urate and other solutes in cells of the

vasculature.

Then, the other limitation is that direct

uric acid infusion in healthy human adults, which

has been performed by Waring et al., did not alter

any hemodynamic or endothelial functions. Urate

handling as well as serum urate levels may differ

markedly in the rat and human and the cellular

effects of soluble uric acid in vitro are subject

69

to artifacts because of potential micro

crystallization.

Basically, what we have is a situation

where uric acid in humans has good effects in that

it is an antioxidant. It is 8 times more abundant

in human serum than ascorbate. Human ascorbate

production actually was lost in evolution in

parallel with uricase. And, uric acid actually

appears to protect against oxidant induced in

hypoxic brain and heart injury. Again, under

certain conditions uric acid may be a pro-oxidant

and soluble uric acid may turn on genes. So, the

good and the bad effects of hyperuricemia may

depend on the nature of the host, much as it

depends on the culture conditions in vitro.

Some food for thought before I talk about

surrogate endpoints for a couple of minutes\--gout

is evolving clinically and clearly refractory gout

and gout are rising. Better preventative efforts

population-wide are needed, including patient

education. Development of new treatments has not

kept pace with medical needs. Typical asymptomatic

70

hyperuricemia has not been proven to directly cause

renal or vascular disease, and gout and

hyperuricemia are well understood in management but

not well enough.

So, we have a situation in which we have

uric acid, indicated by these stars, that is

physiologically kept in solution below about 7 mg

percent, and physiologically eliminated, and when

we have imbalance in either purine production or

intake or urate elimination, we get supersaturation

and tissues are supersaturated. Tophi are formed.

Our goal is to either apply dietary

measures, anti-oxidase inhibitors, uricosurics or

uricase in some circumstances to allow these tophi

to resorb. We will ultimately then see less

intense and less frequent gouty arthritis and we

will have less supersaturation in tissues that will

promote tophus resorption.

How do we do this in somebody who is,

let\'s say, hypersensitive to allopurinol or truly

allopurinol intolerant? Our options really are

limited. You know, the ideal situation is no

71

chronic renal insufficiency and urate under-excretion where

we can apply a uricosuric.

Allopurinol desensitization is a 50/50 proposition

in terms of success and oxypurinol is probably

better than that, as we will hear today from what I

have read. If a patient is allopurinol tolerant

and has refractory gout and we are not putting them

into a clinical trial, do we push allopurinol? Can

we combine allopurinol with probenecid? There is

very little data on these situations.

So, the issues regarding clinically

meaningful and optimal surrogate endpoints for

clinical trials include the synergistic role of

combinations of anti-hyperuricemic therapies. The

problem is that precipitation of gouty inflammation

of urolithiasis are side effects of effective serum

urate lowering, and allopurinol and uricosuric

intolerance and failure need firm definitions. For

example, too low or too high allopurinol dosing

does not constitute treatment failure.

Other issues are that serum urate is going

to be less informative than measuring the total

72

body urate pool, and I would propose that newer

fluorescent labeling protocols be developed by

targeted grants, I would hope, to add better

measures of body urate pool. And, we need to have

better simple measures of uric acid production

levels and uric acid excretion levels in the kidney

than what we have today.

How consistent is urate and how many times

to measure has been raised as an issue. Then,

there is the question of the percent drop in serum

level versus the absolute drop in serum level. Do

you drop to a target \"sweet spot\" level of, for

example, 5-6 mg percent? Or, do you try to go

slower or lower?

What do you do in terms of patients with

chronic renal failure? I think it is important to

point out that creatinine clearance is going to be

a superior measure than serum creatinine to

interpret results, particularly in elderly patients

in these trials.

Serum urate in disease phenotype becomes

an issue because of the effects of gender that I

73

have mentioned; the effects of diabetes itself; as

well as chronic renal insufficiency and CHF; as

well as all the other things patients are doing.

I bring up a few questions. One study of

a calcium channel blocker compared to beta blocker

for hypertension management in patients with

cyclosporine use showed that the calcium channel

blocker lowered serum urate by 10 percent, whereas

the beta blocker lowered urate by zero. So,

sometimes the way that hypertension is managed

alone can have an impact on hyperuricemia depending

on the clinical setting.

Then, the anti-inflammatory properties,

albeit somewhat low grade for statins, also may be

higher grade for PPAR gamma agonist anti-diabetic

agents may have to be factored into interpretation

of clinical trials with modification of gout.

Then, in terms of tophus size, we need

validation of parameters for size change and manual

measurement of superficial tophi, and the threshold

for change by radiographic assessment, such as MRI,

is really not defined, and we don\'t know whether to

74

measure both grossly uninvolved and involved joints

because with the uninvolved joints, if you aspirate

some of those joint fluids, you may see urate

crystals and that is not really rare.

Then the issue of needing quality of life

instruments and assessing the frequency and

severity of gouty attacks; the length of attacks;

the number of anti-inflammatories consumed\--would

those be useful parameters to look at? And, which

shorter and longer specific times points to look

at? We need instruments like an ACR-50 or a HAQ

optimized for gout. The one that we are trying to

play with at UCSD is a drop in serum urate in

milligrams per deciliter, divided by the fraction

of gouty attacks per month between 3-12 months

relative to baseline, and then trying to come up

with some numbers for validating that particular

instrument. It is a very poor instrument but it is

a start.

Then, the role of pharmacogenomics and

optimal clinical trials of anti-hyperuricemic

drugs\--is there a role for identifying patients who

75

have SNPs and URAT1 and other OATs, and UAT? Is it

important to identify hyperuricemia that is

possibly mediated by dysregulated tissue UAT as

distinct from a true increase in the body urate

pool? I think, as we will see maybe 5 or 10 years

from now, this will be a significant issue.

I want to think about identifying also

altered pyrimidine metabolism in non-immune

allopurinol toxicity as another pharmacogenomic

tool. Finally, identifying subject redox stress

may also help in pointing out who is more

susceptible to uricase toxicity.

So, thank you for your attention.

DR. GIBOFSKY: Thank you, Dr. Terkeltaub

for an excellent presentation. I would like to

take a moment, if there are any specific questions

from the panel for Dr. Terkeltaub before we go on.

Dr. Cush?

DR. CUSH: You implied that we should be

looking at tophi as a measurable outcome. Can you

inform us as to the evidence that reducing tophi

improves quality of life and subsequent attacks?

76

You were sort of talking about tophi as sort of a

measurable pool or tangible measurable pool of

total body urate as opposed to just going to serum

uric acid levels. I mean, we would look to prevent

gout by looking at attacks. Clinically we usually

don\'t target tophi because when they show up they

have so many tophi\--we would like them to go away

and we take that as a goal but we often don\'t see

that in practice.

DR. TERKELTAUB: That is a good question.

I think, you know, with modern imaging techniques

we may be able to see in a better manner

microscopic tophi in the synovium, and we will be

able to better understand how to reduce the urate

crystal burden at the joint level. Basically,

given that the disease includes connective tissue

destruction mediated by those deposits, I think

that is a large issue.

The problem here is that as you decrease

tophus size you may get more symptoms vis-a-vis

attacks of gouty inflammation. Whether it has been

studied adequately, clearly not. There have bee so

77

few clinical studies over the last 20 years.

DR. GIBOFSKY: Bob, you pointed out that

erosions can progress even with effective lowering

of serum uric acid. To what extent then ought we

to be considering imaging as an outcome measure in

clinical trials for any anti-gout agent?

DR. TERKELTAUB: Yes, thank you for the

question. I was referring to a study by Bob

Wartman and Geraldine McCarthy about 12 years ago.

Basically, they looked at the first toe and they

saw, with gross radiographs, that there was

progression over a fairly long time period with

adequate serum urate lowering and, basically I

think there is a lot of room for optimizing a

better trial today using more modern imaging

techniques.

DR. GIBOFSKY: Dr. Bathon?

DR. BATHON: I was just remembering one of

the NSAIDs, etodolac, clinical trials that caused

significant lowering of uric acid. I was wondering

if it could be clinically efficacious.

DR. TERKELTAUB: Several of the NSAIDs can

78

modulate urate excretion, not huge effects. I

think they become more important to consider when

you are trying to understand what the etiology of

the hyperuricemia is, other than aspirin, of

course, and salicylates.

DR. GIBOFSKY: Dr. Felson?

DR. FELSON: Bob, that was a wonderful

comprehensive talk. If we are going to consider

uric acid as a surrogate marker, it seems that we

need to know a little bit more about the

repeatability of measurement, the sources of

variability over time of the day and from day to

day. When I was in medical school I learned that

there were a number of different assay techniques

for uric acid and that they weren\'t necessarily

consistent in their results. Could you start with

that? Is that still true or is there some real

consistency across various labs in given specimens

and what levels they produce?

DR. TERKELTAUB: The standard measure

right now for serum uric measurements is adopted

nationwide. There used to be a uricase method that

79

was used in some labs and a distinct method used in

other labs. In terms of the reproducibility

between patients, there haven\'t been terrific

studies done. Most of the studies have been done

on a population level to construct bell curves and

there haven\'t been terrific studies done vis-a-vis

individual patients.

DR. FELSON: Does uric acid vary by time

of day in a given person? It was hard to use

cholesterol, for example, as an outcome measure in

trials because there was a lot of variability from

hour to hour and from day to day in people; blood

pressure similarly. That is one of the reasons why

we get multiple measures of blood pressure to make

a diagnosis. Is there a similar variability in

uric acid?

DR. TERKELTAUB: Not to my knowledge.

DR. FELSON: But it sounds like it hasn\'t

been well studied.

DR. TERKELTAUB: It hasn\'t been well

studied since I have been a rheumatologist. That

is the problem.

80

DR. GIBOFSKY: Any other questions? Dr.

Hoffman?

DR. HOFFMAN: The comments about the

Wartman study and continuing erosive changes after

normalization of uric acid, is that in part because

all gout is really micro tophaceous, it is the

product of so many years of laying down sodium

urate and normalization of serum uric acid is

really the curve towards gradual resorption of

tophi. So, when we look at clinical endpoints

using imaging, it really wouldn\'t be so meaningful

to look at radiographic endpoints for something

less than perhaps a year after the accrual of

increasing micro tophi within the joint was aborted

and resorption had meaningfully progressed.

DR. TERKELTAUB: Yes, I think we believe

that serum urate is the large tip of a large

iceberg, and I would challenge clinical

investigators to look at more sensitive methods of

imaging the synovium of joints to look at small

tophi and to try to calculate the size changes.

DR. GIBOFSKY: Dr. Hochberg?

81

DR. HOCHBERG: If we are going to look at

the recurrence of acute attacks of gout, let\'s say,

in someone who has had prior gout and has

hyperuricemia to assess the efficacy of a long-term

therapy, would one do that in a patient who would

be entered into a trial who is on background

colchicine therapy, which is at least accepted

therapy to reduce the risk of recurrence of acute

attacks, and see whether an agent in addition to

colchicine was better than placebo in addition to

colchicine? Or, would you consider doing this

instead of colchicine?

DR. TERKELTAUB: I would consider doing it

with colchicine pretty much. I think that

basically the most common side effect we see with

allopurinol, for example, is precipitation of acute

gouty attacks. The data are not great for this. I

mean, we know that the gouty attacks are usually

precipitated most frequently in the first couple of

months of allopurinol treatment, but with

uricosuric treatment, which is titrated by

everybody out there more steadily, there is are few

82

gouty attacks precipitated. Has that been studied

in a really good quantitative clinical trial? No,

but I think people who are experienced clinicians

know that is probably the truth. I don\'t think

that withdrawal of colchicine would be a good thing

in terms of constructing clinical trials.

DR. GIBOFSKY: Thank you, Dr. Terkeltaub.

I think at this point we will move to the next

portion of the program which is a presentation by

Cardiome Pharma, Inc. We will ask Dr. Moore, the

Executive Vice President for Clinical Development

and Regulatory Affairs of Cardiome Pharma Corp. to

introduce the program and the speakers for that

portion. Dr. Moore?

Cardiome Pharma, Inc.

Introduction

DR. MOORE: Well, good morning, ladies and

gentlemen. We are here to talk about oxypurinol

for gout. I am Alan Moore and I am the Executive

VP for Clinical Development and Regulatory Affairs

of Cardiome Pharma.

My role here basically is three-fold. I

83

am going to give you a very brief introduction to

Cardiome Pharma. Then I want to talk about the

regulatory history of oxypurinol because it is

really quite extensive, as I am sure you know, and

finally talk about the concepts of the agenda and

the agenda itself.

First of all, let me start with Cardiome

Pharma. We are an R&D company that is based in

Vancouver, Canada. We focus on cardiovascular drug

development. As I am sure you are aware, there is

a large component of anti-inflammatory in

cardiovascular so, consequently, we have frequent

interactions with both FDA\'s cardiorenal and anti-

inflammatory drug divisions as well.

Let me talk about oxypurinol regulatory

history. In 1966 Burroughs Wellcome filed an IND

for the compassionate use program for oxypurinol.

The reason was that in 1963 Burroughs Wellcome had

marketed allopurinol and had quickly observed

allopurinol-intolerant patients. Consequently, in

\'66 this compassionate use program started, which

was designed to provide oxypurinol for allopurinol-

84

intolerant patients.

In 1996 ILEX acquired the IND for the use

of oxypurinol, and in 1998 the drug received an

orphan drug designation. As you will hear later,

this is a very small population of patients that we

are talking about.

In 1999 the pivotal study OXPL213 was

initiated, and you will hear a lot more about that

later on this morning. In 2002, Cardiome Pharma

acquired the IND for this drug and we filed the NDA

on December 23 of 2003 which is, of course, part of

the reason that we are here today.

Dr. Witter had talked about Subpart H and,

as I said, the way the majority of patients who

received this drug was by compassionate use. So,

let me talk about the benefits of Subpart H

approval, which we have been talking about

extensively today with the FDA, versus the current

compassionate use program.

First of all, Subpart H approval provides

patient education; provides restrictive patient

enrollment criteria; provides a patient registry;

85

provides physician education and training; provides

collection of safety data and fewer patients lost

to follow-up. Of course, the converse is true of

the compassionate use program.

So, the proposed indication that we are

looking for oxypurinol is\--let me read it,

oxypurinol is indicated to treat hyperuricemia in

patients with symptomatic gout who are intolerant

to allopurinol and have failed either rechallenge

or desensitization with allopurinol. To be clear

then, this is a doubly intolerant patient

population, and what we are talking about here are

people who have not just failed allopurinol once

but have also failed twice because they failed

either a rechallenge or a desensitization, again,

making the population that much smaller than what

we have been talking about before.

Now, what does oxypurinol provide for

these allopurinol-intolerant gout patients? Well,

it addresses an important unmet medical need. We

have already heard from Dr. Terkeltaub that

allopurinol-intolerant patients have very limited

86

options and, clearly, oxypurinol provides an

option. Secondly, oxypurinol has demonstrated good

clinical efficacy, and we will talk about that

later on in the presentation. Next, it is well

tolerated in the majority of allopurinol-intolerant

patients. Not to emphasize the point here, but the

patients we are talking about are 100 percent

intolerant to allopurinol; they simply cannot take

it, whereas, 70 percent of them can take

oxypurinol, and we will talk about that later as

well. Finally, as Dr. Witter mentioned, under

Subpart H there will be additional safety and

efficacy issues addressed, first by the Subpart H

risk management program but, secondly, by a Phase 4

study, that we will also talk about later in some

detail, that is currently under way in our hands

that talks about clinical outcome and compares that

with serum uric acid as well.

So, let me introduce the speakers and

topics for today. First of all, with have Dr.

Ralph Snyderman, from Duke University, who will be

talking about gout as a serious progressive

87

disease. Secondly, we will have Dr. Garth

Dickinson, from the University of Ottawa, who will

be talking about oxypurinol efficacy and safety.

Thirdly, we have Dr. Robert Makuch, from Yale

University, who will be talking about OXPL213

analysis, and this is our key pivotal study.

Finally, Dr. Leonard Calabrese, from the Cleveland

Clinic, will be talking about his clinical

experience and post-approval issues with

oxypurinol. So, thank you for your attention. Dr.

Snyderman?

Gout: a Serious Progressive Disease

DR. SNYDERMAN: Thank you, Alan. I would

like to thank the FDA and the Arthritis Advisory

Committee for giving us the option to talk but,

more importantly, for recognizing an important

serious, progressive metabolic disease which, as we

have heard from Dr. Terkeltaub\--one of the best

presentations I have heard in a long time\--this is

a problem that is not only with us, it is going to

be increasing as we go ahead, and it is an

important clinical problem.

88

Gout is probably one of the best described

and understood and characterized diseases virtually

in all the history of medicine, having been written

about by Hippocrates and his colleagues; being

discussed by Galain with a description of a tophus;

Garret, in 1844, beginning the revolution in

medical understanding of the metabolic basis of

disease; the development of uricosuric agents in

1950; and the development of allopurinol in the

very early \'60s.

Now, given the fact that gout is a serious

metabolic disease for which there are a number of

treatments, I also feel it has been badly under-recognized,

the degree of the clinical problem that

it is. As I was hearing Dr. Terkeltaub talking, it

is almost the Rodney Dangerfield of rheumatology

diseases. It doesn\'t seem to get the respect that

it deserves.

I actually started at Duke in the

rheumatology division at the time that we had Jim

Weingarten, Bill Kelly, Ed Holmes, Wayne Rundells

who was in the hematology division, and Durham, as

89

many of you know, was a hotbed of moonshine, white

whiskey, and we had an incredible prevalence of

gout and it was very well studied.

Very recently, on an NPR show, public

radio in Durham, from the People\'s Pharmacy I heard

a physician say that gout was no longer a medical

problem, that it was so easily treated physicians

don\'t even think about it anymore. Just having

completed rounds at Duke doing my rheumatology

turn, I can tell you that this is a very prevalent

disease. Just seeing the patients that we are

seeing at Duke, I would agree with Dr. Terkeltaub,

not only is it common, not only is it prevalent but

the patients are much more complicated and usually

are admitted not because of their gout but because

of other serious diseases, but what is bothering

them the most, even though they may be dying from

something else, is their problem with chronic

tophaceous gout.

So, gout is a serious metabolic disease.

In its untreated form it is chronic, progressive

and debilitating. It is the most common form of

90

inflammatory arthritis in men over 40, and we are

seeing it more and more in women. Many patients

with gout have renal insufficiency, with primary or

secondary but we suspect a substantial amount is

primary. We have also heard, and there is very

good epidemiological data, both from the Rochester

studies and in Taiwan, that gout is increasing

dramatically over the last few decades. It is

occurring at a much earlier age. It is increasing

in frequency even independent of other medications\--primary

gout is increasing in frequency and it is

increasing in women. So, we need to deal with it.

This clearly is a problem.

The stages of gout are well described.

The first attack is usually following substantial

periods of hyperuricemia. I think the discussion

of whether or not there are developments of micro

tophi in certain joints, such as the first MTP, is

a very interesting question but we certainly know

from direct experiments that one does not need a

micro tophus, given the elegant studies of Dan

McCarthy and P. Phelps injecting monosodium urate

91

crystals directly in their joint and getting a very

hardy gouty attack. So, I think that is an

interesting question but, nonetheless, acute

recurring gout followed in some by inter-critical

period and then chronic tophaceous gout. What

differentiates these individuals is certainly a

matter of great interest.

I think one of the reasons gout has been

to some degree not given the respect that it truly

deserves is the fact that it has been associated

with conditions that people can bring on

themselves, at least seemingly so. This has been

called the disease of kings. I was interested to

hear that white wine doesn\'t increase gouty attacks

but maybe port wine does and individuals eating

sweetbreads and various other things. So, this was

called the disease of kings and many cartoons show

the obese individual, obviously wealthy, being

carried about by others with a swollen big toe.

But that is not the story of gout as we

are seeing it. We are seeing it as a debilitating

disease that causes a great deal of joint

92

destruction and the tophi, while difficult to

remove, what I would say is that tophi themselves

are debilitating in individuals with large tophi.

There is a lot of weight and bulk to carry around

and many people suffer from this.

As any rheumatologist knows, the way we

used to challenge ourselves sometimes at rounds is

where have you not seen a tophus? Tophi could

develop virtually anywhere and they certainly

develop in the kidney and many people with

prolonged hyperuricemia develop urate nephropathy.

Pathogenesis has already been described elegantly.

Again, this is a disease in which we know so much

and, yet, there are things that we still don\'t

know. Whether the monosodium urate crystal

provides a surface for complement activation or

other mechanisms of inflammation, nonetheless, it

is very pro-inflammatory in most individuals.

The management of gout has been very well

described. I will just say briefly that we are

often focused on treating the acute gouty attack,

whether it is monoarticular or oligo- or

93

polyarticular. But in individuals in Duke Hospital

this is sometimes the greatest problem by far that

a patient is facing, no matter what their other

disease is.

We are virtually never able to use

colchicine. As much as I have used it as a

rheumatologist, I can tell you when somebody is in

the hospital there is always a good reason that you

cannot use colchicine. NSAIDs which work extremely

well also. It seems as though most of the patients

that we have, have a creatinine that is higher than

what we would like to see in somebody using Indocin

or some other nonsteroidal. Corticosteroids\--at

least I see it all the time with the house staff

and it amazes me sometimes that the first-line drug

of choice seems to be the use of corticosteroids,

whether intra-articular or systemic.

The chronic treatment of gout to actually

affect the metabolic cause for development of

monosodium urate crystals is, as we heard,

primarily uricosuric agents, xanthine oxidase

inhibitors, uricase still being looked upon

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experimentally, with the most common utilization

being allopurinol. I remember quite well when the

compassionate clearance became available for

oxypurinol, and I can tell you that for physicians

having to do this is burdensome, very hard to

develop follow-up and very rarely used even though

many clinicians would want to use oxypurinol, in my

opinion.

So, the therapeutic goals in gout\--we need

to decrease the frequency of attacks, the severity

of attacks but what we really want to do is

decrease the continued deposition of monosodium

urate crystals; decrease the frequency of gouty

attacks, tophi, urate nephropathies and renal

colic, and there are a number of different forms of

renal diseases associated with gout.

The major point I want to make, other than

that gout is under-appreciated as a national

problem which is going to be getting worse and it

affects a segment of the population that seem to

have the least options available to them. So, I

believe it is a matter of justice as well to give

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this problem the attention it deserves.

The figure I have is 2.5 million. Dr.

Terkeltaub had 3-5 million. Clearly, this is a

large number of people. As best as we can tell,

roughly 1 million prescriptions of allopurinol are

made each year. There are up to 40,000 individuals

who, for one reason or another, cannot take

allopurinol. The data that will be presented by

others today is that within this population there

are going to be, let\'s say, up to 14,000

individuals whose condition could be satisfactorily

treated with oxypurinol. That is the argument that

will be made by the people at Cardiome.

I would just like to put this a bit into

perspective. If we look at the individuals who

then potentially could be treated effectively with

oxypurinol, we have allopurinol-intolerant gout

patients that have already failed desensitization

and are likely to be affected well by oxypurinol,

you are talking about a serious disease. We think

an awful lot about cystic fibrosis, as we should,

hemophilia, Gaucher\'s and others. I applaud the

96

FDA and the Arthritis Advisory Committee for

focusing specifically on those unfortunate

individuals that have chronic gout that have no

other option open to them. Thank you very much.

The next speaker is Dr. Garth Dickinson,

from the University of Ottawa, who is going to talk

about oxypurinol efficacy and safety.

Oxypurinol Efficacy and Safety

DR. DICKINSON: Thank you, Dr. Snyderman

and good morning, everyone.

In discussing the efficacy and safety of

oxypurinol I would like to focus on two main

trials. The first is the pivotal trial OXPL213 and

the second is the compassionate use program which

is called CUP3362-01. OXPL213 was an open-label,

single-arm, multicenter trial that enrolled 79

patients. The trial duration was 14 weeks.

Everyone enrolled in the trial had mild to moderate

allopurinol intolerance. Everyone enrolled in the

trial had relatively normal renal function. Their

creatinine had to be less than 2.

The primary efficacy endpoint for the

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trial was a serum uric acid reduction of 2 mg/dl.

Oxypurinol was dosed in a graded fashion, starting

with 100 mg per day for the first week, 200 mg per

day for the second, 300 mg per day for the third

week. So, gradual titration in dose. Once a

reduction of 2 mg/dl was achieved in serum uric

acid there was no further dose escalation.

What were the results? You can see that

the patients started off with a mean serum uric

acid of 10.11 so they had significant hyperuricemia

and they were all symptomatic patients. In the

efficacy intent-to-treat population, as defined by

the protocol, of 77 individuals the mean reduction

was 1.90. This was just short of the primary

efficacy endpoint of 2 mg/dl. However, this

reduction was highly statistically significant

compared outcome to the baseline number, at a level

of p less than 0.0001. In the completer

population, the 54 individuals who were able to

complete the 14-week trial, the reduction in serum

uric acid was naturally higher. It was 2.32 mg/dl.

In addition, we looked at perhaps a more

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clinically relevant endpoint, and that was what was

the number of patients whose serum uric acid

actually fell into the normal range, and we found

that in the total efficacy intent-to-treat

population 38 percent dropped into the normal

range. In the population that completed the trial,

50 percent of these individuals had their serum

uric acid reduced into the normal range.

The compassionate use program is not a

clinical trial. It started in 1966 as a result of

a need for patients who could not tolerate

allopurinol. Since that time there have been 533

patients enrolled in that trial. And, 533 patients

represents probably over 5 percent of the

allopurinol-intolerant population that this drug is

intended for so this represents a large component

of the allopurinol-intolerant patient population.

This was a real-world study and 38 percent

of our patients had renal failure as defined by a

creatinine of 2 or greater. Many of these patients

are transplant patients. The average dose that the

patients took at 1 year was 372 mg and there was a

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fairly wide dose range, from 100-1800 mg per day.

One patient in particular took 1600 mg of

oxypurinol daily for 8 years without any

difficulties whatsoever.

The problem with adverse reactions with

oxypurinol tends to be more idiosyncratic rather

than dose related. The average duration of

treatment with oxypurinol is 3.2 years, with 22

years being the maximum that any one individual has

been on the drug, and there are currently 162

patients taking oxypurinol in this compassionate

use program and in the one that followed the 213

trial.

Looking at longer-term serum uric acid

endpoints, you see that at 1 year in both the

extension to the 213 trial\--these were patients who

were able to continue oxypurinol treatment after

completing the 213 trial\--and those in the

compassionate use program, their serum uric acid

fell by about 2.9 mg/dl. This compares to about 3

mg/dl which occurs in patients who are given long-term

allopurinol therapy at 300 mg per day, again,

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a highly statistically significant reduction.

Gout flares have been referred to already

a few times this morning, and they are a problem

when you are trying to measure the effectiveness of

any particular uric acid lowering therapy. In the

213 trial we had 24 gout flares experienced by 12

patients. So, our rate of flares was about 16

percent, which compares very closely to what is

experienced with allopurinol, the rate being quoted

as somewhere between 10-24 percent. So, treatment

with oxypurinol seems to mobilize uric acid and may

be associated with gout flares, just as is the case

with allopurinol.

In concluding about the efficacy of

oxypurinol, there is no question that oxypurinol is

effective in reducing serum uric acid in

allopurinol-intolerant patients. The magnitude of

the serum uric acid reductions are quite comparable

to those seen with allopurinol.

Let\'s move on now to safety. In

discussing safety I will be speaking again about

two trials, OXPL213 and the compassionate use

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program. The safety issues relate primarily to the

30 percent of patients who cannot take oxypurinol,

100 percent of these patients cannot take

allopurinol. They are all allopurinol-intolerant.

Seventy percent can tolerate oxypurinol but 30

percent can\'t.

When you look at the adverse events that

occurred in trial 213, if you look over to the

column on the right side you will see that of the

oxypurinol-related events there were 30 events

considered to be related to oxypurinol and 21 of

these resulted in discontinuation of the drug.

There were no serious adverse events due to

oxypurinol. There was 1 death in the trial

unrelated\--due to cancer of the pancreas. There

were no life-threatening adverse events due to

oxypurinol. There were 3 severe adverse events.

Two of these were severe skin rashes and one was a

significant elevation in liver function tests.

When we look at the adverse events that

prompted oxypurinol discontinuation, you can see a

recurring word here, dermatologic, dermatologic.

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The vast majority of adverse events with oxypurinol

are skin rash, just as is seen with allopurinol.

The other thing that you see here is that

of these 21 patients that had to stop oxypurinol in

the trial, 19 of them had exactly the same reaction

to oxypurinol as they had with allopurinol. So, in

any one individual it is quite predictable what

kind of adverse event you are likely to come up

with.

The final point here is that it is not

just skin rashes. There are other things that can

occur, there are other adverse events. These

typically are clinically silent so it could be

myelosuppression, thrombocytopenia or it could be

elevation in liver function tests. So, it is

important that patients who are started on

oxypurinol be carefully monitored both clinically

and by laboratory evaluation.

In terms of the adverse events that caused

discontinuation of oxypurinol, they occurred early

and 71 percent of them occurred in the first week,

while they are on 100 mg per day. They are

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predictable. In any individual, if they are going

to have an adverse event, there is a 90 percent

chance it will be the same event they had with

allopurinol. So, if they had a rash you watch for

a rash. If they had liver function problems on

allopurinol you watch for liver function problems.

Ninety percent of them were mild or moderate and

all of the adverse events were entirely reversible.

Remember, in this trial we did not enroll anybody

who had had a severe reaction to allopurinol.

These are mild or moderate allopurinol reactions.

When we look at the compassionate use

program, we see that there are many more serious

adverse events. This is an elderly population with

multiple co-morbidities. Importantly though, look

again over at the column on your right side. Since

1966, investigators using oxypurinol have never

reported a serious adverse event related to

oxypurinol. That is a pretty astounding safety

record. There have been no life-threatening

adverse events reported either. Over 1500 years of

patient dosing are included here.

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Let\'s turn now and look at hepatic adverse

events. In the 213 trial 6 patients had hepatic

adverse events to allopurinol who were enrolled in

the trial. Of these, 2 had the same type of mild

liver function abnormalities to oxypurinol. In the

compassionate use program we identified 20 patients

who had had liver function abnormalities on

allopurinol. When they took oxypurinol, 6 of them

again had the same type of liver function

abnormalities and had to be withdrawn. The

consistency here is that still about 33 percent of

individuals were having the same type of reactions;

30 percent of individuals who can\'t take

allopurinol also can\'t take oxypurinol.

When we look at this from a slightly

different angle and we look at all the hepatic

adverse events that occurred in the 213 trial or in

the years of the patients who continued on

oxypurinol, we found 6 episodes of hepatic

dysfunction. Two of these were considered to be

probably related to oxypurinol and in both those

instances the patient had experienced abnormal

105

liver functions while taking allopurinol. So,

these patients dropped out. One dropped out early

in the trial and one completed the trial but

dropped out after the end of the trial and didn\'t

continue on. All of the other hepatic

abnormalities that occurred in these patients were

considered unrelated to oxypurinol therapy by the

principal investigators. In three of the four

cases oxypurinol was continued for prolonged

periods and no further adverse events occurred.

So, for safety conclusions for oxypurinol,

70 percent of patients who are allopurinol-intolerant can

tolerate oxypurinol. The adverse

events that do occur with oxypurinol occur early.

They are predictable. They are reversible. There

is risk of hepatic toxicity and it is important

that any patient who is started on oxypurinol be

followed and managed in an appropriately structured

clinical environment. There has been no evidence

of significant harm with oxypurinol. There have

been no drug-related serious adverse events

reported with oxypurinol. So, in this population

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who are 100 percent allopurinol-intolerant, in this

population oxypurinol is much safer than

allopurinol.

Thank you. I would like to now introduce

Robert Makuch, from Yale University, who will look

at a statistical analysis of the 213 study. Thank

you.

OXPL213 Analysis

DR. MAKUCH: Good morning. I am here to

discuss the analysis of the pivotal trial for

oxypurinol, OXPL213. I would like to take a step

back just for a minute and summarize my recent

involvement in this effort. This included my

review of numerous documents, including the pivotal

study data, the study protocol, the analysis plan

and related documents. Based on my independent

assessment, there were certain limitations to the

study that included inconsistencies or

incompleteness of various efficacy endpoint

definitions in the analyses.

This led me to propose, prior to looking

at any of the data, alternative endpoints and

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analytic methods. What I would like to do this

morning is review for you these alternatives with

two goals in mind. The first is to provide you

with additional information that may be useful in

your discussion today regarding guidelines for

chronic gout studies. Secondly, to help you

understand more fully the results from this pivotal

trial.

To review briefly, for the primary

efficacy objective for this pivotal study the goal

was to demonstrate the efficacy of oxypurinol in

lowering serum uric acid by at least 2 mg/dl after

14 weeks of its administration to symptomatic

hyperuricemic patients who have developed an

intolerance to allopurinol. This primary objective

was operationalized by defining the primary

efficacy endpoint as follows: One would consider

the mean of the 3 baseline assessments and from

that, for each subject, subtract the mean of the

assessments made at weeks 12, 13 and 14, or for

those subjects who did not have values at these

time points we would then consider the last

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available assessment that would then be used for

the analysis.

This endpoint definition, as you can see,

is somewhat inconsistent in the sense that we used

the average of 3 values for patients at their

treatment termination for those who did make it to

the end of the study and we only used one value for

those who discontinued early. We will return to

this issue later.

I would like to just review for you

briefly the patients that will comprise the basis

for my analysis. There were initially 79 subjects

enrolled who took at least 1 dose. On the other

hand, there were 2 subjects for whom there were no

post-baseline serum uric acid values available.

They were discontinued for reasons unrelated to

study drug and so, per the protocol, the ITT or

intent-to-treat efficacy population then becomes 77

subjects. Of the 77 subjects, of those who

completed 14 weeks of they, we had a total of 54

subjects. The remainder discontinued early with 23

such subjects meeting that particular criterion.

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Of those 23, there were 8, in fact, who had no

post-baseline serum uric acid values.

So, my analyses then will focus on two

groups. One will be the original ITT per protocol

population of 77 subjects. The other will be the

77 minus the 8 subjects who did not have post-baseline, or

69 subjects then who had at least 1

post-baseline SUA value. The reason, in part, is

that this often is used as the intent-to-treat

population in other studies.

To focus just for a minute on the 8

subjects who did not have a post-baseline SUA who

were unable to tolerate oxypurinol, we note in the

analysis that they were originally assigned a SUA

change value of zero. Clearly, this would

compromise the ability to detect a SUA reduction of

greater than or equal to 2.0 since we have 8

subjects of the 77 having a value imputed of zero.

This is not an optimal statistical approach for two

reasons. One, for these 8 patients we are imputing

a value of zero. More generally though, the change

value doesn\'t take into account all the data that

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were collected on these patients. In fact, the

data were collected on these patients not only at

baseline and at weeks 12, 13 and 14 but, in

addition, we had data collected as well at week 6

and at week 9. So, in fact, we have a good set of

information available on all subjects as they

proceeded through their entire treatment course.

What I would like to then do is to just

briefly describe some of the alternative endpoints

that I considered prior to looking at the data, as

well as an additional analysis that I thought would

be meaningful in terms of getting a fuller

appreciation for these data. The alternative

endpoints included the proportion reverting to a

normal SUA level, and you have already heard Dr.

Dickinson present the results for that. The second

alternative endpoint is to consider the baseline

average for all the subjects but just minus the

last value. So, what we are then doing here is

applying a consistent definition to all the

subjects. Namely, we are going to take the last

value for all the subjects as opposed to taking

111

several values for some subjects and taking just

the last value for other subjects, as was done in

the original protocol and the original analysis

plan.

Secondly, I will also present the

regression analysis which takes into account all

the data. The reason I find this to be very useful

and perhaps the preferred method is that it does

use all the data in the full intent-to-treat

population of 77 subjects and, secondly, we do not

impute any data.

To summarize the results of this analysis,

again, we have the 77 intent-to-treat for the

population and here we are looking at the change

from average baseline to just the last value.

Therefore, upon the reduction in the SUA we get a

slightly different result than what was presented

to you earlier because it was based on somewhat

different data in terms of some patients\--3 values

for some patients and other patients just 1 value.

Here we are taking just the last value for all the

subjects and then you do get a reduction of 1.95

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with a confidence interval as seen and, again, a

highly statistically significant reduction in the

SUA values between baseline and week 24.

The second analysis includes all those for

whom we had at least 1 post-baseline SUA value, the

69 subjects. For that group we then get a

reduction in the SUA value of 2.12, again with the

corresponding confidence interval as you can see,

again a highly statistically significant reduction

in the SUA values over time associated with

oxypurinol. Clearly, the mean value then does

exceed 2.0.

The best way I think to look at these data

is with a regression analysis since it uses all the

data for all the patients, with no data imputation.

At Yale I guess we call this the spaghetti plot.

It looks sort of like you threw spaghetti on the

graph but essentially this is all the data that we

have and, as you can see, it does point out the

information that we have at week 6, week 9, 12, 13

and 14 which are the values at which measurements

were taken, as well as all the information for all

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the subjects.

The dark line is the regression line that

we will describe next. One point though is to note

that there is a market decline between baseline and

week 6 and then that levels out from week 6 out to

week 14. This is actually quite consistent with

the dose escalation scheme that was used in the

study, in which the doses were increased up until

the week 6 period and then modifications were made

for those who did not achieve a 2.0 mg/dl

reduction. So, in some sense, this trial was dosed

in a way that was titrated towards a reduction of

2.0, which I think has to be considered when

looking at the results at the end of the study

which, again, are around 2.0.

So, in the regression analysis, just to

describe it, we did a linear regression with both

linear and quadratic terms. When one applies it to

the data that we saw in the previous slide, at week

14 there is a mean drop of 2.37 mg/dl in the serum

uric acid level. Moreover, the 95 percent

confidence limit ranges from the low of 2.06 to

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2.67. So, not only is the average drop in excess

of 2.0 but also the lower 95 percent confidence

limit for this mean also exceeds 2.0.

So, the conclusions are that using and

considering alternate endpoint analyses, whether we

look at the N of 77, which is the full intent-to-treat

population in which we have, for the last

value analysis, a value of 1.95 being the mean

drop, or the 69 subjects, all of whom have at least

1 post-baseline SUA value\--again, an intent-to-treat

population often defined in protocols, or

whether we look at the regression analysis which

uses all 77 full intent-to-treat population per the

protocol and in which we have a significant drop

and you saw the confidence interval earlier which,

again, is in excess of 2.0, clearly all the

analyses show a highly statistically significant

reduction in the serum uric acid values.

In my opinion, future studies then should

consider at least regression analysis since they do

look at all the data for all patients with no data

imputation. Admittedly,; the current study, as

115

designed and analyzed originally, did not meet the

primary endpoint of a 2.0 or greater decrease.

However, these results should be considered in the

context of these alternative analyses, the dosing

schedule used in this particular study\--you will

hear more about this, and you have heard a little

bit already, that a restrictive Subpart H risk

management program is being proposed, and that a

Phase 4 study has been designed to address

limitations of this current pivotal study.

Thank you. The next speaker will be Dr.

Calabrese who will discuss clinical experience and

post-approval issues.

Unmet Medical Need/Clinical Experience

and Post-Approval Issues

DR. CALABRESE: Good morning, Mr.

Chairman, members of the committee and members of

the FDA and guests, it is my charge to talk about

some practical clinical issues with oxypurinol. I

would like to start by saying that Dr. Terkeltaub

and Dr. Snyderman have already elegantly described

gout as a disease not only of antiquity but a

116

disease where there is considerable morbidity and

mortality. I like to tell house staff and students

that for the vast majority of cases of gout, it is

a very, very treatable disease, eminently

treatable, but for a small percentage of patients,

and a percentage that I think is increasing, as

previously described, with multiple co-morbidities,

particularly those with drug intolerance given the

few drugs that we have available, it is really a

complex situation.

One of the more particularly vexing

problems for clinicians is when we face patients

who are allopurinol-intolerant, particularly those

with high urate loads, chronic tophaceous gout

which is so often complicated by mild renal

insufficiency, leaving only two pathways to deal

with these patients. One is to pursue allopurinol.

One could rechallenge. One could subject them to

desensitization technique, which is complex and

laborious, not universally available and one that

is flawed given the sizeable number of patients who

will fail desensitization. Oxypurinol for this

117

population is the only option, and I will talk a

little bit about the experience with it, which will

actually treat the underlying metabolic disorder.

Otherwise, we are relegated to a treatment

path if symptomatic and supportive care. Yes, we

can reduce the number of gouty attacks. We can

reduce morbidity. We do nothing to affect the

metabolic problem that belies the disorder and to

forestall end-organ damage from this infiltrative,

destructive and inflammatory disease.

Now, at the Cleveland Clinic we have a

sizeable experience with oxypurinol. I reviewed

this in anticipation of this meeting and I was

surprised to find out that my experience with this

drug goes back over 20 years. It seems just like

the other day that I started putting patients on

this. Sixteen patients, including 13 in the

compassionate use and 3 in the pivotal trial, and

consistent with the data that was just presented,

of these patients, 2 were intolerant and had mild

cutaneous reactions and were withdrawn. The

remaining patients were treated from approximately

118

a month to over 10 years.

I would just like to share with you three

vignettes of patients that I currently have on

long-term oxypurinol, just to give you a flavor of

how I have come to understand this drug and utilize

it in my armamentarium of treating this disease.

One is a patient I have treated for a

number of years who had increasingly frequent gouty

attacks, intolerant to allopurinol, mild renal

insufficiency, and he has been totally controlled

on oxypurinol and has been gout-free for a number

of years.

The second patient I think is familiar to

all of the rheumatologists in this room. This is

an elderly woman who had a successful renal

transplant. She also has draining tophi. She is

highly allopurinol intolerant, and she is on long-term

calcineurin antagonist with cyclosporine that

maintains her creatinine in the mid-2s. I have had

her on oxy at a dose of about 300-400 mg a day and

she has been gout-free and has been experiencing

regression of her tophi over the past few years.

119

The final case is really instructive to me

and has meant a lot to me, and I want to share this

vignette in just a slight amount of detail. This

is a patient JH. He is a very robust, well-traveled civil

engineer who, in the early \'90s,

became increasingly debilitated by gouty attacks,

increasing in frequency, tophaceous, and he had

reached a point where he had enlarging tophi,

including one on his foot, very similar to the one

Dr. Terkeltaub showed that graphic picture of. It

involved the toe, complexly involved the web space,

had eroded through the skin, was chronically

draining, was a site of recurrent cellulitis.

He was treated by a fine internist in

Cleveland who knew that this guy was an allopurinol

candidate and needed allopurinol, and he treated

him and he rashed. He also has a creatinine of

about 2.5. Knowing that he had no other options,

he retreated him and he rashed again. Knowing the

desperation of this individual with this

progressive course, he actually instituted low dose

graded desensitization, and with each gradation of

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dose Mr. JH had progressively more severe rashes

and intolerance. He ultimately was referred to me.

I entered him on compassionate use and

escalated his oxy up to 400 mg a day under the

cover of colchicine. I can tell you the experience

summarily. One, this man has never had another

attack of gout in over a decade. Number two, his

tophi have either regressed; some have disappeared

but the largest ones are still there but totally

healed over. There is no doubt\--you don\'t need a

statistical instrument to assess his quality of

life.

Now, having seen this patient every three

months, giving him this drug over the years, we

have become friends and I talked to him about

coming to this hearing today. He kind of

sheepishly told me, he said, I want you to tell

them. He said because when I first came to see

you\--you know, he had been engineering at all these

large dam projects, a really kind of a manly guy\--he said, I

was depressed; I was nearly suicidal\--because he was looking

at a transmetatarsal

121

amputation. It is a vignette but meaningful to me.

So, based upon this experience and

utilizing this drug with some comfort, you know, I

am trying to make a case that I think that

risk/benefit is favorable but there are still

outstanding issues with this drug clearly. One, it

would be highly desirable to obtain clinical data

from a study, a meaningful clinical endpoint. And,

should it reach regulatory approval, I would want

to see a system in place that limits access to this

to appropriate patients, used in a wise manner by

knowledgeable physicians.

I believe there are two programs here,

including this Phase 4 trial that was alluded to

and the risk management program that I would just

like to briefly describe in closing.

The Phase 4 protocol, which is just

getting under way, was crafted with consultation

with the FDA, and this is a 2-year randomized,

placebo-controlled trial of oxy in 240 patients.

The primary endpoint of this study will be

reduction in gouty attacks. Patients have to have

122

at least 6 attacks during a calendar year coming

into the study. It will also assess reduction in

tophi. There are quality of life measures and

serum uric acid reduction.

I think all of us would agree that if this

study were completed it would provide meaningful

information about some issues that we just don\'t

have at the present time, correlating clinical

outcomes to serum uric acid.

In addition, the risk management program I

think is critical. What has been proposed is that

this drug would be distributed by a centralized

pharmacy and there would be a physician education

program that would ensure a knowledge base before

being able to write for this. This would be web-based.

There would also be a resource of patients

to help them understand their disease and its

treatment.

Once a patient has met the criteria for

going into the study, a form would be

electronically transmitted and this would be

verified before dispensing drug. I think most

123

importantly, this type of risk management system

would allow the tracking of outcomes and ongoing

analysis of AEs.

So, overall when I consider risk/benefit

in this, first of all, I think that efficacy-wise

in my mind\--I know that this drug works and it

clearly reduces serum uric acid. I am impressed

with its safety, recognizing the gravity of

allopurinol hypersensitivity states. These are

rare cases that were referred to but you don\'t have

to see more than one case of true hypersensitivity

syndrome to be humbled by this.

One of the points I would like to make is

that in patients who have been enrolled in this,

mild to moderate, which means patients with true

hypersensitivity syndrome, Stevens-Johnson and TEM,

are not candidates for this. There has been no

upgrading of toxicity in the entire oxy experience.

In other words, if you have a mild to moderate rash

with allopurinol you get a mild to moderate rash

and there has never been single case of

hypersensitivity syndrome, Steven-Johnson or TEM,

124

reported. So, I think this favorably influences my

willingness to subject patients to the prodrug of

the drug that they have been hypersensitive to.

Furthermore, I think this risk management program

makes sense.

So, to conclude, for the patients that I

have described to you, who are allopurinol

intolerant, I have no other therapeutic

alternatives for them and I think that this is a

valuable drug. I think that the data that have

been presented thus far, at least in what I

consider to be my experience with this drug, has a

positive ratio of benefits to risk. I do believe,

having been through this compassionate use program

for so many years, that the proposed risk

management program will be a better program. It

will make this more widely available to patients

because many patients have dropped out of the oxy

program when they have moved and they couldn\'t find

a physician to do this, and it certainly will allow

better monitoring of this overall issue. Thank

you.

125

DR. GIBOFSKY: Thank you, Dr. Calabrese.

We are a few minutes behind, however, in the

interest of open discussion I would like to afford

the panel the opportunity to ask questions of any

of the previous speakers. If there are questions

from the panel, we will entertain them at this time

before we take our break. We will make up the time

later in the session. Dr. Felson?

DR. FELSON: A quick question for anyone,

I think Len Calabrese has laid out the design of

the Phase 4, which sounds like a randomized trial

with a placebo control, with a primary endpoint of

number of clinical attacks, it sounds like. Why

was that chosen as the primary endpoint, especially

given the discussion we have heard so far about

potential surrogates, as opposed to using uric

acid?

DR. MOORE: Let me start with that.

Basically, that was an extensive discussion we have

had with the FDA on acceptable parameters.

Clearly, we would have benefitted from discussion

with this panel, but a part of the requirement for

126

approval of this drug is that we had to get a Phase

4 study under way. So, that is how we designed it.

It seems a perfectly beneficial clinical outcome

that one would reduce tophi and so that is the

basis for the study design.

DR. GIBOFSKY: Dr. Hochberg?

DR. HOCHBERG: When we go through our

training, those of us who train medical students,

residents and fellows, we recommend that the serum

uric acid be normalized often to below 5 mg/dl or 6

mg/dl. So, maybe somebody could comment on what is

a clinically important reduction or a clinically

meaningful reduction in serum uric acid for someone

who starts at 10? You know, what does it mean to

have a reduction of 2 mg/dl even if you are still

having an elevated serum uric acid level?

DR. CALABRESE: Marc, I think that is a

great question. First I would like to point out

that in most patients treated with oxy we have been

able to effect far more than 2. That trial is

biased by the fact that drug escalation was stopped

when they hit t 2 mg. In most patients that I have

127

treated we have got 3 or more.

Now, asking the question of what is

clinically meaningful, I think that this is a

subject of debate. You know, there are data from

Ralph Shoemacher that suggest that even the mere

fact of escalating frequency of gouty attacks may

be seen before even normalization. I have been

impressed by patients on oxy in whom we have

maximized their dose, keeping them in the range of

6, 7 or close to 8, the frequency of attacks have

been decreased. So, I think this is an issue that

needs to be addressed in a clinical study that will

correlate clinical outcomes with SUA. This hasn\'t

been done in any rigorous manner.

DR. GIBOFSKY: Dr. Geis?

DR. GEIS: Do you have anything in the

literature that says what if you gave placebo to a

bunch of patients, what would their uric acid

levels do? I mean, because this is open-label it

is kind of hard to interpret it but do we know

about historical data with placebo studies?

DR. MOORE: I think there is very little

128

literature data on that today. Clearly, we will be

studying that in our Phase 4 study and have a much

better handle on it then. But, as Dr. Snyderman

pointed out earlier, gout is a progressive disease

and so one would clearly expect it to get worse and

not better. So.

DR. GIBOFSKY: Dr. Finley?

DR. FINLEY: Dr. Calabrese, when you are

thinking about clinical endpoints, and you

mentioned tophi reduction and you described your

vignette, are we talking about size, the number,

healing? How do we do that? How do we validate

that between raters and those kinds of things?

DR. CALABRESE: I am just a clinical

rheumatologist taking care of people with sore

toes, and I will leave some of these discussions to

the experts here. But my experience, even with

allopurinol, is that, you know, you don\'t see these

things disappear over time, but certainly there is

an element of regression because I have seen these

draining areas receding. You don\'t see that cheesy

stuff through the skin. You see a decrease in

129

girth that could at least be palpated. What the

best way to measure this is, I would leave that to

others.

DR. GIBOFSKY: Dr. Moore or Dr. Calabrese,

help me understand how a compassionate use program,

where the drug is restricted, would be less

effective or not as good as a Subpart H approval

where the drug would be restricted under your risk

management program.

DR. MOORE: Let me begin. Basically, our

experience has been with the compassionate use

program to date. It is a less than perfect

collection of data. So, what we are looking at is

a much more controlled situation, creating a

patient registry, which we don\'t have with

compassionate use. As you know, compassionate use

is more at the prerequisite of the individual

investigator and not the company. Whereas, with a

company controlled environment, which would be the

Subpart H, we get much better feedback on risk and

side effects to the patients. We would also get

less of this loss to follow-up issue. We would be

130

able to track the patients. So, I think I would

feel that we would have much better control of what

was going on.

DR. CALABRESE: I would just like to

mention that in addition to a smoother bureaucratic

process for the physician, it would be much easier

to register into this than become an investigator

and do this. The compassionate use program really

did not include any type of formal physician or

patient education and this actually has the

requirement for a knowledge base that a third party

would check off on, actually looking over these

report forms. You know, over 20 years ago they are

fairly embarrassing.

DR. MOORE: Thank you. One final point on

that as well is accessibility for patients. For a

compassionate use program people have to hear about

a drug one way or another and it is very hard for

them to get on this program. Whereas, if the drug

is actually marketed, albeit on a very limited

distribution program, they will know it is

available, physicians will know it is available.

131

DR. GIBOFSKY: I take that point, but the

concern in the back of my mind is if the drug is

available, albeit in a limited distribution, is

there not the concern that the drug will be used

beyond its primary indication by physicians who may

think, based on the data, that perhaps oxy is

superior to allo and why not start with oxy?

DR. MOORE: That is an excellent question

and that is one of our greatest concerns as we go

into this. So, in fact, what we have is that as

the physicians request the drug there will be a

very formal form, and in the NDA we have all of

this material described where there is not just

education material but the physician will have to

formally describe the patient, and there are

criteria which qualify them for receiving the drug

and part of this is double allo intolerance. So, I

think it is a very restricted system and it is a

very good way of controlling it.

DR. GIBOFSKY: Dr. Anderson?

DR. ANDERSON: I have a question going

back to the design of the study that is currently

132

under way, and it has to do with the eligibility

restriction that the patient has to have had at

least 6 attacks in the previous year. I was

wondering what is known about the distribution of

number of attacks per year in gout patients and

what drove that\--you know, what made you decide

that?

DR. MOORE: It is a matter of powering the

study, frankly, and what we are looking at is that

a lot of these people are sicker anyway because by

the time you get to an allopurinol-intolerant

patient population they have been trying other

treatments for a long while. So, often many of

them are very sick patients. It is not that

difficult to find people who have 6-8 gout attacks

a year. We have 6 patients right now who are ready

to come onto this study. But really it is a matter

of powering the study, showing the efficacy of the

drug in terms of this clinical outcome and, at the

same time, being able to compare this to lowering

serum uric acid, how much it goes down and where it

goes down to.

133

DR. ANDERSON: Can I just follow-up on

that?

DR. GIBOFSKY: Sure.

DR. ANDERSON: This wasn\'t presented here

but it was in the background material we have, it

was indicated that you would need a hundred centers

to find those patients, which seems to run a bit

counter to what you just said.

DR. MOORE: No, no, if I gave the

impression they are easy to find, I didn\'t mean

that. What I should say is that we have access, of

course, to all of the physicians who have been

recruiting into a compassionate use program. We

are the only people who distribute oxypurinol. So,

it is easier for us to find these kinds of patients

because we already have access to the physicians

who have them.

No, my bet is that we will get about two

or three patients per site. This isn\'t your

average clinical study where you have one patient

per month per site. This is going to be much more

restrictive than that.

134

DR. GIBOFSKY: Dr. Geis?

DR. GEIS: You didn\'t present any

demographic data about the patients that you did

study. How do you know they are representative of

the intended patient population?

DR. MOORE: I am not sure I understand the

question.

DR. GEIS: I mean, in most clinical trials

I have been involved in, you usually want to give

the demographics and show this really does

represent what the literature says the patients

will look like.

DR. MOORE: Oh, I see.

DR. GEIS: I think in one of the documents

that we were given in advance the ratio of males to

females was really not different from what I heard

historically is the ratio by gender in the gout

patients. So, it made me think who are you really

studying.

DR. MOORE: No, as Dr. Dickinson said

earlier, first of all, this is a rather small

patient population that we are looking at, the

135

allopurinol-intolerant gout patient population.

Secondly, we have the largest database of anyone on

these patients. So, we believe that our database

on 612 patients truly represents the demographics

of the broader patient population. We have

anywhere from 5-10 percent of them right now.

DR. GIBOFSKY: Dr. Mandell?

DR. MANDELL: In 213 the numbers that you

have, 9 of 77 by ITT had less or equal to 6. I

understand it wasn\'t pushed to do that. Since most

of us would be pushing, if we are going to be

treating, the uric acid down probably lower than

just the targeted 2 drop, what information do you

have on the safety or efficacy of the drug used in

that manner, pushed to really try to drop the uric

acid level?

DR. MOORE: Let me start and then turn to

Dr. Dickinson. The most information we have is

from our compassionate use program where, as Dr.

Dickinson described, we have gone up to 1800 mg.

So, I think for safety we have good safety data for

prolonged periods of time at very high doses.

136

For efficacy, clearly the Phase 4 program

will fill in more of that, although we do have good

data from the compassionate use program, as Dr.

Calabrese described. We get lowering of 3-4 mg/dl

with these higher doses. Remember that the 213

study was designed to reach the endpoint of 2 only.

So, that was really limited titration.

DR. MANDELL: How many patients does that

include actually at those high levels?

DR. DICKINSON: The average serum uric

acid at start was 10.1. So, about half the

patients had higher than 10 and half had lower than

10 as a starting SUA. The oxypurinol maximum dose

in the 213 study was 800 mg. I believe there were

9 patients that went up to 800 mg. That was the

limit on that study. Again, once a patient had

dropped their serum uric acid, if they dropped it

from 11 to 9 they were not eligible for any further

dose escalation because they had achieved the

endpoint in that study, which was a 2 mg/dl decline

in serum uric acid.

DR. MANDELL: So, we don\'t have a lot of

137

patients actually treated with the higher doses

here.

DR. DICKINSON: We do in the compassionate

use program, which is a real-world program where

there are patients with renal insufficiency, renal

transplantations. We have a number of patients who

have been treated with 1200 mg, 1400 mg, 1600 mg a

day.

DR. MANDELL: Do you know how many those

are?

DR. MOORE: The mean dose that was used in

the compassionate use program was 372 mg and we are

asking for approval up to 800 mg for this

indication. The vast majority of patients were in

the middle, between 300-400 mg so there was really

a distribution curve down on the other side. But

in that program were 533 patients. So, you have a

large distribution with the majority being in the

middle with 300-400 mg coming out on the slope.

So, we do have data on high doses.

DR. GIBOFSKY: Dr. Bathon, do I see your

hand up for the last question?

138

DR. BATHON: Yes, along that same line

just as a follow-up to that, how then are you

guiding physicians in the Phase 4 trial to dose the

drug since you are using a clinical endpoint as

your primary?

DR. MOORE: It is a titration study and

that is the same way that allopurinol is dosed.

So, they would go up in 100 mg doses over a 16-week

period. There is a 2-week run-in placebo period

and then an 18-week titration study. Of course,

being that this is a double-blind study the serum

uric acid will be read by an unblinded outside

physician so that will be guided by that. The goal

is to lower the serum uric acid to 6 mg/dl. That

is the goal.

DR. GIBOFSKY: I would like to thank the

presenters for giving us some additional food for

thought this afternoon. At this point we will take

our break for exactly 15 minutes and resume at

11:08 by that clock.

\[Brief recess\]

DR. GIBOFSKY: We are ready to begin.

139

Will all the panel members please take their seats

and the audience find theirs? At this point we

have a presentation by Dr. Lourdes Villalba, who is

the medical officer for DAAODP of the Food and Drug

Administration, and she will speak on oxypurinol

for symptomatic gout in allopurinol-intolerant

patients. Dr. Villalba?

Oxypurinol for Symptomatic Gout

in Allopurinol-Intolerant Patients

DR. VILLALBA: Good morning. The goal of

my presentation is to show you data from a specific

new drug application, an example as a starting

point for discussion of clinical trial design

issues in chronic gout. The proposed indication

for this drug, oxypurinol, is a very specific one

in a very specific population. But when you go

through the data I would like you to think about

how these data may apply to other drugs and trial

design issues in general.

Allopurinol, as mentioned earlier, is the

first-line treatment of hyperuricemia in gout. The

active metabolite of allopurinol is oxypurinol and,

140

because of the short half-life of allopurinol and

long-life of oxypurinol, it is believed that the

pharmacodynamic effects of allopurinol reside in

the oxypurinol moiety.

There is limited data on comparison of

allopurinol and oxypurinol. There are some studies

in the literature that have compared them. For

example, there is a crossover study of allopurinol

and oxypurinol in close to 100 patients but those

studies were not adequate for comparison of the

efficacy or the safety. In any case, the

literature suggests that allopurinol is more

efficacious in reducing uric acid levels as

compared to oxypurinol. The limited data available

in the literature really has not shown a difference

in safety between the two.

We do have one pharmacokinetic study

looking at the conversion of allopurinol into

oxypurinol. This study was conducted by the

sponsor as part of the NDA and is an open-label

bioequivalence study of 42 patients that showed

that the relative bioavailability of single dose

141

oxypurinol is about 30 percent that of allopurinol

for the 100 mg dose. That means that a single dose

of oxypurinol levels is equivalent to 58 mg of

allopurinol. The pharmacokinetic characteristics

of oxypurinol non-linear. Therefore, the data in

this particular study shows that 800 mg of

oxypurinol produced oxypurinol serum levels

equivalent to 112 mg of allopurinol. This, again,

is single dose. We do not have data on multiple

dose conversion.

Allopurinol is generally well tolerated,

however, up to 10 percent of patients present

intolerance. Despite the fact that the drug has

been used for decades, the mechanism of toxicity is

not well understood. There is some toxicity that

is immunologically mediated and 204 percent of

patients present with hypersensitivity reactions,

and that is the main limitation to the use of

allopurinol. As already explained earlier, most of

the events are skin reactions, mile to moderate,

occasionally severe including Steven-Johnson and

toxic epidermic necrolysis. Other hypersensitivity

142

reactions include fever, hepatitis, nephritis,

hematologic such as aplastic anemia and

thrombocytopenia, and a very rare form of the

hypersensitivity syndrome, and 20 percent of the

cases may be fatal, the allopurinol

hypersensitivity syndrome which involves all of the

above\--skin, fever, hepatitis, nephritis. It is

usually associated with eosinophilia. The

mechanism is unclear. It seems to be type IV

hypersensitivity mediated, T-lymphocyte mediated

with production of cytokines, including IL-5.

However, there is also non-immunologic

toxicity that involves mainly renal and liver

toxicity. In animal studies, for example, the

toxicity is mainly liver, renal and cardiac and the

hypersensitivity syndrome is not reproduced in

animals.

I distinguish between these two forms of

toxicity, however, in the clinical setting

sometimes it is very difficult to distinguish one

from the other. For example, if we see a patient

with transaminase elevations, unless there is also

143

a rash or fever or eosinophilia it is going to be

very difficult to say that that was related to

hypersensitivity or not. It is unclear whether the

hypersensitivity reactions to allopurinol are

directed to allopurinol, oxypurinol or other

metabolite.

The literature suggests that allopurinol

desensitization may be of use or may have a role

for some patients with mild to moderate cutaneous

intolerance. There are some case reports in case

report series and the most persuasive one is one by

in arthritis and rheumatism that reports a

retrospective evaluation of 32 patients who

received allopurinol desensitization for over a

month period and then continued on allopurinol for

a mean follow-up of 32 months. Of those 32

patients, 28 tolerated doses up to 50-100 mg daily

and 21 of those patients did so without any adverse

reaction and 7 of those patients actually presented

with some form of cutaneous reaction that was

managed with symptomatic treatment and by modifying

the schedule of the desensitization program. Four

144

patients required discontinuation.

It is important to note that the serum

uric acid levels went from 10.4 mg/dl at entry to

5.3 mg/dl at the end for those patients who

tolerated allopurinol. Also, I would like to point

out that there were patients with renal

insufficiency included in this retrospective study,

with a mean creatinine level of 2.8 mg/dl. It is

also important to point out that there were no

patients with severe intolerance included in this

retrospective review.

Regarding oxypurinol, the sponsor has

already talked about the compassionate use program.

Oxypurinol has been available for patients since

1966 as part of the compassionate use program. The

sponsor has collected a large amount of data from

approximately 500 patients in an open-label manner.

I would like to point out that it was not a study

that was prospectively designed to evaluate the

efficacy or the safety of oxypurinol.

This was actually a retrospective

evaluation of patients who were seen over a period

145

of 40 years. That is why there is less than

optimal documentation of, for example, allopurinol

intolerance prior to entry, also the efficacy and

safety during the study. Clinical laboratories

were not systematically collected, were collected

at the discretion of the investigator. There are

missing data. For example, serum uric acid

baseline levels were missing in 32 percent of

patients and post-baseline levels were missing in

24 percent of patients.

Regarding the demographics, up to 30

percent of patients were missing the age or the

ethnicity data. Also, 25 percent of patients were

missing baseline creatinine data. Regarding the

patient disposition, 28 patients were lost to

follow-up. Therefore, data from this program,

although encouraging, is not adequate to assess in

a robust way the efficacy or the safety of

oxypurinol.

Let me say that the day suggest that the

drug is effective in reducing serum uric acid

levels, and also that some patients develop who

146

develop allopurinol intolerance tolerate

oxypurinol. However, that was not enough for

marketing of the drug and the sponsor entered

discussions regarding additional data needed for

marketing. Protocol OXPL213 was started at the end

of 1999, beginning of 2000. It is important to

remember that this is an unmet medical need in a

population who is at high risk of developing

allopurinol intolerance and severe reactions; that

this drug was already available in compassionate

use. So, at that time and in that setting it was

thought that a 2 mg/dl change in serum uric acid,

used as a surrogate endpoint, would be something

reasonable. In addition to the uric acid levels,

the study needed to assess efficacy and, if

successful, a post-marketing study would be

conducted for evaluation of meaningful clinical

endpoints.

This is the study design, and you may have

an idea already because of the prior presentation.

This was a prospective, open-label, uncontrolled

dose-escalation study of 14 weeks. That was the

147

base study and it included 79 patients. Those

patients who completed the study were offered to

continue into the extension and 48 patients

continued into the extension. The extension is

still ongoing.

Entry criteria included patients with

symptomatic hyperuricemia with documented

allopurinol intolerance. Documentation could be a

single episode of intolerance as documented by the

primary physician or rheumatologist or, in addition

to that, the patient could actually have a history

of rechallenge or desensitization. One-third of

those 79 patients approximately\--there were 26

patients who had undergone rechallenge or

desensitization.

The exclusion criteria, as mentioned

earlier\--those patients with severe prior reaction

to allopurinol did not enter the study. The use of

diuretics and uricosuric agents were also exclusion

criteria. Regarding renal function status,

patients with creatinines of 2 mg/dl or above and

liver function tests of 3 times the upper limit of

148

normal or higher were excluded from the study.

Again, I want you to think about all these entry

criteria.

The treatment scheme, you already saw that

this is a fixed dose escalation study, starting

with 100 mg and going up to 800 mg daily according

to the fact if the patient achieved or not the

desired endpoint. Most of the patients, 60 percent

of the patients were on the 300 mg dose and I

believe 8 or 9 patients were on the 800 mg dose.

The others were on doses in between. Of course,

some patients received the 100 mg dose and

presented with reactions and were discontinued but

most of the patients were on 300 mg.

Regarding the endpoints, the primary

outcome was the serum uric acid level. However, I

would like to point out that there was not a

central laboratory. That means that each site

worked with different labs and those labs had a

different normal range.

The primary analysis was a landmark

analysis of comparison of the mean baseline and

149

mean final value of week 2, 13 and 14, and there

were also measurements of serum uric acids at week

6 and week 9 for those who had not achieved a 2

mg/dl drop by week 6. The primary analysis was to

be in the ITT population and it was to show a

decrease of at least 2 mg/dl.

These are the baseline characteristics of

the study. The mean age was 61 years. Fifty

percent of patients were male. The mean serum uric

acid was 10.1 mg/dl, with a range from 7.7-13.7

mg/dl. The mean creatinine at entry was 1.3 mg/dl,

with a range from 0.8 to 2.2. There were 26

patients who had failed prior rechallenge or

desensitization.

Regarding concomitant medication, 43

percent of patients were on colchicine,

prophylactic colchicine; 6 percent of the patients

were on low dose aspirin; 53 percent were taking

diuretics, although this was one of the exclusion

criteria for this study; and 49 percent of the

patients were taking NSAIDs or COX-2 inhibitors.

Regarding prior history of allopurinol

150

intolerance, most of the patients had skin

intolerance, 8 percent of the patients had skin

intolerance, and 20 percent had other

manifestations such as hepatic, renal, malaise, all

3 or fever. Again, these patients had mild to

moderate allopurinol intolerance, and there were no

patients with prior history of hematologic

intolerance or severe skin or liver intolerance.

The definition of intolerance for liver intolerance

was ALT elevation of 2.5 to 5 times the upper limit

of normal, and for renal it was BUN or creatinine

1.5 to 3 times the upper limit of normal. There

was no requirement for these to show eosinophilia.

I mean, the word of the investigator was taken who

thought these were allopurinol intolerance

reactions.

The results of the FDA analysis are a

little different from the sponsor analysis. In the

ITT population at 14 weeks\--and we looked at the 79

patients, all patients who were included in the

study and received at least 1 dose of medication\--the mean

change from baseline was 1.78 mg/dl. In

151

the sponsor\'s analysis, in 77 patients it was 1.9

but in 79 patients when they looked at the whole

thing it was 1.85. But, actually, that doesn\'t

matter too much. I think that the important thing

here is that the study did not achieve the primary

efficacy endpoint. But even if it, let\'s say it

achieved 2 mg/dl, the issue is if 2 mg/dl is

something that one would like to see as the goal

for treatment for gout.

In the completer analysis the change in 54

patients was 2.32 mg/dl. This change was highly

statistically significant, with a p value of 0.001.

That means that the study rejects the null

hypothesis that the change of serum uric acid level

associated with oxypurinol is equal to zero.

Another way of looking at the data is by

looking at final mean serum uric acid. In the ITT

population it was 8 mg/dl. In the completer

population it was 7.5 mg/dl. By our analysis of

the data set, 10 patients achieved a serum uric

acid level of 6 mg/dl or below and 2 patients

achieved 5 mg/dl or below. This is the most

152

important difference, I would say, that I found

with the sponsor presentation. We have not

clarified yet why there is this difference. We

have to go through the data set again with the

sponsor probably.

There was no evidence of dose response and

that may have something to do with the study

design, the fixed dose escalation. Another factor

that may have something do with it is the

pharmacokinetic characteristics of oxypurinol. As

we saw, that is non-linear in a single dose and we

don\'t know the data for multiple dose.

There were 12 flares and 8 of them were

during the base study; 5 only during the base study

and 3 of them in the base and extension, and 4 were

only during the open extension. Four patients had

tophi complications, such as infection, drainage or

pain, 2 in the base study and 2 in the extension.

In the absence of a placebo-control arm this is

very difficult to interpret. Is this oxypurinol

effect on serum uric acid or is this spontaneous

flare that occurs despite the drop in uric acid?

153

We looked at the characteristics of the

patients in the base study. All patients with gout

flares dropped their uric acid levels, and the

range was from 1.5-3.9 in some patients. So, there

was a drop of uric acid level. Half of the

patients were on colchicine. None of the patients

were discontinued from the study. They were

treated with steroids or NSAIDs and continued and

completed the study. I don\'t have the data from

the extension. The extension is still ongoing so

data is incomplete.

I am going to show you a few slides about

the safety. There were 5 deaths. One during the

base study. That was a pancreatic carcinoma.

There were 4 during the extension. One patient

died of end-stage liver disease; one was found

dead. One patient had GI bleeding and worsening

COPD, and one patient died of sepsis after a

surgical procedure. All these events, in the

opinion of the investigators, were unrelated to

study drug.

Regarding serious adverse events, non-fatal

154

serious adverse events, there were 7 in the

base study and 15 in the extension. Again, all of

them seemed to be unrelated to study drug. I would

like to point out 2 definitive myocardial

infarctions and 1 questionable myocardial

infarction in the base study. So, we see 3

patients with cardiac events in a 14-week study of

79 patients. Maybe this finding may be related to

the cardiovascular high risk population that is

under study with the co-morbidities and associated

factors like hypertension, obesity and diabetes

seen in patients with hyperuricemia, and also

hyperuricemia itself may be an independent risk

factor.

Regarding discontinuations, 54 patients

completed so 25 patients discontinued. Of those

discontinuations, most of them were due to skin

intolerance. Sixteen patients discontinued because

of skin intolerance. One patient was reported to

have discontinued because of liver intolerance.

One patient had thrombocytopenia. We had the

pancreatic carcinoma and one patient was a protocol

155

violator, and there were 5 cases that I classified

as miscellaneous and I would like to expand a

little bit more on these.

One of the patients was discontinued

because of monitor decision. After one dose of

oxypurinol, this patient developed a fever,

followed by chills, skin sensitivity,

polyarthalgias and viral syndrome. This patient

was excluded from the sponsor\'s analysis because it

was considered unrelated to study drug. However, I

think that it may have been related but, in any

case, in an efficacy ITT analysis I think it should

be included in the analysis.

One patient had a hypersensitivity

syndrome. It was described as hypersensitivity

NOS. That means no other symptoms and there is

nothing more in the case report form. So, it isn\'t

clear exactly what the reaction was of this

patient.

One patient had fever, chills, headache

and allergic rhinitis, probably unrelated. One

patient discontinued because of nausea and vomiting

156

after one dose and this patient had a prior history

of liver intolerance.

One patient developed elevation of ALT and

BUN and it was considered by the investigator to be

a protocol violation because the patient was not

complying with the medication. So, this may be

unrelated, this elevated ALT, but still should be

included in the analysis of safety.

In addition to the patients who

discontinued, there were 3 patients who completed

the base study but had hypersensitivity reactions

and did not enter the extension. Two of them had

liver function test elevations and one had a rash.

Therefore, in summary, approximately 30

percent of patients developed intolerance; 70

percent of patients with intolerance showed skin

intolerance\--I am talking approximately, I am not

giving an exact number\--70 percent within the first

week. Most of the patients showed the same kind of

intolerance as before and none of them was

considered serious. There were 2 cases that were

different from baseline, 1 with thrombocytopenia

157

and the other with LFT elevation.

This slide focuses on the patients who had

actually undergone and failed rechallenge or

desensitization. There were 26 patients. Of these

patients, 10 discontinued because of

hypersensitivity reactions again. The

hypersensitivity reactions were the same as they

had in the prior allopurinol experience. That is

40 percent of the patients. There were 3 deaths, 1

in the base study and 2 in the extension, and in

the extension that included the patient with end-stage liver

disease and 1 patient with sepsis.

Therefore, in summary, 79 patients were

enrolled; 54 completed the 14-week study; 48

entered the extension. At the time of the analysis

there were 37 patients available in the safety

population. Ten patients achieved serum uric acid

levels of 6 mg/dl or below and 5 mg/dl or below at

14 weeks. Eight patients had flares during the

base study.

Regarding adverse events, there were no

serious hypersensitivity reactions. Most of them

158

occurred within the first week. Most of them were

cutaneous and similar to what the patient had

presented before. Others, beside the skin,

included a few liver intolerance events; 1

thrombocytopenia; 1 viral syndrome. This was in a

population of patients with mild to moderate

intolerance to start with and with normal renal

function or mild renal insufficiency.

Therefore, our challenge is to define a

population for a favorable risk/benefit in which a

modest decrease in serum uric acid would outweigh

the risk of 30-40 percent intolerance in a

population which is at increased risk of

intolerance and in the setting of a not well-defined

clinical benefit.

So, all these data are for you to take and

help us in the discussion of the discussion points.

That is the end of my talk.

DR. GIBOFSKY: Thank you, Dr. Villalba.

Are there questions for Dr. Villalba? Dr. Hoffman?

DR. HOFFMAN: That was very helpful. I

was going back to the data that you showed us that

159

concluded that there was no evidence of dose

response.

DR. VILLALBA: Yes?

DR. HOFFMAN: I was curious about the

rigor with which we come to conclusions about that

data because there were only 54 completers in that

trial, and it wasn\'t clear\--well, we didn\'t see the

data on how many patients were at each dose level

and followed for what period of time, perhaps up to

14 weeks, perhaps longer, for us to know whether or

not there was adequate sample size at each dose

level to really address dose response. If it not

adequately addressed in this study, do we have from

the applicant additional data about dose response?

Do we also have the necessary data about dose

response in allopurinol to come to conclusions

about linearity of dose response?

DR. VILLALBA: Well, regarding the data

from the sponsor for oxypurinol, yes, we did the

analysis and we looked at the sponsor\'s analysis

with the data that we had. I can say that it

cannot be said that there is a dose response. I am

160

not saying that there is no dose response. That is

the database that we have.

DR. GIBOFSKY: Dr. Villalba, please use

the microphone. It is a bit difficult to hear you.

DR. VILLALBA: I am sorry. So, that is

the database we have and I think it is inadequate

to address that.

DR. HOFFMAN: I think it is a terribly

important issue if we are talking about a new

protocol in which our goal is to achieve a uric

acid of 6 or less by dose escalating. If there is

really no dose response, I think we need to clarify

that before we feel comfortable about a protocol

that uses a dose escalation strategy.

DR. VILLALBA: Yes, I agree.

DR. GIBOFSKY: Dr. Geis?

DR. GEIS: In your analyses did you look

at changes in other risk factors which could affect

uric acid levels, like blood pressure, weight,

alcohol use, thiazide changes?

DR. VILLALBA: We looked at concomitant

medications. We didn\'t look at other factors but

161

regarding concomitant medications\--let me think\--there were

8 patients who were started on NSAIDs or

COX-2 inhibitors but I don\'t think that would

affect the serum level but it may affect the

symptoms. There were 2 patients, I believe, that

started new diuretics but there was not much change

other than that. And, 4 patients started

colchicine in the study.

DR. GIBOFSKY: Dr. Mandell?

DR. MANDELL: Following further really on

the question of the pharmacokinetics and

pharmacodynamics of the drug, in looking at trying

to get a dose response in the multi-dosing setting,

was creatinine clearance taken into consideration

in that analysis or are the numbers too small,

number one, really relating to the pharmacokinetics

of why there might or might not be a dose response?

Two, do we know anything about the pharmacodynamics

in patients who are allopurinol sensitive as

opposed to non-allopurinol sensitive patients on

the sensitivity to oxypurinol?

DR. VILLALBA: I don\'t think we have any

162

data on that. Regarding the first question, the

data we have on pharmacokinetics is only single

dose. There is no data on multiple dose.

DR. MANDELL: So, what you said about the

non-dose response was the single dose analysis?

DR. VILLALBA: No, no, that was in the

study, the result of the study.

DR. MANDELL: So, some of those patients

had various levels of creatinine clearance in

there?

DR. VILLALBA: Yes, but as per the entry

criteria, only patients with creatinine up to 2

mg/dl could enter and the mean creatinine at entry

was 1.3.

DR. MANDELL: There is a wide spread of

clearance.

DR. VILLALBA: Yes, but we don\'t have data

on clearance.

DR. GIBOFSKY: Dr. Anderson?

DR. ANDERSON: My concerns are only partly

to do with safety. I found it very disturbing that

the study was not placebo controlled because, as

163

you commented earlier, in the absence of a placebo

control or any kind of control you really cannot

interpret the safety results and even the efficacy

results. It is not clear from other discussions

that have been held here whether a drop of 2 mg is

clinically important and, given the lack of

knowledge about the reliability of this measure, is

it even a minimally important difference? It could

be that you need at least 3 mg or, if you are

starting high, 10; you need to have an even greater

milligram drop for it to be clinically important.

I guess those are just concerns that I

have about the study, and also about the revised

analysis, the revised analysis that was presented

by the sponsor. You know, this was an analysis

that was devised after the initial analysis didn\'t

quite work. So, those are all concerns I have.

DR. VILLALBA: Yes, regarding the first

concern, we agree completely. That was our concern

all along and the sponsor\'s concern too. That is

why it was agreed that a Phase 4 study would be

conducted. Regarding that change, it is precisely

164

what we wanted to decide because that is our issue

too. We are not sure that 2 mg/dl should be

considered acceptable as adequate evidence of

efficacy.

DR. GIBOFSKY: Dr. Boulware?

DR. BOULWARE: Regarding study 213, I am

sort of bothered by drawing conclusions about dose

responsiveness and the ability to hit the endpoint

of 5 mg/dl or 6 mg/dl which we considered desirable

when the study was designed, that you stop the dose

escalation once you dropped by 2. When I think

about that and I looked at the earlier spaghetti

gram provided to us by the sponsor, the number of

patients entered who had a baseline SUA within 2

points of the desired endpoint are very limited.

There are only about 2 or 3 patients. Anyone who

had a drop of 2 from their baseline had their dose

stopped. So, it is very difficult, in my mind, to

draw any conclusions about its inability to be dose

responsive and also its inability to achieve a

target of 5 mg and 6 mg. Is that appropriate?

DR. VILLALBA: I completely agree with

165

you.

DR. GIBOFSKY: Dr. Hochberg?

DR. HOCHBERG: I would like to get your

comments about safety. I am a bit concerned, and

let me refer to a couple of your slides. First,

the proposed indication, which is your slide number

3, is for treatment of hyperuricemia in patients

who are intolerant and have failed either

rechallenge or desensitization with allopurinol.

In the 213 study, in your presentation only 26 of

the subjects had actually had a prior rechallenge

or desensitization so the majority had not.

It appears to me that there is an

imbalance in the incidence of adverse experiences

during 213, with a higher rate of adverse

experiences in those who had failed the prior

rechallenge or desensitization than in those who

had not had the desensitization or rechallenge.

The one death that occurred during the study

occurred in someone who had failed the rechallenge

or desensitization. Half of the deaths during the

follow-up extension occurred in that population.

166

So, does the lack of data, relative absence of data

in the people who actually would fulfill the

criteria for this indication concern you?

DR. VILLALBA: Yes, and I agree with you.

DR. GIBOFSKY: Dr. Felson?

DR. FELSON: I guess I am going to pose

this to you but I would also be happy to pose it to

the sponsor, the idea that you get exactly the same

side effects if you get oxypurinol reaction and

that the bioavailability of oxypurinol is

substantially lower than allopurinol might suggest\--and also

that there is a good deal of literature

suggesting that the side effects of allopurinol are

often oxypurinol-mediated\--that might suggest an

explanation of oxypurinol efficacy, that it is

simply administering lower dose allopurinol. Why

not just give lower dose allopurinol? Is that an

explanation that is consistent with the data

presented?

DR. VILLALBA: I agree with your concern.

That is all that I can say.

DR. GIBOFSKY: Are there further questions

167

from the committee? If not, at this point let me

make one brief announcement. Several members of

the committee have asked for additional information

to educate themselves, so we can do our job, about

Subpart H. As alluded to by Dr. Witter, 21 CFR

314.510 etc. I suspect many of my colleagues are

not adapt at reading the Code of Federal

Regulations so I have asked Dr. Harvey to please

provide us, sometime over the next 24 hours, with

either the website where that can be perused at

leisure\--if anyone peruses the CFR at leisure\--as

well as perhaps an executive summary and some

examples of where Subpart H has been invoked. With

that, we are at lunch. We will resume at exactly

one o\'clock.

\[Whereupon, at 11:49 a.m., the proceedings

were recessed for lunch, to resume at 1:00 p.m.\]

168

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

DR. GIBOFSKY: Thank you, we will now

begin the afternoon session. Before we begin the

public hearing we have a couple of administrative

matters. Dr. Harvey has completed his homework

assignment that I gave him before the break and he

would like to present some comments to the

committee. Dr. Harvey?

DR. HARVEY: Thanks very much. I just

wanted to give you a quick blurb on Subpart H.

Actually, I really don\'t want to go into too much

detail but I want to be able to give you the

information you need to go and read all about it.

My memory did serve me correctly, there was a panel

meeting, an Oncological Drug Advisory Committee

meeting on March 12 and 13 of 2003 where they

actually spent a whole day on Subpart H. So, you

can see that this is an area where, if you wanted

to go into some depth, you could really spend

literally a whole meeting just on Subpart H.

The transcript of that, the summary, all

the related material is on the website. So, for

169

those of you who are not initiated to the web, you

just go to the FDA web page, so www.fda.gov and you

get the main page. There is a little box up on the

upper left-hand corner where you can actually do a

search. In this case you just put in Subpart H.

If you just put in that simple term, Subpart H, you

will get everything in the world you want to know

and, luckily, the first hit on that search is

actually a printout of all of the NDAs that have

ever been approved by FDA under Subpart H. As I

said this morning, the vast majority of those are

in the areas of HIV treatment where viral load was

the surrogate endpoint, and the other area was

oncology, as I said this morning, where tumor

response and variations in tumor response themes

were used as a surrogate endpoint.

So, really that resource, which is

publicly available, is really the best way to go

ahead and get your hands around the whole issue of

Subpart H. Really, in light of today\'s discussion,

it really is just sort of a peripheral part of what

we are discussing, which is really the clinical

170

aspects of clinical trial design and your expertise

in the area clinically as well as scientifically.

But I wanted to get you that information and that

is really the best resource to answer that

question.

DR. GIBOFSKY: Thank you, Dr. Harvey.

Before the break there were some questions

addressed to the sponsor, Cardiome, and,

unfortunately, my back was turned and I did not see

them raise their hand. There was a specific

question I believe from Dr. Felson to them. So, in

the interest of collegial discourse I extend my

apologies for not recognizing that they had a

comment to make and would ask them to respond to

some of the discussion this morning. Dr. Moore?

DR. MOORE: No apology is necessary but

thank you very much for giving us the opportunity.

We are going to show you very quickly some data

that addresses the issue on rechallenge versus non-

rechallenge patients, and I will make a comment on

PK values as well. Dr. Dickinson?

DR. DICKINSON: Can I have the slide? One

171

of the questions that arose is the dosing in

patients in the CUP program. This just gives you

the range of doses. As you can see, the range is

from less than 100 and, in fact, goes up to 1800

and this is the range of dosing. So, is pretty

broad. Not everybody is at 300 mg, and it tends to

be higher than 300 mg, as you see, with

allopurinol.

The next slide. The other question that

came up was about allopurinol rechallenge. In

fact, we did have information on 97 percent of all

our patients, whether they had been rechallenged or

not. Approximately 38 percent had been

rechallenged and the remainder, 62 percent, had

not. When we looked at safety data here we could

find no difference between these groups. When we

looked at the data in 213 as to whether or not

these patients could tolerate oxypurinol, it was

exactly the same, 28 percent could tolerate

oxypurinol whether they had been rechallenged or

whether they were just considered to be intolerant

on the basis of the usual one clinical reaction to

172

allopurinol. So, we didn\'t find that the

information about rechallenge was particularly

helpful. Thank you.

DR. MOORE: Finally, a comment on the PK,

is oxy low dose allo? In fact, the usual

literature statement is that oxy is half as

bioavailable as allopurinol. We have a chronic

dosing study in congestive heart failure where in

31 patients we have measured the blood levels to

600 mg to oxypurinol and that is 11.3 mcg/ml. What

you would expect from 300 mg of allopurinol is

between 6-10 mcg/ml. So, again, 600 oxy equals 300

allo seems to hold and we agree with Dr. Villalba

that we think those results were an artifact of the

single dose that was given on the PK. I mean, we

did it and those were the results but chronically

it looks quite different. So. Thank you very

much.

DR. GIBOFSKY: Thank you. One small

administrative item, more for the guests in

attendance than the members of the committee,

outside there was a sheet showing the list of

173

tentative meeting dates for the Arthritis Advisory

Committee being 10/21 and 10/22/04. Staff was made

to realize several weeks ago that that is in

conflict with the American College of Rheumatology

meeting and so we are currently canvassing the

committee to determine when an appropriate next

date will be. As soon as that determination is

made it will be posted on the website for those of

you who are interested in attending that meeting,

but it will not be October 21 and 22 as posted on

the sheet outside.

We are going to move into the open public

hearing section at this time. Before we begin I

would just like to read a statement into the

record. Both the Food and Drug Administration and

the public believe in a transparent process for

information gathering and decision making. To

ensure such transparency at the open public hearing

session of the advisory committee meeting, the FDA

believes that it is important to understand the

context of an individual\'s presentation.

For this reason, the FDA encourages you,

174

the open public hearing speaker, at the beginning

of your written or oral statement to advise the

committee of any financial relationship that you

may have with the sponsor, its product and, if

known, its direct competitors. For example, this

financial information may include the sponsor\'s

payment of your travel, lodging or other expenses

in connection with your attendance at the meeting.

Likewise, the FDA encourages you at the beginning

of your statement to advise the committee if you do

not have any such financial relationships. If you

choose not to address this issue of financial

relationships at the beginning of your statement,

it will not preclude you from speaking.

Our first speaker in the open public

hearing session is Mr. Edward G. Mihalo. Mr.

Mihalo?

Open Public Hearing

MR. MIHALO: Good afternoon. My name is

Ed Mihalo and I am a pharmacist in the Pittsburgh,

Pennsylvania area. Cardiome has said that they

would pay me for travel and some lodging.

175

Besides being a pharmacist, I am a gout

patient and I currently use oxypurinol since I had

an allergic reaction to allopurinol. To fully

understand how my quality of life has improved, you

need to know a little about my history. I had my

first kidney stone at age 20. I continued having

stones periodically until urologist prescribed

allopurinol. My serum uric acid was already well

over 10 mg/dl but I had not yet experienced gout.

Three to four weeks into the treatment

with allopurinol I developed a rash from head to

toe. The allopurinol was discontinued and I was

treated with diet and increased fluid intake alone.

By age 35 both gout and kidney stones were causing

me a great deal of pain and suffering on a regular

basis. My wife and kids also had to endure my pain

and depressed moods. They watched me crawl into

the house because I was in such pain. I had to go

to work on crutches, which didn\'t help because one

gouty foot touched the ground and it does hurt. My

co-workers tried to help by moving me around the

pharmacy on a chair so I could get from station to

176

station.

Finally, I was led to a rheumatologist who

had heard of oxypurinol. My treatments up to this

point included steroids, NSAIDs, mild narcotics and

colchicine which caused me great gastrointestinal

distress. For about eight years I was on

oxypurinol and I was well controlled both for gout

and kidney stones.

Unfortunately, when I was 43 my physician

moved out of the country and I could not find

anyone to replace him and the oxypurinol. There

was an immediate backslide into gout attacks,

kidney stones and incapacitating pain. At times I

would pass more than one kidney stone a week and

have a gouty attack concurrently. The incidence of

gout episodes was increasing as well as the

duration of the attacks. The kidney stones went

from the size of tiny grains of sand to something

that resembled small sea shells. I began

collecting the stones and in this small plastic bag

which contains about 40 stones in that period just

between the first treatment and the second\--I

177

thought soon I would have enough for my own private

beach\--

\[Laughter\]

\--but I wouldn\'t have been able to enjoy

it anyway. Believe me, there was no joy in life

during these attacks. It was during these years

without oxypurinol that I seriously thought that

amputation might be a better alternative to dealing

with the excruciating pain. Then I had a severe

episode in my knee so now I couldn\'t even crawl

around the house. Also, two of my fingers began to

develop tophi about the size of peas.

About three years ago my daughter located

Cardiome Pharma through an Internet search. They

helped me to locate a physician in the area who had

experience in treating a patient with oxypurinol.

He agreed to help me and now I can stand here to

speak to you pain-free. My serum uric acid is

normalizing so gout attacks have ceased. I haven\'t

added a kidney stone to my collection, which has

reduced my fear of impaired kidney function. The

tophi on my fingers are disappearing.

178

Additionally, I have had no rash or unusual blood

work.

Without oxypurinol I merely existed. I

had no quality of life. I had reached the point of

desperation of many times. Now oxypurinol has

given me my life back. I am able to perform my job

as any professional would. I can also enjoy all

the social activities that I had in the past, and I

am grateful for the supply of oxypurinol and I

would like to thank all of you for being attentive

to my story.

I have also been asked to read a letter

from\--You can come back for that.

MR. MIHALO: Come back for that? That is

fine. Thanks very much.

DR. GIBOFSKY: Thank you, Mr. Mihalo. Our

next presentations are going to be delivered

jointly, sharing some time, by Dr. Nancy Joseph

Ridge and Dr. Jane Osterhaus. They will be sharing

15 minutes.

DR. JOSEPH-RIDGE: Thank you and good

afternoon. My name is Nancy Joseph-Ridge. I am a

179

rheumatologist and I work at TAP Pharmaceutical.

We are currently designing a clinical program

looking at a new xanthine oxidase inhibitor so we

would like to share our view as a proposed clinical

trial design for chronic gout.

As you heard this morning, the treatment

of hyperuricemia is indicated for gout; tophaceous

gout; and also renal calculi due not only to uric

acid but also calcium oxalate. The goal, we

believe, is to reduce and maintain serum urate to

less than 6 mg/dl\--fairly well published and

documented.

I want to just go over a couple of

literature reports on observational studies that

have been done. The first one is by Lee Yu and Dr.

Schumacher from Pennsylvania, in General

Rheumatology in 2001, looking at the treatment of

hyperuricemia in patients with gout treated with

allopurinol. This was 57 subjects treated

prospectively for 10 years.

There were 2 groups divided from serum

urate of less than 6 mg/dl and those that were

180

greater than 6 mg/dl. Those with less than 6 were

noted to have reduction in tophi and tophi were

greater in those greater than 6, with 37 percent of

the subjects versus 16 percent of the subjects when

their serum urate was less than 6. Fewer crystals

were noted in the joint fluid of the aspirates in

44 percent of subjects with less than 6 mg/dl

versus 88 percent.

Then, something that we have been talking

about today, fewer gout attacks over a period of 2

years, and that went from a mean gout attack of 1

attack per year versus 6 attacks per year when

serum urate was greater than 6 mg/dl. So, we see

these three outcomes looking at reduction of serum

urate.

The next publication I would just like to

highlight is one from Perez-Ruiz. This was in

Arthritis Care Research, in 2002. He actually

looked at 63 patients who were treated with

allopurinol, benzbromarone or a combination of

both. What he did was look at tophi and measured

then using calipers to see how fast they reduce.

181

The mean duration of tophi resolution actually was

20 months and the time span was anywhere from 6

months to 64 months for the tophi to totally

resolve.

What he noticed was that the resolution

rates of those tophaceous deposits were directly

related to how low your serum urate level was.

With allopurinol there was a 0.57 mm/month

resolution with a serum urate mean rate of 5.37.

Benzbromarone decreased tophi by 1.21 mm/month when

the serum urate was 4. With combined hyperuricemic

activity of both agents in combination, 1.53

mm/month and the serum rate was 3.97 mg/dl. So, a

direct correlation between decreasing serum urate

with reduction of tophi.

What we have seen in our current clinical

trials and what we are proposing as clinical trial

design for chronic gout is for the primary endpoint

to be the maintenance and reduction in serum rate

to less than 6. This is key and may take a while

before you can see clinical benefit up to one year

or maybe longer because of total body urate load

182

having to be decreased over that period of time.

The second endpoints being those of

clinical endpoints in tophi reduction. These

measures via either imaging MRI, ultrasound or the

way that Dr. Perez-Ruiz did using either calipers

or physical measurement. Reduction in gout flares

over a period of time, which would be a long-standing gout

flare reduction over at least a year

period. Inclusion of a comparator to look at

safety and efficacy of allopurinol and/or placebo.

Placebo is very important to look at adverse event

background rates, with adverse events being noted

with concomitant drugs that we give, such as

colchicine, NSAIDs or the other concomitant drugs

that our subjects have to be on. Minimally to

demonstrate equivalence to comparator is also key.

We also think that we should consider a safety dose

which would be 2 times the maximum clinical dose to

give you that idea as far as the adverse events.

Finally, long-term controlled studies, at

least one study having a one-year duration. The

older literature with carbon-14 radiolabeled uric

183

acid shows that it takes at least one year for

total body urate loads to sometimes normalize and

those subjects with tophaceous deposits may take

longer.

The study population should resemble the

gout population and include renal impairment and

those with other co-morbidities, and finally, a

proportion of subjects with higher baseline serum

urate or seeing with epidemiology data that higher

baseline serum urate is a factor and that efficacy

and safety of the drug should be analyzed with

that.

DR. OSTERHAUS: Good afternoon. Jane

Osterhaus, I am a consultant to TAP in the area of

health outcomes. It has clearly been touched on a

lot already this morning, but I would like to

encourage the committee to consider the necessary

inclusion of humanistic information in gout

clinical trials. With the renewed interest in gout

treatments\--we heard that there hasn\'t been a new

treatment in about three to four decades almost, so

I think we have this new increased interest in

184

gout. We also have heard this morning that the

prevalence of gout in the U.S. is certainly

expected to increase due to the aging population,

obesity, increasing rates of type 2 diabetes.

Coupled with the new interest in gout, I

think we have also learned a lot over the last

decade or so about patient-reported outcomes and

their importance in medical decision-making. When

I think about patient-reported outcomes I am

talking about health-related quality of life, work

productivity, functional status\--things that are

quite important I think to the rheumatology

community.

Currently there is no existing guidance on

patient-reported outcomes for gout clinical trials,

but if you think about gout and what we know about

it, it certainly isn\'t a silent disease. We have

pain. We have heard about swelling, tophi and some

of the long-term potentially emotional consequences

of gout as well. Given that, I think it is

reasonable to consider measuring outcomes such as

patient functioning, well-being, symptom relief and

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satisfaction with treatment.

The types of measures that you can

consider recommending or including in clinical

trials range from general health status instruments

such as the SF-36 to disease specific ones. The

SF-36 I think would be a very reasonable choice for

a general health status assessment. It is

certainly well-known in the clinical trials

community. It is probably the most commonly used

health status measure that is a general measure.

Its reliability and validity are certainly well

established and, certainly, if you think about the

rheumatology committee it has certainly been used

in osteoarthritis and rheumatoid arthritis trials.

We also can compare across conditions.

In terms of disease-specific measures, the

HAQ is, again, a very frequently used and widely

recognized instrument that is used in RA clinical

trials. It has 8 domains and it may be useful in

got, although its usefulness may be limited by the

joints of the gout patients that are actually

affected. So, HAQ may or may not have some

186

validity in a gout population.

We have identified no disease-specific

gout measures in the literature and we thought that

it did make sense to probably think about an

instrument that actually focuses on specific

aspects of gout that are not captured in general

instruments like the SF-36. So, TAP has developed

a gout assessment questionnaire that currently

consists of 21 items and 7 domains. We just have

some information based on 2 cross-sectional data

sets. Within that cross-sectional setting we see

good internal consistency, and we see adequate

reliability for its initial use but there is

clearly work that needs to be done on going. We

need to confirm the hypothesized scales. We need

to gain some experience in different gout

populations and we really need to understand the

relationship between the measures in the GAQ with

clinical measures that people have talked about

today. We also need to understand things like

minimal clinical important difference and change

over time.

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If you are going to be including

humanistic measures in clinical trials, it also

makes sense to think about the timing of those

measures. Given the comments that we have heard

earlier that the initiation of gout therapy might

result in more acute gout flares early on and that

it could take up to a year for total body urate

load to decrease to normal, we would recommend that

for patient-reported outcomes you evaluate longer-term data

with considering the impact of gout

treatment from patients\' perspective as opposed to

very short-term data. Thank you.

DR. GIBOFSKY: Thank you, Dr. Osterhaus.

We will next hear from Dr. Zeb Horowitz. Dr.

Horowitz?

DR. HOROWITZ: Members of the advisory

panel, members of the FDA, ladies and gentlemen,

thank you for this opportunity to make a brief

statement to the committee about issues we face in

the design of clinical trials for pipeline product

for refractory gout patients, puricase.

Puricase is a genetically engineered

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recombinant porcine urate oxidase that we are

developing to control hyperuricemia in patients

with severe symptomatic gout in whom conventional

therapy is contraindicated or has been ineffective.

This recombinant uricase has been modified by

covalent detachment of methoxypolyethylene glycol,

which is expected to extend the duration in the

circulation and to reduce the potential for immune

response.

In a Phase 1 study conducted at Duke

University, intravenous puricase appears to be

effective in achieving a dramatic and a prolonged

reduction in circulating uric acid to sell below

the solubility limit. A Phase 2 trial is ongoing

to confirm and extend these results.

We anticipate that rigorous and continuous

control of hyperuricemia throughout the dosing

interval is achievable in most patients with

otherwise refractory gout. Currently approved

agents for the treatment of chronic gout have

demonstrated efficacy in lowering circulating uric

acid but have no definitive evidence regarding

189

their effect on long-term clinical outcomes.

It is our hope that chronic administration

of puricase may prevent or eliminate the

accumulation of uric acid in joints and tissues

that leads to acute gout attacks and other long-term

consequences of chronic hyperuricemia,

including destruction of joints, bones, cartilage

and tissue. However, demonstration of these

clinical benefits within the context of a

registration program is impractical at this time.

We believe that the continuous control of uric acid

well below the solubility limit is the appropriate

registration endpoint for this product.

Major hurdles must be overcome before a

rigorous, well-controlled clinical endpoint trial

can be implemented in patients with refractory

gout. Some of these hurdles are heterogeneity of

patient symptoms in relation to circulating

concentration of uric acid; lack of reliable

information relating rate of change of circulating

uric acid to symptoms; unpredictability of gout

flare frequency and severity; lack of a validated

190

disease-specific instrument to assess clinical

severity and change; lack of a validated

methodology to assess tissue stores of uric acid

quantitatively; lack of a validated methodology to

assess gout tophi quantitatively; and, finally,

ethical concerns about placebo-controlled design in

long-term clinical trials in refractory gout

patients even though these patients are already

inadequately treated with available therapies.

In view of these hurdles in trial design

for the treatment of refractory gout, what is the

most appropriate efficacy endpoint in pivotal

trials today? The circulating concentration of

uric acid is the most reliable measure of drug

efficacy in hyperuricemic gout patients for whom

conventional therapy has failed to control disease,

or who are unable to use alternative therapies due

to intolerance. These refractory gout patients

have chronic hyperuricemia even while using

allopurinol or uricosuric agents. Such patients

suffer chronic, debilitating pain and deformity.

No spontaneous remissions occur.

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We know that chronic hyperuricemia leads

to tissue accumulation of urate, but we cannot

directly correlate the degree of urate accumulation

with the effective drug treatment on urate

accumulation with clinical outcomes.

Puricase offers the possibility of

continuously and dramatically lowering circulating

uric acid levels on a chronic basis. We have

observed puricase to do this in the first day of

administration of a single dose, and to maintain a

very low level for up to one month. We anticipate

that very low levels of uric acid can be maintained

on a chronic basis in most patients upon multiple

dose administrations at multi-week intervals.

The effect of puricase on tissue levels of

uric acid is unknown. We hypothesize that over

periods of time, perhaps long periods of time,

tissue deposits of uric acid can become gradually

mobilized into the circulation where puricase will

safely destroy it. Over months or years a

beneficial reduction in painful symptoms of gout

may become observable in otherwise refractory gout

192

patients. The number, volume and symptoms of gout

tophi may become reduced.

As long as the maximum concentration of

circulating uric acid remains continuously below a

very conservative threshold, perhaps less than 6

mg/dl, over a long period of time it is reasonable

to expect a highly favorable clinical outcome. But

we cannot predict when and in what specific way

these benefits will accrue. In this context, we

believe that the most appropriate efficacy endpoint

for pivotal trials of a new agent, as effective as

puricase is in lowering the circulating uric acid

concentration, is the circulating acid

concentration. Thank you.

DR. GIBOFSKY: Thank you, Dr. Horowitz.

Dr. Horowitz is senior vice president and chief

medical officer of Savient Pharmaceuticals, Inc. in

East Brunswick, New Jersey. Our next presentation

will come from Mr. Edward Mihalo, reading a

statement from Mr. Walter J. Clifford who is unable

to attend due to travel problems. Mr. Mihalo?

MR. MIHALO: I am Walter Clifford, a

193

resident of Colorado Springs, Colorado, where I

reside with my wife of 37 years. We are the

parents of 8 children. I will shortly be 60 years

of age. My academic training and professional work

are in the areas of immunology and microbiology. I

own and operate a small specialty lab which

provides immunologic clinical testing and research.

Although I have been aware that gout has been a

problem to members of my extended family for

several generations, I did not personally recognize

the problem in myself until approximately the age

of 45 years.

Our family has an atypical manifestation

of the condition which strikes in the ankles,

knees, hips, shoulders, elbows, wrists and hands

but very seldom in the great toe. Fluid aspirates

from the wrist, elbow and knees have demonstrated

the abundance or classical uric acid crystals. The

outward manifestations of regional swelling, hot,

red tissue and severe restricted mobility have all

been present during flares.

Initial treatment with indomethacin and

194

colchicine were ineffective. For a period of about

six months allopurinol seemed to help. However, I

developed the classical allergic response to the

allopurinol, including swelling, hives on the

torso, back and face, elevated heart rate and

difficulty in breathing. Intolerance of

allopurinol required intermittent prescriptive

doses of benadryl and other histamines under the

direction of an allergist. Clinical effectiveness

of the allopurinol diminished until it was finally

discontinued altogether.

Gout flares became frequent and severe and

could only be controlled with methyl prednisolone

in Medrol tapered dose packs. The Medrol is

usually restricted to three or at most four uses

per year. However, my condition became severe

enough that packs were used every four to six weeks

and, on a few occasions, back to back. My

rheumatologist worked with me to manage diet and

other considerations, as well as to try various

approaches to control the gout.

Nothing seemed to make much difference in

195

either frequency or severity of the flares. As I

began to lose mobility of my hands and wrists, it

became harder and harder to work at my profession

and in the lab. The flares in my knees and ankles

made it difficult to safely drive the car and I

became dependent on my wife to drive me where I

needed to go. I very seriously began to search for

an alternative as the flares became more frequent

and severe.

When my doctor approached me about taking

part in a clinical trial study involving oxypurinol

I eagerly agreed in the hope that something might

be found to help me. I began the study in July,

2000\. Within a few weeks I began to find

substantial relief from the gout and immobility.

Since time I have only had two flares, both of

which were substantially shorter and more moderate

than previously experienced. Both subsided quickly

with a single Medrol dose pack.

Today I seldom worry about gout. The

oxypurinol has worked well and seems to fit in well

with the medications being taken for unrelated

196

conditions. It has not only been highly

instrumental in my being able to perform my work

and to be self-reliant, but has made a monumental

difference in quality of life.

I have been a light aircraft pilot and an

organist for many years. Gout made both of these

pursuits virtually impossible. I could not manage

the communications and navigation equipment in the

plane and I lost the ability to safely operate the

controls in the aircraft. While serving in the

Army in Vietnam I provided volunteer musical

service to the various chapel services whenever my

duties permitted. I could handle service music,

including high mass, while wearing combat boots.

Sadly, at the height of the gout flares I could not

manage even simple service hymns due to loss of

mobility and agility. Since starting on the

oxypurinol program I have been able to regain

sufficient freedom of movement and again provide

volunteer musical services at the church and

elsewhere. I suspect my flying days are past.

For very selfish reasons, I wanted to be

197

able to continue in my profession, as well as to

enjoy an improved quality of life. I earnestly

hope that oxypurinol makes it to market. I cringe

at the thought of losing it, expecting that I might

well live out my remaining life as a cripple if the

gout returns. I am most appreciative of the folks

at Cardiome Pharma for their contribution to my

health and that of others. I also appreciate the

opportunity to have something to put before the

committee. Thank you, Walter J. Clifford.

DR. GIBOFSKY: Thank you, Mr. Mihalo. Our

next presentation will be from Mr. Allyn Hamilton.

Mr. Hamilton?

MR. HAMILTON: I hate to bore you all

again with the crutches, and all that sort of

stuff. When I met Dr. Hustetter, who put me on

this, he was a new doctor in his arthritic office

in Chattanooga, Tennessee. He said, \"what are you

doing about it?\" I told him, I said, \"well, I\'m

drinking a lot of water and I\'ve cut down\"\--I used

to eat liver, calves liver and cooked onions and I

could feel my knees swell up while eating this. I

198

told him I was quitting that. I was drinking a lot

of water, keeping my feet elevated, trying to build

up my legs because I a golfer. I couldn\'t even go

18 holes in the golf cart. Now I carry my own bag.

But some of the medicines that we tried,

colchicine, allopurinol, Benemid, Indocin which was

good for attacks, butazolidin, Clinoril, anturane,

cortisone\--of course, he would shoot me with

cortisone every time he drained the thing, Zyloprim

and all my stuff is very dated because I have been

on oxypurinol for 20 years and it works like a

charm. So, I don\'t know anything about all these

things you all are talking about. I never had to

worry about them. But Zyloprim was the medicine of

choice for a maintenance drug when I was going

through this. The first pill I took, I didn\'t even

get home before I had violent swelling in this

shoulder and I think it created an attack. So, I

called the doctor back up and he said get back down

here. This was a different doctor, of course. I

went to about 20 doctors before I finally got on

oxypurinol. I went down there and he gave me a

199

shot of adrenaline and sent me home. He said I

don\'t know what you can do about it, outside of

just the normal eating colchicine by the handful,

dosing with a bunch of pain pills, with your feet

propped up on top of the sofa for days. Just

excruciating pain.

Real funny, Dr. Hustetter, when I started

with him, he said, \"you know, you\'ve got a

fantastic threshold for pain.\" Let me tell you how

painful this stuff is, when that pressure builds up

it is horrible. Anyhow\--let me see, that is pretty

much it really. Thank you very much. Cardiome\--how do you

pronounce it?\--is covering my expenses

and stuff. Thank you.

Committee Discussion and Questions

DR. GIBOFSKY: Thank you, Mr. Hamilton.

That concludes the presentations during the open

public hearing. The committee will now begin its

consideration of the questions posed to us by the

members and staff of the FDA. You have before you

a list of questions. There are in eight broad

categories with multiple sub-bullets. In the

200

interest of clarity and efficiency, while many of

these issues appear to be inter-related in terms of

surrogacy endpoint clinical differences and what

patients should be enrolled in trials, I would ask

that we consider them in order seriatim rather than

kind of go back and forth. So, we will begin with

the first question.

Please discuss the utility of serum uric

acid as a surrogate marker for the chronic

treatment of gout. There are several sub-bullets:

If an appropriate surrogate, what level of serum

uric acid or amount of change would be considered

adequate v of efficacy?

Would an analysis comparing mean change

for treatment populations reflect efficacy? Would

analysis comparing numbers of individuals in each

treatment arm reaching a prespecified level or

amount of change adequately reflect efficacy?

Are there advantages to choosing an

analysis of either the uric acid levels at last

visit or the uric acid levels over time, based on

AUC? Does the choice of surrogate as the efficacy

201

endpoint influence the decision of what is

considered acceptable risk?

The question is now open for discussion by

the members of the panel. Come, come, don\'t be

shy! Dr. Cush?

DR. CUSH: I think for everyone who

practices rheumatology uric acid as a marker for

success makes incredible sense. It is, in fact,

what we look to do in the management of our

patients. But as a sole basis for a drug\'s

approval, withstanding other information, it

becomes a little bit difficult. Again, I think we

sort of make that leap of faith that if we control

uric acid we control the disease but I don\'t think

we have enough really quality data to tell us that

control of uric acid leads to better quality of

life, less joint destruction, better survival. For

attacks, I think there is probably enough evidence

to say that, but I think the idea is that it is a

large leap that this committee would have to make

to back that, and I think to accept that as a

surrogate and then require all this other stuff to

202

show these facts may be passable.

But I think, you know, really there is no

reason that a drug in development at this stage

can\'t have one of these surrogates as a primary

outcome along with the clinical outcome, and that

trials be constructed using both placebo and active

controls for extended periods of time to answer

these questions.

DR. GIBOFSKY: Dr. Williams?

DR. WILLIAMS: I listened to all this and

it certainly isn\'t one percent of the population.

That would be as frequent as rheumatoid arthritis

and that is not true in my practice. I think that

while I would like to see as an endpoint the

decrease in joint destruction and decrease in the

number of acute attacks, I think as a practical

matter we need to use some sort of surrogate so you

can identify the disease by the presentation of

crystals. But I think you can use serum uric acid

level as a surrogate. We certainly do as we

monitor these patients. If we can get it down

below 6 we would anticipate that that would

203

decrease the frequency of attacks and improve the

joint function.

DR. CUSH: It goes against the

anticipation that that would happen. I think what

we have done, we have been holding manufacturers to

a higher level of evidence and they need to show us

that in truly objective measures.

DR. GIBOFSKY: Dr. Williams?

DR. WILLIAMS: That would be the ideal,

but I think that you are going to have trouble

getting the number of patients necessary to really

get good data to show that you made that kind of

change. I hear them saying 6 attacks per year. It

is going to take 100 clinics to get 200 patients

and those trials are going to be very difficult to

do. So, in the meantime I would use it as a

surrogate because I think that that is the way we

use it now in practice.

DR. GIBOFSKY: To what extent is the serum

uric acid a surrogate for total uric acid? We have

all seen these pictures of tophi and the tophi can

be quite extensive and, yet, the serum uric acid

204

may be only mildly elevated. So, I guess the

question that has been coming up to me again and

again is while serum uric acid may be a marker, is

it an appropriate marker for total uric acid? Is

that what the gold standard should be? Dr.

Williams?

DR. WILLIAMS: I think it is a marker of

the total serum uric acid. We can lower the serum

uric acid faster than we can lower the pool.

However, over time if you keep the uric acid low

you will gradually lower that pool. Rapid lowering

of the serum uric acid may have very little impact

on the total pool to start off.

DR. GIBOFSKY: Dr. Cush?

DR. CUSH: Earlier today we heard from Dr.

Terkeltaub that measuring total body urate by

looking at tophi would make some sense, or maybe

even more specialized means. Now we are examining,

you know, using a surrogate marker for a disease

and its activity, and now we are talking about a

laboratory test to look at a disease and its

activity. My point is gout is an easy disease.

205

They hurt. You know, clinical measures work. I

think everything else is going to be icing on the

cake and I don\'t see any reason why we can\'t

require strong clinical outcomes. I mean, this is

predominantly a disease of pain.

Going to Jim\'s point, I don\'t have these

people in my clinic either, and over 3600

practicing rheumatologists, we take care of a very

small minority of almost 5 million people who have

this disease. That means they are out in the

private sector. They are being treated by primary

carers and emergency room docs, and that is why we

don\'t see them. So, obviously, the trial is not

going to be done in my office as well as it is

going to be done in a hospital and its emergency

room.

DR. GIBOFSKY: Dr. Felson?

DR. FELSON: I actually sketched out the

primary endpoints and the pros and cons of each of

them. Serum uric acid could be defined in one of

three ways as an endpoint, I guess. One is by the

regression, sort of continuous measure and does it

206

change on treatment more than in the comparator.

The good news about that is it is powerful because

it is continuous. The bad news about that is it

may be trivial and be significant.

Then, there is sort of the arrangement

that was made for what was called the pivotal trial

for oxypurinol, which was at least a 2 mg/dl

decrement as the lower bound of the 95 CI of

improvement. I actually have a bunch of problems

with that. One is that it suddenly dichotomizes

the continuous measure and, therefore, makes it

less powerful. Another, which I think has been

said a few times here, is that I am not sure

whether it is clinically important.

Then, the last one would be a reduction to

an arbitrary level on the part of a certain number

of patients. That is bullet number three, would an

analysis comparing the number of individuals in

treatment arm reaching a prespecified level or

amount of change\--we just talked about the

prespecified amount of change; this is the

prespecified level. The obvious one, based on the

207

literature and based on the physicochemical

solubility of uric acid, sounds like it is less

than 6 over a period of time.

That seems to me the only supportable

primary efficacy measure that you would use for

serum uric acid, if you used one. Now, the problem

there is the ability to get to that level would

likely depend on the baseline level in a given

person or group of people, and it would be harder

to reach if some people start off with very high

levels. I think one could argue that since there

are effective therapies here already, even though

not maybe not in some subsets of patients, it might

be okay to ask for a high threshold level of proof,

which this would be.

Then, the alternative is the Jack Cush

alternative. You know, it is interesting, I came

here this morning thinking I would choose that.

Then as I listened to the serum uric acid

discussion I think you guys all convinced me we

should go to serum uric acid. Then I think as I

thought about what Jack was saying, I think I came

208

a little bit back towards that because it is such a

symptomatic, easily characterizable symptomatic

disease and attacks are the central manifestation.

The problems with using clinical attacks

are that they increase early in uric lowering

therapy so one would have to define it after a

certain period of time on treatment or start

enumerating them. I think there is another issue

in these particular types of patients who would be

eligible for these trials. Frankly, I see a lot of

these because I practice in a municipal hospital

and I am not sure when a given attack begins and

ends in any of these patients. They often have

very continuously active, smoldering disease and it

might be difficult to enumerate attacks in some of

these patients.

Then the other thing I think Marc or

someone else brought up earlier is that the number

of attacks might be affected by co-therapy to

prevent attacks. I think you could probably get

around that design issue by just requiring

constancy of some co-therapy so that it doesn\'t

209

vary through the course of the trial. Then you

would have an outcome, so you would do number of

attacks sort of starting at three months or six

months after initiation of therapy per month, or

something, and that might work the best of all.

DR. GIBOFSKY: Dr. Hochberg?

DR. HOCHBERG: Dr. Felson is always a hard

act to follow because he is so thoughtful in the

way he lays things out. I want to step back to the

issue of whether uric acid is a surrogate. I guess

when I think of a surrogate I think of sort of the

evidence-based medicine approach. There is

actually a paper that speaks directly to this as to

when something is a good surrogate and when it is

not a good surrogate. We know from the

epidemiological data that measurements of serum

uric acid predict the development of gout. So, it

is great for that.

We have some observational data, although

not from placebo-controlled, randomized trials,

that suggest that if you change the measure of uric

acid you get an improvement in some of the clinical

210

outcomes in terms of a decrease in size of

tophaceous deposits, as well as a decrease in the

number of attacks.

I think putting those two together, you

would say, yes, this behaves as a surrogate

endpoint. Now, the problem is that the drugs lower

serum uric acid so that you are treating

hyperuricemia, but the treatment of gout is

different because gout is arthritis, and gout is

painful and it is clinically characterizable, as

Jack, David and others have commented. In a trial

which is focused on a drug which would lower serum

uric acid the patients are not going to come in

naive to treatments for gout. They will either be

on colchicine or they will be on NSAIDs or they

will be on glucocorticoids. So, they will need to

have some background therapy and then one deals

with the issue of are you recruiting subjects for a

study who have failed previous hyperuricemic

therapy in order to determine whether a new agent

will lower serum uric acid levels as the primary

endpoint, or the secondary endpoint of will it

211

reduce the number of, let\'s say, attacks of gout or

the severity of arthritis during the course of time

in a population that is already being treated for

their arthritis.

So, I would look at uric acid as, yes, it

is a surrogate marker for gout but it is something

which is an appropriate endpoint in and of itself

in the patient with recurrent attacks of gout or a

chronic gouty arthritis.

DR. GIBOFSKY: Dr. Williams, did you have

a comment?

DR. WILLIAMS: As usual, I agree with

David Felson but if someone lowered their uric acid

by 2 degrees or by 30 percent and they still had a

uric acid of 8, I wouldn\'t find that very

satisfactory. So, I would agree that we would have

to set a fixed level, and from the data it would

appear to be 6 mg/dl.

However, I have one problem with using

acute attacks as an endpoint, besides those that

have been mentioned, and that is that the disease

is so episodic and so unpredictable. So, you are

212

going to have to follow them for a significant

period of time to get enough attacks or enough

expected attacks to make a difference. It is not a

continuous problem like rheumatoid arthritis and I

think that that makes the trial much more difficult

and longer and larger to get adequate numbers.

DR. GIBOFSKY: Dr. Cush?

DR. CUSH: Not to be a broken record, but

when my patients come back with gout the first

question I ask is not what is your acid, I don\'t

even care if I have the lab and the chart, you very

easily ask them what has happened since the last

time I saw you. The last time I saw you I may have

started you on allopurinol or on probenecid or

colchicine and loaded prednisone to the mix, and

successful therapy is whether you have had attacks

or not. Then I feel good about myself when I see

that uric acid went down. I don\'t actually have a

target. I mean, I would like them all to be less

than 6 but in practice that is not commonly

achievable. But what is achievable is control of

the disease.

213

DR. GIBOFSKY: Dr. Hochberg, as you know

and as we heard, there is a poor correlation

between serum uric acid and gouty attacks. To what

extent would that factor into the assessment of

lowering serum uric acid as a surrogate marker?

DR. HOCHBERG: Well, I think in terms of

the prediction of the development of gout there is

actually probably a very good correlation, from the

population data at least, for having hyperuricemia

and having the subsequent risk of developing gout.

With regard to the individual patient who

comes in with acute gout, you know, you are right

in that there is a large proportion who will have

normal serum uric acid at the time that they

present with acute gout. So, I personally think

that uric acid has to be looked at separate from

the issue of gouty arthritis and go back at least

to the way I was taught to practice, which was to

treat the arthritis, probably the way Jack Cush

treats the arthritis\--not too different from the

East Coast and Texas\--but to focus on the serum

uric acid as a measure\--and Dr. Terkeltaub can

214

correct me and maybe tell us how good a measure it

is\--of total urate pool and the fact that probably

reduction in the uric acid will be associated with

reduction in the size of tophi, and that needs to

be addressed separately.

DR. GIBOFSKY: Dr. Hoffman?

DR. HOFFMAN: I would concur with Marc\'s

observations. While we have all seen patients with

normal or borderline uric acid levels come to us

with gout, I don\'t think the issue is so much is

there a direct linear relationship between the

serum uric acid at any one point in time and will

someone get gout. I think it is more of an issue

of being supersaturated over time\--how long has

this patient been building micro tophaceous

deposits until the time comes when they actually

have what we think of as strip mining of sodium

uric crystals from those deposits. If somebody is

acutely hyperuricemic, that may not be terribly

relevant compared to the person who has been

sitting at a uric acid level of 8.5 for 15 years.

But to get more to the bullet point that

215

we are addressing, is serum uric acid an

appropriate surrogate, I think the alternative

question is what do we have as a better surrogate?

Unless you would like to call on Bob Terkeltaub

again to address this, but as far as I know we

don\'t have a means of measuring total body urate

pool so we can\'t use that as a surrogate. And, I

am not aware of any other surrogate that is going

to serve us better than serum uric acid. A change

in uric acid, is it an adequate measure of

efficacy? Well, it is one measure of efficacy. I

don\'t think we can use that as the only endpoint in

a study. I think we have to use it in conduction

with reduction in attacks of gout.

As Jim Williams pointed out, if we are

dealing with people who are not having very

frequent attacks of gout, that is going to be

difficult and going to require a very large number

of patients to do that study. So, there are some

logistic issues in study design there.

But I think the issue is very complicated

because we know it is not just a matter of what

216

your serum uric acid is or at what point at time,

but it is over time and then there are other

variables such as crystallization\--perhaps there

are some that we know of and perhaps more that we

don\'t know of that determine why there are patients

whose serum uric acid maybe 10 for 10 years who

never get an attack again.

DR. GIBOFSKY: Well, we have heard from

the East Coast; we have heard from Texas; we have

heard from part of the Heartland. Comments from

the West Coast? Dr. Finley?

DR. FINLEY: Mr. Chairman, I share the

concern that we do need to have a clinical marker

as a surrogate as well as the serum uric acid. As

we have heard from the public comments, for the

patients, as Jack Cush mentioned, they are not

concerned about what their uric acid is. I also

share Jim Williams\' concerns about us conceiving

and recommending to the FDA a study that, you know,

for the sponsors is not attainable in a fashion

that would be acceptable to the non-rheumatologists

who treat most of this disease.

217

DR. GIBOFSKY: I would hope that the FDA

would not allow us to recommend the perfect as the

enemy to the good, particularly for patients with

gout. How about the Deep South? Dr. Boulware?

DR. BOULWARE: I am actually very

comfortable with using serum uric acid as a

surrogate marker for this study. I am reading it

now more broadly in terms of this broad discussion

of a surrogate marker for the treatment of gout.

We started off by talking about a very select

population and we have boxed ourselves in, saying

we probably can\'t use clinical outcomes of patients

because it may be too small or restricted a patient

population. But if you really wanted to see if a

drug was effective for the chronic treatment of

gout and open it to all gout patients, not just

those who have intolerance to allopurinol, then we

maybe could answer this question. So, I would

favor using a clinical outcome marker too, but not

if it means that you essentially hamstring the

study.

DR. GIBOFSKY: Any other comments from

218

other colleagues in Baltimore, Dr. Bathon?

DR. BATHON: I would agree that I think a

dual kind of outcome is appropriate. I like the

idea of serum uric acid but I think it should have

a clinical correlate. If I had to choose what

outcome of serum uric acid I would like, I think it

would be to hold it to the most rigorous

expectation, which would be to normalize uric acid

and ensure that correlates with reduction in

clinical episodes.

DR. GIBOFSKY: Dr. Terkeltaub, your name

was invoked for perhaps some clarification of one

of Dr. Hoffman\'s issues. I wonder if I could ask

you to address that at this time briefly.

DR. TERKELTAUB: I have some concern that

if trials aren\'t constructed properly, when looking

at serum uric acid levels we are going to be

impairing development of drugs to treat patients

with difficult gout and a high body burden of serum

uric acid. The numbers in terms of trying to use

serum urate to interpret effects on urate pool size

change, if you take a normal man that has a urate

219

pool of about a gram and that man has 5 L of

plasma, then what is in the plasma at a level of 7

mg percent reflects about a third of the total body

pool. Whereas, you know, some of the patients that

we see with really bad gout have 5, 10, 25, 30

grams of uric acid and then the serum urate

reflects really a couple of percent of the total

body urate pool.

So, my concern is that when trying to

evaluate urate lowering therapies, if we only use

serum urate and if we try to pigeonhole people to a

level that is considered normal, 6 mg percent, that

we are not going to be really looking at people

where they have a shrinking tumor burden of tophus

and that would be a great mistake.

DR. GIBOFSKY: Dr. Felson?

DR. FELSON: Bob, if the physicochemical

solubility is at 7 and we lower it to 6, they have

to be, at least at some rate, taking some of that

stuff that was out of solution and putting it back

into solution and if their kidneys are working, you

know, peeing it out or getting it converted to

220

something else. I mean, it has to be shrinking,

doesn\'t it? Aren\'t we messing with the dynamic

flows of their uric acid pool?

DR. TERKELTAUB: Yes. I think the

question is when you have a serum urate level of 10

and you reduce it to 8, are you failing to control

the disease? There, I think the serum urate is a

problem. You don\'t get urate crystallization in

plasma and serum; you get it in the tissues. And,

I don\'t think serum urate accurately reflects what

is going on at the tissue level in that

circumstance. You know, if you are reducing the

manufacturing of uric acid and you are reducing

tissue deposits, which clearly happens in many of

our patients who are stabilized on drugs such as

allopurinol, then you are not really getting an

accurate readout on the serum level.

DR. GIBOFSKY: Thank you, Dr. Terkeltaub.

Dr. Geis?

DR. GEIS: I just want to clarify what I

think I am hearing. Are you saying if you powered

a clinical trial with a primary endpoint being some

221

measure of uric acid levels, then you would have a

manageable sample size to do a trial? And, if you

collected clinical outcomes and you weren\'t powered

to see a difference necessarily from placebo but

you saw numerical differences, and you were

statistically better with uric acid levels, are you

then saying you could interpret to mean that drug

treats gout? Is that what I am hearing people say?

And, if a sponsor replicated that, then you would

say, yes, the drug treats gout. It doesn\'t just

treat the uric acid, it treats the gout as long as

you had some measure of clinical outcome, although

not statistically significant? Is that what I am

hearing?

DR. GIBOFSKY: I am not sure we have gone

that deep into trial design. We have just been

focusing on the utility of serum uric acid as a

surrogate marker based on the comments we heard

before\--

DR. GEIS: Okay.

DR. GIBOFSKY: To what degree a study is

powered, or should be powered, perhaps we will get

222

into with one of the other broader areas. Dr.

Williams, you were next with a comment or question.

DR. WILLIAMS: Actually, that addresses

exactly what I wanted to say, and that is, when I

was referring to an endpoint of less than 6 mg/dl

as an endpoint to show that you have efficacy, it

doesn\'t necessarily mean that it would be the total

approach that it is an effective treatment for

gout. I was trained that if I am trying to lower

the serum uric acid pool I would like to get the

uric acid to 3 or 4. However, I would not make

that the level to demonstrate that you are

effective in lowering uric acid.

DR. GIBOFSKY: Dr. Hochberg?

DR. HOCHBERG: I guess before I ask my

question, which is really a question to Dr.

Terkeltaub, I would comment back to Dr. Geis\'

question. In one of Dr. Witter\'s slides on the

approved indications for the products that we are

discussing, this sort of class, I like the

indication that says for the treatment of

hyperuricemia associated with gout. I think that

223

is what we are talking about now because I still

consider gout to be a form of arthritis and when I

am treating gout I am treating the attack of gout.

When I am treating hyperuricemia I am treating

hyperuricemia.

So, I would sort of like to know if there

are relatively straightforward, reliable methods

which are not too expensive to measure the total

body burden or total body pool of urate that

function better than the serum uric acid level.

DR. GIBOFSKY: A quick replay, Dr.

Terkeltaub?

DR. TERKELTAUB: No.

DR. GIBOFSKY: Thank you. That was quick.

Dr. Anderson?

DR. ANDERSON: I would just like to

comment on the relative power of an outcome as

change in uric acid level or reaching a certain

level in uric acid versus the clinical outcome of

the number of attacks in a time period like a year.

Actually, the power for an outcome where you would

be comparing two groups for number of attacks per

224

year is really pretty good. You know, it is fairly

reasonable to assume that these attacks follow a

Poisson distribution and I think that the study

that was proposed by Cardiome is actually

overpowered. You know, by the description that is

given, it is overpowered for the outcome of cutting

the number of attacks by 50 percent. So, really

just isn\'t such a hard thing to do. That is really

what I am trying to say.

DR. GIBOFSKY: Dr. Cush?

DR. CUSH: I like the way Marc has divided

it up. To make the analogy with rheumatoid

arthritis, you know, I treat the arthritis

utilization now I am also looking for treatment

that would focus on the CRP, treatment that would

lower CRP. CRP is a little bit different than uric

acid but they are pretty close. CRP is a direct

extension of IL-6. Anyway, I have a little bit of

a problem with that approach but I think we should

get to the real issue which, again, is a surrogate

marker, comparing to HIV and bone density and

lipids, where there are clear-cut, defined benefits

225

to control or lessening of those levels. Again,

what is the clear-cut evidence for taking a patient

who has defined gout\--we certainly know that having

elevated uric acid levels increases one\'s risk of

having attacks but take it the other way around,

they have gout and I presume they have

hyperuricemia, what is the evidence that lowering

hyperuricemia gives you X benefit as far as quality

of life, attacks, extra-articular manifestations,

x-ray erosions, damage, disability, blah, blah,

blah? I am not aware that there is a lot there.

Is there anything there that hasn\'t been presented

today?

So, again, it is a gigantic leap of faith

that we are making based on what we have done for

years and years and years, which is the problem

with the whole gout literature and the research.

It has been an empiric disease since Hippocrates.

DR. GIBOFSKY: Dr. Williams?

DR. WILLIAMS: However, in clinical

practice if we lower their uric acid we decrease

the frequency of their gout attacks.

226

DR. CUSH: We do?

DR. WILLIAMS: It seems to be so in my

practice and we heard from some people here today

who have done well on lowering of their uric acid.

DR. CUSH: I don\'t doubt that but the

evidence is what I am concerned about.

DR. WILLIAMS: I agree, we don\'t have

solid evidence.

DR. CUSH: I don\'t know how I can tell FDA

and you, know, draw up a guidance document for this

to, you know, leap forward on leaps of faith rather

than good evidence.

DR. GIBOFSKY: Are you having a problem

with a faith-based initiative?

\[Laughter\]

DR. CUSH: You are my lawyer, I can\'t ask

you for advice for how to answer that.

DR. WILLIAMS: However, we are not going

to have any more new treatments. If we don\'t move

ahead we are going to stay where we have been over

the last 30, 40 years.

DR. GIBOFSKY: Ms. McBriar?

227

MS. MCBRIAR: Yes, I think it is time to

do something. There hasn\'t been anything new for

quite a few years and the patients obviously have a

need, and we are seeing an increased prevalence and

I think we have to choose the best ideas that

people have here and move with them and see what we

learn.

DR. GIBOFSKY: Dr. Bathon?

DR. BATHON: I agree with what Dr. Cush

was saying but I think, drawing the analogy to

rheumatoid arthritis again, we learned a lot about

the natural history of the disease and the efficacy

of a drug that we have been using for a decade or

more, called methotrexate, when we did the clinical

trials of new TNF antagonists. I think we have

that opportunity here. We have to accept the fact

that we don\'t have a lot of data to base our design

on right now but if we design the best trial that

we can, given the data that we have, we might be

able to answer these questions a couple of years

down the road and have a better handle on the

natural history and the impact of allopurinol, much

228

less the new drugs.

DR. GIBOFSKY: Dr. Hoffman?

DR. HOFFMAN: I am trying in my own mind

to synthesize what we have been hearing from a

number of people, and I think what I am hearing,

including from Dr. Terkeltaub, is that there are

people who clearly have reduced frequency of gouty

attacks even if their uric acid is not brought down

to some magic number, perhaps 6 or less. We are

not sure about how adequate a serum uric acid

change of whatever amount you want to choose is in

being an absolutely adequate surrogate of efficacy\--

decreased gouty attacks.

So, if we don\'t have that degree of

certainty, it would appear that the endpoints for a

gout study would have to be two-fold. On one

level, decreasing serum uric acid and on the other

level numbers of gouty attacks per patient over a

unit of time. I don\'t think I could advocate a

study that did not include both endpoints.

DR. GIBOFSKY: I think we have had

considerable discussion of question I. I would

229

like to drill down on the five bullets. There will

be ample opportunity for further discussion. Our

charge was to discuss the utility of serum uric

acid as a surrogate marker for the chronic

treatment of gout and now perhaps we can just try

and get some consensus, without formal vote, on the

five bullets. Is there a consensus there is an

appropriate surrogate? Is there anyone who would

disagree that it is an acceptable surrogate? Not

the acceptable surrogate but an acceptable

surrogate?

\[No response\]

Then, what level of serum urate or amount

of change in serum uric acid level would be

considered adequate evidence of efficacy? Dr.

Cush, you had your hand up so I will let you tackle

that one.

DR. CUSH: I will reiterate that it is not

percentage change, it is absolute value and I will

stay with 6 as my target.

DR. GIBOFSKY: Okay. The second bullet,

would an analysis comparing the mean change in

230

serum urate for treatment populations adequately

reflect efficacy? Dr. Hochberg?

DR. HOCHBERG: No.

DR. GIBOFSKY: Discussion? Disagreement?

\[No response\]

Would an analysis comparing the number of

individuals in each treatment arm reaching a

prespecified level or amount of change adequately

reflect efficacy? Dr. Anderson?

DR. ANDERSON: If it was a prespecified

level, yes.

DR. GIBOFSKY: Dr. Felson?

DR. FELSON: I didn\'t understand

Jennifer\'s answer.

DR. ANDERSON: Well, the question was

would an analysis comparing the number of

individuals in each treatment arm reaching a

prespecified level of SUA adequately reflect

efficacy? And, I said yes to that, but no if it

had been amount of change.

DR. GIBOFSKY: Are there advantages to

choosing\--I am sorry, Dr. Cush?

231

DR. CUSH: Going to the prespecified

level, I want to get to a point I made earlier, the

cholesterol analogy. Cholesterol trials took off

because we had drugs to lower cholesterol levels

and we thought it was a good idea, and we had

prespecified levels we were shooting for. When we

did all that we actually didn\'t know what the long-term

benefits would be. That didn\'t happen until,

you know, 50,000 or 100,000 people were treated in

long-term trials and we saw reductions in

cardiovascular mortality, and what-not. So, there

it became a great surrogate. But when it was first

used it was probably assumed to be a good

surrogate. David?

DR. FELSON: I think, Jack, you made the

exact right point earlier when you said we don\'t

know what going to 8 mg means with respect to

clinical effect. In cholesterol there were a

variety of epidemiologic data that suggested that

if you lowered it to a certain amount you would get

a lower rate of the endpoint. That is why it was

acceptable. The only evidence we have that a

232

particular level is going to lower the risk of

attacks is the level of 6. Since that is what has

been studied, that is where we have the evidence.

It may well be, as Jim was saying, that if we lower

from 10 to 8 we get less attacks but there is no

evidence for that. I think it wouldn\'t be a good

idea to suggest that that be the endpoint because

it doesn\'t necessarily have any clinical meaning.

DR. GIBOFSKY: Don\'t go away from the

microphone, Dr. Felson. Are there advantages to

choosing an analysis of either the uric acid level

at last visit or the uric acid level over time,

based on the AUC?

DR. FELSON: There are always advantages

in terms of power\--well, not always but almost

always, to choosing uric acid levels over time

because the average one might be a noisy thing. I

think the one exception is if the curve shows that

on treatment uric acid levels continue to decline,

perhaps be dose is going up, then if you pick the

very last level you will get the very best

reduction. So, I think it depends on the

233

particular treatment and what the curve of therapy

is doing to the uric acid level. I think the other

thing is, frankly, increasingly we are interested

in effects that have duration. So, I think doing

something over time is reasonable.

DR. GIBOFSKY: Let me introduce the last

bullet by referring you back to Dr. Villalba\'s

slide 27, entitled, the oxypurinol challenge.

Define a population for a favorable risk/benefit\--benefit,

modest decrease in serum urate; risk,

intolerance. With that as background, is the

choice of a surrogate as the efficacy endpoint

influence the decision of what is considered

acceptable risk? Dr. Finley?

DR. FINLEY: The short answer is I think

yes. Even though we have been talking about the

surrogate as the serum uric acid, you know, in our

discussion we talked about who really treats these

folks and I think Jack mentioned where the studies

will be done, and I still concern myself that as we

ask the sponsors to aim for some target, whatever

surrogate we pick, and remember who is going to be

234

doing the studies, and probably not a preponderance

of them will be in the hands of rheumatologists

necessarily, that choice of surrogate is clearly

very important. I would advocate, you know, we

consider things beyond the serum urate.

DR. GIBOFSKY: I think we have adequately

discussed question I. I would like to move on to

question II. There will be much more time for

discussion as we go along. We have eight topic

areas to consider. So, if we can put up question

II, for a drug to be approved for the treatment of

hyperuricemia associated with gout, what additional

information besides uric acid levels are important

to collect? That topic is now open for discussion.

I think we have already alluded to some of that.

Perhaps we could just have a reiteration in the

context of this particular question. Anyone want

to tackle that one? Dr. Williams?

DR. WILLIAMS: Well, I think we have

discussed that we would like to see some clinical

change as well. So, I would like to see both

reducing the number of episodes of acute gout plus

235

decrease in the size of the tophi, two that are

mentioned up there.

DR. GIBOFSKY: Certainly, I think we have

also commented on renal function in our patients,

and to the extent that renal function can cause

gouty attacks and to the extent that gout and

hyperuricemia can cause decreased renal function,

that would be something that would be worth

assessing as well. Any other suggestions for

information? Dr. Cush?

DR. CUSH: As was mentioned earlier,

quality of life and humanistic outcomes I think are

important. Obviously, if we are going for this as

a surrogate marker we want to see long-term

benefits; these are long-term trials. So, joint

outcome, disability, work, humanistic function,

etc.

DR. GIBOFSKY: Ms. McBriar?

MS. MCBRIAR: I also would like to see

quality of life and also perhaps a pain scale,

looking at people\'s pain.

DR. GIBOFSKY: Any other comments? Dr.

236

Williams?

DR. WILLIAMS: I would just raise a

question. Since we talked about radiographic

damage, I think most of that is done associated

with tophi. I think the damage is a little less

predictable maybe than in rheumatoid arthritis. I

personally think that we can\'t have trials that

will be long enough to see significant enough

changes but I would be interested if others feel

differently.

DR. GIBOFSKY: Let me pose a question to

Dr. Felson. Given the extensive co-morbidity in

patients with gout, to what extent would a disease-specific

instrument be preferable to a general

instrument measuring quality of life, or to what

extent would a general instrument be preferable to

the disease-specific instrument, and can you tease

out the effect of one co-morbid condition on

another, and which instrument should we be looking

at in health-related quality of life assessment?

DR. FELSON: No, I think disease-specific

instruments are both more sensitive to change and

237

evaluating the therapy of a given disease and in

this situation, where there are so many co-morbidities that

are affecting generic quality of

life, I think you almost have to use it. I think

it is a secondary outcome measure but I think some

kind of disease-specific or arthritis-specific

measure\--I am not sure that HAQ and the AIMS are

such bad ideas here, but those would be better.

I think, by the way, it was shocking how

many people died of cardiovascular and other things

in some of these studies and I am wondering\--you

know, we are talking about long-term studies here

so the attrition rates would be concerning. I

think trying to identify eligible patients not just

on the basis of their gout or their renal disease

but also who don\'t have class IV congestive heart

failure or even class III might not be a bad idea.

DR. GIBOFSKY: Ms. McBriar?

MS. MCBRIAR: I would also like to see a

general quality of life because it then can be

compared against other diseases and that is always

important information.

238

DR. GIBOFSKY: So, you would want to see

both disease specific and general health-related

quality of life?

MS. MCBRIAR: Yes.

DR. GIBOFSKY: Dr. Cush?

DR. CUSH: Since we are talking about

using a surrogate as a means of approval and

looking for other things downstream, I think you

have to also then be mindful that this should be a

study that really reflects real use, and not use

the usual restrictive entry and exclusion criteria

but have people who have obesity, and heart

failure, and renal insufficiency, and diabetes

included here because there are going to be real

life issues. You know, as Bob showed earlier about

hyperuricemia predicting cardiovascular problems

later on, and as David pointed out, I think that is

a real concern that one would have to answer by

doing these longer-term trials.

DR. GIBOFSKY: Dr. Hochberg?

DR. HOCHBERG: I guess the other issue in

following up on this is because of the association

239

with cardiovascular disease you have a population

of people who should be, if they are not already,

taking low dose aspirin. One has to consider in

the design of the trial the effect of low dose

aspirin on urate handling and, if all the patients

aren\'t on it, whether that would need to be

stratified in terms of the randomized process as

well.

DR. GIBOFSKY: Thank you, Dr. Hochberg.

That is category VIII, subsection 3 and I will come

back to you and ask for your comments specifically

when we get to that point as well. Are we ready to

drill down on the three bullets? Any further

discussion of the specific question II as to

whether additional information is needed to be

collected? If not, let\'s drill down.

Clinical endpoints of a reduced number of

gout attacks and decreased size of tophi in trials

of uric acid lowering drugs. Dr. Cush, want to

tackle that one?

DR. CUSH: I think that reduced number of

gout attacks can be done. There are some problems

240

with defining gout attacks but we probably anguish

over it more than we should. Our patients seem to

know exactly when they are. My secretary can

diagnose over the phone\--

\[Laughter\]

\--but decreasing tophi sounds about as

intelligent as measuring nodules in rheumatoid

arthritis trials. It depends on the person doing

the assessments; it depends on the tools you have

and using calipers. I think there is a real value

in measuring tophi but, you know, it is only a

small reflection of total body urate load and maybe

we can only see it really well in the elbow and not

so well in the feet. As Dr. Terkeltaub mentioned

earlier, I think we need newer methods here.

Whether it is scintigraphy or labeling or MRI, or

what-not, I think that should be done.

DR. GIBOFSKY: I confess I am not sure

that there are many of us who actually take

calipers to a tophus when we see it.

DR. CUSH: I would be afraid to.

DR. GIBOFSKY: And I can understand why.

241

But that said, are there or ought there to be

preferred methods for measuring tophi? Dr.

Mandell?

DR. MANDELL: You can certainly do it with

calipers. I think, from a logistics side, that is

probably the most cost-effective way to do it. You

can certainly follow people who get reduction. But

the issue is can you find one that you can actually

measure at the same spot under that skin as it

moves each time, and I think that is going to be a

challenge.

I would like to comment on the gouty

attack issue. You know, I didn\'t say much before

about it. I didn\'t say anything before about the

surrogate marker. I am comfortable with targeting

uric acid lowering as a marker, but I also think we

do have some issue relating to the arthritis, and

the design challenge I think is going to be the

unique part that when you give this drug, which

should decrease long-term attacks, has a very high

likelihood of increasing attacks in the short term.

That is going to need to be built in and I don\'t

242

think we really understand the timing of when that

window should be when we should not count that.

So, the drug looks worse or better based on the

likelihood of getting an attack early and I think

that is going to be a real challenge in trial

design.

DR. GIBOFSKY: Dr. Hoffman?

DR. HOFFMAN: I think that is a terribly

important point but I think it could be

circumvented if you started counting attacks

perhaps three months after initiation of therapy.

But the major heading that we are addressing these

issues under are for a drug to be approved. I

think at looking at reduction of tophus size would

build into a study something that is untenable. We

would all like to know it but if you are going to

take a year or two or three to see a meaningful

change in tophus size at a point where we don\'t

have anything more sophisticated than calipers,

then I think that is not feasible to build into

these trials. But I can\'t imagine the trials not

taking into account frequency and number of gouty

243

attacks, perhaps starting three months after drug

has been initiated and we, hopefully, have achieved

equilibration perhaps also under cover of treatment

with a second agent, that is colchicine which is

the standard of care.

DR. GIBOFSKY: So let me pose the question

under bullet three to you, Dr. Hoffman\--I am sorry,

there was a question or a comment before? Dr.

Bathon?

DR. BATHON: Yes, I think we do a lot of

very inaccurate methods of assessment, including

joint counts. So, calipers seem even more

sensitive to me than perhaps the feel of a finger

on a joint.

I want to come back to that point about

the early attacks after starting treatment. That

is another thing that we learned but are there data

that really support the fact that these drugs

increase the incidence of attacks? Do we know from

the data that before treatment there are X number

of attacks and after initiation of gout treatment

there is an increase in X number of attacks? I bet

244

there aren\'t real data to support that either.

DR. GIBOFSKY: Dr. Felson?

DR. FELSON: I guess, Joan, sometimes

there aren\'t data because it is reasonably clear.

I think it is reasonably clear but then, again, I

am not usually an anecdotal type guy.

I would like to paraphrase Nancy Reagan

with respect to her comment about measuring

tophaceous deposits\--\"just say no.\" It is going to

be very hard to measure reliably. We have many

other better measures here, and I think it is also

the time it would take to get change is unknown and

would be a mess.

There is one question we haven\'t

addressed, which is number of attacks or reduction

of attacks. I wanted to try to address that

briefly. I think number of attacks is a better

choice than reduction in attacks. The reason for

that is reduction in number of attacks is

contingent upon two things. One is knowing the

current number of attacks and the other is knowing

how many attacks occurred before this drug was

245

started, i.e., before the patient experienced the

three months worth of potential flares of attacks

they might have gotten. So, I think to ask them to

remember six months before, or something like that,

how many attacks they used to have last year and

whether they got a reduced number now is a problem.

The other way to do this would be a very

long run-in prior to therapy in which you enumerate

the attacks. I don\'t think that is a good way\--I

mean, I think a run-in is nice but if we are

talking about a six-month run in to get enough

attacks to be able to enumerate and follow, I think

that is asking a lot of patients. So, I would be

inclined to measure or quantify the number of

attacks and not try to figure out whether they

dropped.

DR. GIBOFSKY: Dr. Hochberg?

DR. HOCHBERG: I would agree once again

with David. I would like to throw out a question

about another potential measure, and that would be

radiographs of the feet to look at the metatarsal

phalangeal joint and look at erosions, and possibly

246

joint space narrowing. You know, we have very

good, reliable scales to assess damage to the MTP

joints in patients with rheumatoid arthritis, and I

am not sure there are any data that have applied

these scales to patients with gout but, in fact,

that might be something where one could generate

such data either as an exploratory outcome in

studies or even just for data collection in order

to move the field forward.

DR. GIBOFSKY: Marc, are you suggesting

that the Sharp score methodology could be applied

to a trial of gout treatment agents?

DR. HOCHBERG: Well, I think it would be

of interest to see if it could. I guess it is

something that Almarack and John Sharp might be

interested in doing.

DR. GIBOFSKY: Dr. Cush?

DR. CUSH: It is my understanding Almarack

has discussed that but I don\'t know the details.

Sort of to piggyback on what Marc said, fingers and

calipers\--I agree with David, just say no to tophi,

but this may be one situation where ultrasound

247

might make sense. There are a few centers that do

them. Obviously, it would be a select sub-study

for any trial but I think that ultrasound could

easily identify and quantify tophi over a period of

time.

DR. GIBOFSKY: Any other comments on

question II? I think we have covered all three

bullets. If there are no other comments on

question II, please put up question III.

Individuals with gout may demonstrate a

broad range of uric acid levels. We have two

discussion questions and two specific questions.

Please discuss the range of uric acid

levels that would reflect meaningful inclusion or

exclusion criteria.

Are there any advantages to recruiting

patients with uric acid in a specified range, such

as 8-12 mg/dl?

Please discuss whether there is a

rationale for studying individuals with values of

uric acid over 12 medication/dl.

Is there value in stratifying patients by

248

uric acid level?

So, first bullet, please discuss the range

of uric acid levels\--I think we have already

touched upon that. Does anyone want to come back

and discuss that again? Dr. Williams?

DR. WILLIAMS: Just to address this

question in general, I think that to include

patients they ought to have hyperuricemia and acute

gouty arthritis but I don\'t know that I would

stratify it further.

DR. GIBOFSKY: Dr. Cush?

DR. CUSH: Extremes in uric acid

determinations I think bring into play other

diseases. So, if we are just talking about gout I

don\'t think we will have these extremes. They will

be there but there will be so few of them I think

that going after a specific disease indication and

characterizing the disease on clinical grounds

rather than on uric acid levels I don\'t think this

becomes anything more than a moot point.

DR. GIBOFSKY: Everyone comfortable with

that formulation?

249

\[No response\]

Are there any advantages to recruiting

patients with uric acid in a specified range such

as 8-12 mg/dl? Dr. Hochberg?

DR. HOCHBERG: I guess based on what Dr.

Terkeltaub has said, I am not sure we can assume

the statement that is in the parentheses is

correct. Probably based on the data that have been

shown to us and that which is in the literature,

most patients with gout who would be eligible for a

study in which they would receive a hyperuricemic

therapy would have uric acid levels above 7 and

would fall in the range between 8-12. So, it is

likely that with randomization one would achieve

some comparability between the groups. I think if

one got to the rationale for including people who

had levels above 12, they would be less likely to

reach the outcome just because they are starting at

a much higher level. So, you would probably want

to stratify prior to randomization to make sure

they were evenly distributed. So, you would

stratify patients above 12 and not necessarily

250

between 8-12\--I mean, not necessarily but I don\'t

know enough to inform myself that that is a good

thing to do, to stratify between 8-12.

DR. GIBOFSKY: Is the committee

comfortable that the parenthetical statement in

bullet two is probably not accurate, given what we

have heard today, that the serum urate probably

does not represent the total body load of uric

acid?

\[No response\]

Any other comments on bullet two or bullet

four, which we have kind of alluded to? Anyone

else on that or are we comfortable with the

comments that have been made? I think Dr. Hochberg

also indicated the issues that might be present in

patients with values of urate over 12 mg/dl, the

possibility of other conditions, but does anyone

feel that there might be a rationale for including

these individuals in a hyperuricemia related to

gout study? Dr. Bathon?

DR. BATHON: I am sort of antagonistic to

the idea of setting an upper limit of normal as

251

long as we exclude cancer patients and that type of

thing. I think we want a range of patients with

moderate disease and severe disease and we

shouldn\'t exclude those above 12.

DR. GIBOFSKY: Dr. Finley?

DR. FINLEY: I would agree with Dr. Bathon

and I would harken back to something that Dr.

Hochberg said earlier. We have a growing

population of patients who have undergone

transplantation and are going to fit this, and the

indication I think Marc spoke to was hyperuricemia

associated with gout. I have no notion of how big

the population might be that would come under

scrutiny but certainly would want to know that

data, especially when we are talking about

rheumatoid arthritis and other diseases that we all

treat, longitudinal disease, and perhaps the

indications for using these in those settings might

be different.

DR. GIBOFSKY: The Chair would have great

interest in following the data on uricemia in

transplant patients. Dr. Cush?

252

DR. CUSH: Just to make a statement in

favor of over 12 is that that is what the

indication is for, uric acid therapy. So,

competitors of allopurinol need to compete in that

market and those patients should be included and,

if need be, if there are enough of them to be sub-analyzed.

DR. GIBOFSKY: Any other comments or

discussion on question III? If not, I think we

will take one more question before our break. We

are running a bit ahead of schedule but we will

continue, nonetheless, and take question IV. I

think we can deal with question IV relatively

easily.

Patients with gout may have renal

insufficiency. Patients with renal insufficiency

may have gout. Discuss the value of including or

excluding such patients in clinical trials. If

they are to be included, what range of serum

creatinine levels would be important to consider

for inclusion? Dr. Boulware, do you want to take a

stab at that?

DR. BOULWARE: I think we should include

253

patients who have renal insufficiency because that

will represent a population of patients that we are

going to take care of. I am not really clear that

establishing serum creatinine levels is as useful

as creatinine clearance because that as a surrogate

marker of filtration is probably even worse than

what we are talking about. So, I don\'t know what

that level should be but I think we should include

renal insufficiency.

DR. GIBOFSKY: Is the committee

comfortable with the notion of creatinine clearance

rather than serum creatinine as the more precise

measure of renal status? So, that should be the

recommendation? Dr. Cush?

DR. CUSH: More precise although not

ideal. Other measures of direct clearance are far

better than calculated or measured 24-hour urines

for creatinine clearance. There are obviously

going to be problems as far as how accurate those

are, especially in situations where there is some

mild to moderate impairment. It is better than

254

serum creatinines however. I think that is clear.

DR. GIBOFSKY: Dr. Williams?

DR. WILLIAMS: I agree it is better than

serum creatinine but I think as a practical issue

it doesn\'t make a lot of difference.

DR. GIBOFSKY: So, is there a general

consensus about including patients with renal

insufficiency in these trials as opposed to

excluding them? The inclusion is probably, as we

have heard, more real world. The exclusion might

be more pure but we are aiming for real world. I

see nods around the table so we would reaction the

inclusion of patients with renal insufficiency.

So, what range of creatinine or creatinine

clearance would be important to consider for

inclusion? How low can we go? Dr. Cush?

DR. CUSH: Or how high in serum creatinine

can we go? I think I would exclude patients who

have end-stage renal disease and patients on

dialysis. That is another can of worms. I am

comfortable up to 4 as far as the serum creatinine

and maybe as low as 30 cc on a 24-hour creatinine

255

clearance but, again, I think that I would be more

concrete and just make dialysis and end-stage renal

disease as a cut-off.

DR. GIBOFSKY: Anyone else? Dr. Felson?

DR. FELSON: Is this a generic set of

concerns or is this relevant to just the oxypurinol

trials? Because oxypurinol is renally cleared.

DR. GIBOFSKY: I think this is posed as a

generic question for incorporation in guidance by

the agency in any trial. Is that right, Dr.

Harvey? Dr. Witter? They are shaking their heads

so it is generic.

DR. CUSH: But David\'s point is that there

needs to be appropriate adjustment for renally

cleared drugs.

DR. GIBOFSKY: Right.

DR. FELSON: I think you might be inclined

to constrain eligibility for oxypurinol trials with

respect to renal insufficiency more than you might

for another therapy which is hepatically cleared

and where it might not matter so much.

DR. GIBOFSKY: Dr. Mandell?

256

DR. MANDELL: The other issue though was

that your creatinine clearance drops as your

ability to use prophylactic therapy to prevent

attacks so if that is going to be a primary

outcome, that is going to need to be stratified or

handled some place along the way.

DR. GIBOFSKY: Dr. Williams?

DR. WILLIAMS: With no more data than Jack

has, I would have said 3 as a creatinine.

DR. GIBOFSKY: Okay. You are agreeing

with him?

DR. CUSH: Yes.

DR. GIBOFSKY: Then he can\'t be right!

\[Laughter\]

Dr. Hoffman?

DR. HOFFMAN: I think trials generically,

as we are discussing them, have to include people

with renal insufficiency but perhaps not people on

dialysis because, again, we are talking about

application to real world situations and these are

often the people that we are treating. I think

while we can include people with varying degrees of

257

renal insufficiency, we just need to stratify them

in looking at outcome efficacy.

DR. GIBOFSKY: Any other comments on the

renal issue? Dr. Bathon?

DR. BATHON: I think Dr. Mandell\'s point

is really important. I think all of the medicines

that we use for acute attacks can have adverse

effects in patients with renal insufficiency and

the design of the trial would have to be really

careful in terms of spelling out how you could

manage acute attacks or how to analyze the data in

renal insufficient patients who couldn\'t get as

many ancillary acute management strategies like

colchicine and NSAIDs compared to those that could.

DR. GIBOFSKY: Dr. Hochberg?

DR. HOCHBERG: I would just raise the

question for discussion, would we want to know or

would the sponsor want to know the 24-hour urine

uric acid excretion in a subject at entry into a

study?

DR. GIBOFSKY: Thoughts on that? Dr. Cush

is nodding his head.

258

DR. CUSH: Obviously it depends on the

mechanism of action of the drug, but it seems like

a smart thing to do. You know, the drug that we

are talking about here we are looking at long-term

outcomes over two years or five years and I am not

sure that is going to be as important as in a more

short-term trial.

DR. GIBOFSKY: Dr. Hochberg, since you

posed the question, do you have some feelings on

that topic?

DR. HOCHBERG: Well, I was thinking if we

are going to suggest that a sponsor collect a 24-hour urine

on every participant in order to

calculate the creatinine clearance as an estimate

of GFR, then you could use that urine to calculate

the 24-hour urine uric acid excretion. But it

would seem to me that most of the treatments that

are being discussed at least, that were discussed

this morning and around lunchtime, are focused on

decreasing production of the uric acid as opposed

to increasing excretion of uric acid. So, I am not

sure that it would inform us at all with regard to

259

the mechanism of action or provide useful

information.

DR. GIBOFSKY: Good point. Any further

discussion on topic IV? If not, this is a perfect

segue, since we are talking about renal

insufficiency and urine flow, to take our break and

we will resume at exactly 3:02 by that clock for

the remaining four questions.

\[Brief recess\]

DR. GIBOFSKY: Can I ask the panelists and

guests to please take their seats so we can begin

the second half of the afternoon? Let\'s resume our

discussion with question V, which is a statement

followed by a short essay.

Uric acid lowering drugs such as

allopurinol are sometimes used at doses higher than

those labeled. Discuss the utility of studying

multiples, such as twice the higher dose, of the

proposed maximum efficacious dose of a new drug. Comment

from the panel? Discussion? Dr. Williams,

let me impose on you to kick off the discussion, if

you would.

260

DR. WILLIAMS: If we are looking at the

efficacy as bringing the uric acid to a specific

level, I think the dose that brought the uric acid

to that level would be the maximum efficacious

dose. I am not sure you need to go higher than

that. Since at least the drugs we have right now

seem to be relatively\--their reaction seems to be

idiosyncratic rather than dose related\--that you

push the dose to that which will bring it down to

the level you are searching for, and that would be

your maximum dose. You don\'t need to go higher

than that.

DR. GIBOFSKY: Dr. Geis, let me solicit

your feelings on this point.

DR. GEIS: I guess would that then raise

the question, if the sponsor did that and it

worked, that people would say, well, in the real

world physicians will keep pushing the dose if we

get the patients down to a certain level with a

therapeutic and do you, therefore, have efficacy

and safety at even higher doses. That is always

the struggle I have found that we run into.

261

DR. GIBOFSKY: So, the suggestion is that

a study at higher than the maximum efficacious dose

is likely to result in greater use of that greater

dose than a study that doesn\'t study the multiple

and efficacious dose.

DR. GEIS: Right.

DR. GIBOFSKY: Dr. Cush?

DR. CUSH: I was confused by your point.

Could you say that again?

DR. GIBOFSKY: I am suggesting that

hypothetically if there were a study in which more

than the maximum efficacious dose were studied and

found to be maximally efficacious, or minimally

more so, that could lead to greater use of a higher

dose than a study which did not study a higher

dose, if I understood Dr. Geis. If I didn\'t, then

we will move on to the next question. Any other

thoughts on this? Dr. Anderson?

DR. ANDERSON: Do I understand what you

are saying as being that whatever is the maximum

dose that you study, there will be doctors who will

double it in practice, with possibly accompanying

262

safety issues?

DR. GIBOFSKY: Dr. Cush?

DR. CUSH: That is a natural tendency for

all drugs, or a lot of the drugs that we use that

are marketed. They come out with a marketed dose

with an acceptable toxicity profile and then, once

they get to the market, use tends to creep up.

Often that is met with some acceptable outcomes,

that there isn\'t much increase in toxicity and

there is more efficacy, as in the case of ibuprofen

for instance. In the case of methotrexate, we

started out with 7.5 mg and now it is a laughable

dose. So, time will determine what the real

maximally efficacious and acceptably safe drug dose

is going to be. Again, I don\'t know that we can

advocate this as a routine part of drug

development. I think that it is the responsibility

of the FDA to oversee the patient safety and for

the manufacturer to get the best possible efficacy

while maintaining that safety, and it is up to them

to figure out the dose. I don\'t think we should

tell them once you have figured out the dose, now

263

give us a double dose study. I think that is

something that can be done in post-marketing

studies by the manufacturer.

DR. GIBOFSKY: Dr. Geis?

DR. GEIS: I guess where I am going with

this is that in my experience in other arthrities

we would push the dose to show that you got to a

plateau, and that by keeping and pushing the dose

you didn\'t get a better, a greater effect.

Therefore, it sort of gave the physicians the data

that said there is no benefit in keeping on pushing

the dose. That is what I am saying here. Would we

want to do something like that?

DR. GIBOFSKY: Dr. Mandell?

DR. MANDELL: I am not sure in this

setting, where you are talking about an enzyme

inhibitor in a heterogeneous population, that you

are going to see a maximum efficacious dose. If in

a large percentage of your population you increase

and increase dose, you still may be lowering the

uric acid further. So, I think the maximal

efficacious is going to be a difficult thing to

264

define from early preclinical or Phase 1 trials.

moxifloxacin

DR. GIBOFSKY: Good point. Any other

comments on this? Dr. Hochberg?

DR. HOCHBERG: I guess part of develop, as

Dr. Geis says, is to determine the maximally

effective dosage with safety. I think that here,

even if it is an enzyme inhibitor, you will have

some doses, let\'s say, at the lower end of the

spectrum which may be effective in a certain

percentage of subjects but are ineffective in

another percentage of the subjects and then you

will have to do escalation as part of Phase 2 in

order to really find out what the sort of maximal

effective and safe dose is in order to get to the

top of the range. Because, if you never get to the

top of the range, then you are never sure you have

the right dose once you go into Phase 3. Then, if

you end up getting marketed, what will happen is

what Dr. Cush says, you know, the practitioner will

end up pushing the dose above that range unless

there is evidence that there is clear toxicity

265

associated with it.

I think another aspect that we have to

consider now and that the FDA may want to think

about in terms of advising companies is the whole

issue of pharmacogenomics and why people don\'t

respond to what might be the maximally effective

dose. Maybe they are never going to respond to

that agent. This ought to be something that maybe

companies should think about studying or collecting

data on in order to be able to study it as they

bring drugs from development towards the

marketplace.

DR. GIBOFSKY: Thank you, Dr. Hochberg.

Further comments on question V?

\[No response\]

I think we will move on to question VI.

Please discuss the what could be considered an

optimal duration for these trials. Dr. Boulware,

may I ask you to begin the discussion?

DR. BOULWARE: This is one of those

questions that probably should have had bullets

under it because I think it depends on what your

266

endpoint is going to be. If you want to look just

for lowering of serum uric acid you probably could

achieve that quicker and, depending on what your

endpoint is and where you started from, maybe

within 12 weeks. If you want to look at the

reduction in the number of attacks, you probably

have to go longer and it would depend on what kind

of patients you entered into the study and how

frequent the attacks were.

Another outcome we didn\'t discuss earlier

but which probably is important is the severity of

their attacks. If we maintain the number but

reduce severity of attacks and duration of an

attack, that may be an important outcome that too

and my guess is that is going to take at least six

months of a trial.

Finally, if we are looking at reducing

tophi size, and we have talked about ways to do

that, we saw in earlier presentations a mean of 20

months I think, plus/minus 10 months in order to do

that, so that is going to take a long time to do,

at least a year to see an effective reduction, but

267

it depends on the sensitivity of the method you

use. With ultrasound maybe you could see a 50

percent reduction in\--I don\'t know\--six months.

DR. GIBOFSKY: So, the optimal duration

might be different for lowering serum uric acid,

for educing size of tophi and for reducing either

the incidence or severity of attacks of gout. Is

that what you are saying? Dr. Bathon?

DR. BATHON: Yes, but even within one

endpoint like reducing serum uric acid it is going

to depend on the mechanism of action possibly with

the rapidity with which the drug achieves that.

So, something that immediately inhibits xanthine

oxidase might be relatively quick whereas something

that is a uricosuric agent may take longer to have

an effect. So, I think it depends on mechanism,

the rapidity of the effect of the drug and then,

obviously, whether you are doing dose escalation

versus starting out with one single dose will make

a big impact.

DR. GIBOFSKY: Also depending on

concomitant therapies which we will get to in just

268

a few minutes. Dr. Cush?

DR. CUSH: I like Dr. Boulware\'s

stratification based on the surrogate marker only,

which would be a much shorter trial, you know, 24

weeks, as Joan says, depending on surrogate marker

plus the primary clinical outcome, which is attacks

being longer in 6 months or maybe longer. You

could use IC\'s guidelines for numbers to apply

this, you know, 300-600 I guess for a 6-month

trial. Then, they are going to have to do the

long-term trials if they are going to get the

surrogate marker indication and that is going to

have to be 2 years, and that is for quality of

life, humanistic outcomes, x-ray outcomes, nodular

outcomes even, morbidity, mortality stuff. I think

real long trials with larger numbers are going to

be mandated.

DR. GIBOFSKY: Ms. McBriar, do you think a

20-year period of time is appropriate or too long

for assessing changes in health-related quality of

life by patient-reported outcomes?

MS. MCBRIAR: I would think at least one

269

year and see it hold. I think it will be hard on

the sponsor but I do think it is important if you

want the long-term effect of these drugs to be

known.

DR. GIBOFSKY: Other comments on point IV?

Dr. Anderson?

DR. ANDERSON: A comment more about the

number of attacks, and something that concerns me a

little about some of the discussion before about

that is that it was suggested that maybe the number

of attacks in the first three or six months of the

trial could be ignored. But I think it would be

better to just keep track of the number of attacks

per six-month period and take all of that into

account. Depending on the mode of action of the

drug, it seems conceivable that one drug might

increase them in the first six months and then

decrease them after and another one just sort of

decrease them slowly. So, that is a feature that

one would not want to lose sight of. It isn\'t

strictly speaking on this point.

DR. GIBOFSKY: Any further comments on VI?

270

Have we adequately discussed this to everyone\'s

satisfaction and provided some input for the staff

of the agency to consider?

\[No response\]

We will move on to VIII, please.

DR. CUSH: Michael and I were just talking

about this, you know, over time for quality of life

outcome measures this is much more a saw-tooth

pattern of disease than even RA because they do

spike and the question is if their spikes are

infrequent and not that large, then the cumulative

hit to the being is going to be less and,

therefore, I think a lower duration of follow-up

for quality of life outcome is going to be

important.

DR. GIBOFSKY: No argument there. Number

VII, please discuss the implications of placebo

versus active controls and superiority versus non-

inferiority designs for clinical trial of uric acid

lowering drugs. Is there sufficient data available

in the literature to establish a generally accepted

response rate for allopurinol\--presumably the

271

appropriate comparator\--that could be used for

calculating a non-inferiority margin? Dr. Felson,

can I ask you to kick off the discussion here,

please?

DR. FELSON: Yes, I think we talked a lot

about patients who really have no other options

where allopurinol has failed them. I think in that

situation a placebo-controlled trial is appropriate

and a conventional design that is, you know, reject

the null hypothesis design, powered appropriately,

is also what you probably should be recommending.

If these were therapies that were going to be

tested as first-line urate lowering agents against

allopurinol I think a non-inferiority design would

be better. The only circumstance I was thinking

about where you could do a non-inferiority design

was if you decided\--because it sounded like even

though the trial we heard about was supposed to be

in double failures\--what you guys called double

failures\--in fact, wasn\'t in double failures; it

was in single failures mostly, that is, people who

had some kind of trouble with allopurinol and

272

hadn\'t actually been rechallenged or desensitized.

So, one I guess non-inferiority design one could

conjure up which wouldn\'t be uninteresting would be

to test a new agent and compare it to

desensitization. So, what you could do is do a

randomized trial. You would have to sort of

desensitize to placebo, I guess, and that would

work. Then, that might be some kind of non-inferiority. I

guess that is a non-inferiority

design although you don\'t necessarily know what the

response rate for desensitization is. I think it

would be better probably initially to do a placebo-

controlled trial in people who can\'t take

allopurinol and just deal with it in a conventional

design fashion.

DR. GIBOFSKY: Dr. Cush?

DR. CUSH: But, again, we are talking

about gout which is sort of maybe the most painful

condition that we manage so I really worry about

placebo-controlled trials and I don\'t want to use

them unless it is absolutely necessary. But I do

think that my education here at the FDA has been

273

that they like to see a placebo-controlled trial

and that might be the perfect instance, to have a

small trial for those kind of patients. I don\'t

know how small it would be. If it is 60-120

patients for a limited duration, maybe that is

acceptable. But for larger numbers, as you

suggested, a head-to-head comparison with

allopurinol would make more sense to me using a

non-inferiority design.

DR. GIBOFSKY: Dr. Williams?

DR. WILLIAMS: I agree with David. If you

are looking at patients who are allopurinol toxic

so they can\'t use it, we don\'t have another

treatment so then I could see a placebo-controlled

trial because you are going to use pain relief as

your escape. But if you are looking at trying to

bring in a new drug, then I would compare it to the

standard which is allopurinol.

DR. GIBOFSKY: Along those lines, is there

sufficient evidence in the literature to establish

a generally accepted response rate for allopurinol

that could be used for calculating a non-inferiority margin?

274

Dr. Hochberg, are you aware of

the literature here?

DR. HOCHBERG: No, I am not aware of a

generally accepted response rate in terms of the

proportion of patients who would have a serum uric

acid level below 6 mg/dl with appropriate dosing of

allopurinol.

DR. GIBOFSKY: And to the extent that we

have been talking about that level as an

appropriate surrogate marker, it would be important

to have that in the literature.

DR. HOCHBERG: I think so. One of the

papers that was referred to by a presenter earlier

in justifying that as a level of clinical

importance, only about a third of the patients who

were in that observational study actually reached

that level with treatment.

DR. GIBOFSKY: Any other comments on this

point about methodology of superiority versus non-

inferiority or placebo versus active control? I

think we have established that the answer to the

bullet is no, but that doesn\'t preclude us from

275

making those suggestions as outlined. Ms. McBriar?

MS. MCBRIAR: I would just want to make

sure that the sponsor had decided how to rescue

people. This is a pretty serious, potentially

damaging disease and it is obviously very painful

and I wouldn\'t want people to be in pain for too

long.

DR. GIBOFSKY: I think you are echoing Dr.

Cush\'s concern about placebo trials in such an

acutely painful condition. Any other comments on

question VII? Dr. Hochberg?

DR. HOCHBERG: Just a comment about the

issue of rescue, if the number of recurrent attacks

of gout, let\'s say, is going to be a secondary

outcome, presumably in the protocol there would be

a standardized method of treatment of those acute

attacks when they occur with an agent which, let\'s

say, would not affect serum uric acid levels which

presumably would be the primary outcome measure.

So, again, if we are going to be looking at agents

which are designed to lower serum uric acid levels

in patients with gout, then we would anticipate

276

that those individuals in the study, whether they

be in the placebo group or in the active treatment

group, are going to have attacks of gout during the

course of the study and that they will need to be

treated.

DR. GIBOFSKY: Any other comments?

\[No response\]

Let\'s move to VIII. Please discuss the

implications of concomitant therapies. Can

concomitant drugs such as colchicine or non-steroidals be

continued during clinical trials for

chronic gout? Discuss the implications of

permitting or prohibiting the use of concomitant

diuretics or low dose aspirin. Is there value in

recommending or prohibiting a particular diet? Is

it appropriate to restrict alcohol use\--presumably

in the context of a clinical trial? Please discuss

issues concerning the enrollment of patients with

kidney stones and inclusion of transplant patients,

especially those on drugs such as cyclosporine.

Dr. Hochberg, I threatened earlier to call

on you to begin the discussion here so I will

277

fulfill my promise.

DR. HOCHBERG: Well, these are all

important areas and necessary to discuss. I don\'t

want to go at them bullet by bullet but starting

with bullet one, definitely, concomitant agents

should be continued during the trial. You know, I

think as Dr. Cush and others have mentioned here,

the hallmark of therapy in patients with recurrent

attacks of gout is chronic colchicine therapy in

order to prevent recurrent attacks of gout, and we

remember that that has sort of come into the

armamentarium not from randomized, placebo-controlled trials

but from before and after

studies. So, obviously colchicine should be

continued. There apparently is a sizeable

proportion of patients\--again, we don\'t really know

what number it is\--who are intolerant of colchicine

therapy who usually are on chronic NSAID they for

prevention of recurrent attacks of gout. So, I

think yes, that has to be included. Again, it

might be something that one wants to stratify on.

You don\'t want to stratify on too many variables

278

but you want to make sure that patients that are on

them are at least able to continue them in the

study, and certainly not washed out.

Do you want me to keep going?

DR. GIBOFSKY: Please.

DR. HOCHBERG: Bullet number two is

discuss the implications of concomitant diuretics

and low dose aspirin. Well, I guess that depends

on the co-morbid condition. Certainly, the

population with cardiovascular disease which should

be taking low dose aspirin, I think, again, should

be in the study. We, again, need to consider the

effects of low dose aspirin on renal handling of

urate, but since most of the compounds that have

been at least discussed earlier today and probably

would be in development would be focused on

inhibiting xanthine oxidase and production of uric

acid, I don\'t think that is a problem. Maybe

diuretics aren\'t a problem as well in that regard,

although if the diuretics are being used for the

management of hypertension in clinical practice

oftentimes you try and switch agents so that might

279

be a consideration. But I don\'t think that I would

exclude people who are on diuretic therapy and low

dose aspirin.

DR. GIBOFSKY: We will stop there and have

further discussion of those two bullets before we

go on to the other subheadings. Dr. Williams?

DR. WILLIAMS: I totally agree on bullet

number one. Bullet number two, I would think they

could continue on their diuretics and low dose

aspirin if they had been on them for a month prior

to the study and remained constant during the

study. I think any impact they had would wash out.

DR. GIBOFSKY: Dr. Bathon?

DR. BATHON: With regard to the first

bullet, with NSAIDs and colchicine, I wonder if it

wouldn\'t be a more sensible design to just have a

PRN mandate like a week of treatment for each acute

attack, or something where you could get them off

continuous treatment and just use it for acute

management. For renal failure patients where you

might not want to be using NSAIDs and colchicine,

have a third possibility of using steroids.

280

DR. GIBOFSKY: Dr. Hoffman?

DR. HOFFMAN: There is an old study\--I was

discussing with Bob Terkeltaub earlier; I think it

probably goes back to the \'60s\--where people were

made normal uricemics who previously had gout and

were kept on colchicine, I think it was for six

months, or not placed on colchicine and there were

some recurrent attacks of gout in both groups

between there was clearly a difference of fewer

attacks of gout in the patients maintained on

colchicine. It is with that in mind that I have

always treated patients with colchicine for six

months and sometimes even up to a year, realizing

that urate stores were going to take a long time to

be mobilized. I would be more comfortable with a

protocol where, unless there was a contraindication

to colchicine or unless colchicine was not

tolerated, to have colchicine as the standard of

care along with starting a uric acid reducing

agent, and to use alternative therapies only if

colchicine was contraindicated.

As far as the other points are concerned,

281

other concomitant therapies including thiazides, I

agree with Jim on that. I think that is reasonable

clinical practice and should be part of protocols.

DR. GIBOFSKY: Dr. Cush?

DR. CUSH: Prior to this discussion I

would have excluded diuretics and low dose aspirin

because it would just complicate matters, but

certainly you could stratify for those patients

and, on further consideration, I think it is

actually better to include them because it is

common but, more importantly, such patients will be

primed to get in trouble; they will be more likely

to have hyperuricemia and troubles with that. You

know, it is basically selecting for a naturally

occurring high risk population and I think we will

see more numbers to make judgments as far as the

outcomes in efficacy and safety.

DR. GIBOFSKY: Any other comments on

bullets one and two? If not, we will move to

bullet three, is there value in recommending or

prohibiting a particular diet?

At Cornell we have the maxim \"when all

282

else fails, find out what the patient likes to eat

and forbid it.\" I am wondering if that is

appropriate in this setting given what we heard

from Dr. Terkeltaub earlier. Comments?

DR. CUSH: The point would be to note make

the diet an issue. So, you could screen patients

if they are taking a particular diet, but I think

any diet restrictions should not be a part of the

clinical trial. I think you want to take a

population that does not have a dietary restriction

going in. That would be my guidance.

DR. GIBOFSKY: Other comments on this?

Dr. Felson?

DR. FELSON: I think this and the next one

we can knock of probably at the same time. They

are both similar issues. Maybe alcohol is part of

the diet, maybe it is not. I think this is

probably a good clinical practice issue. I would

be inclined to let people know what the issues are

about diet and just proscribe dramatic changes in

diet. You know, if you are part of this trial, we

would like you not to adopt the Atkins diet in the

283

middle of it because that might affect your uric

acid and we might not be able to evaluate the

therapy we are trying to evaluate.

With alcohol, I think I would be inclined

to do more or less the same, with the exception of

trying to exclude, as we often do, patients who

tend to use excessively in part because that is

going to be very difficult for you to deal with for

uric acid levels and in part because they are

likely to be non-compliant and would introduce a

variety of other considerations and concerns.

DR. GIBOFSKY: Ms. McBriar, could I ask

you to comment on the feasibility of instituting

these kinds of life style or social habit changes

in patients with chronic disease?

MS. MCBRIAR: I think it is probably one

of the harder pieces to do. I think it is

important and I think it is part of the overall

care for patients and that should be a message that

we all get out, but I think if we are trying to

study the drug we are right not to throw too many

different things into it that might complicate the

284

answer.

DR. GIBOFSKY: Any further discussion on

those two bullets?

\[No response\]

Let\'s go on. Discuss issues concerning

the enrollment of patients with kidney stones. Dr.

Boulware, your thoughts on that?

DR. BOULWARE: I guess I have always

thought of renal stones as being part of the whole

spectrum of gout so I would not think you would

want to restrict them but include them in there. I

guess it would require a separate stratification

for looking at success of treating stones and

recurrent stones, but we are all rheumatologists

treating gout and arthritis attacks separately too.

But I would think you would want to include them.

DR. GIBOFSKY: Any other comments? Dr.

Finley?

DR. FINLEY: The question is phrased as

kidney stones generically. Is there a feeling\--I

don\'t know, I thought it was in the slides that

there is an indication for this not only with uric

285

acid stones but calcium oxalate stones as well.

Would that have to be teased apart, or would there

be a recommendation to the sponsor, or would the

FDA be interested in defining what the stone is,

what the makeup of the stone is?

DR. GIBOFSKY: I suspect we would learn

that not all of our patients are as compulsive and

diligent as our colleague who came to us with his

stones for us to analyze, if need be. But the

question is should we stratify patients with or

without nephrolithiasis in a study looking at

reduction of serum urate as a surrogate marker for

gout. That is the question on the table. Anyone

else want to comment on that? Dr. Felson?

DR. FELSON: I think you let your patients

in. I think it becomes an interesting sub-study to

evaluate the effect of lowering uric acid on that

outcome, and I would hope that the sponsor,

whichever sponsor this would be for the studies,

would be inclined to fund that part of the sub-study, which

wouldn\'t be all that difficult to do.

It would be real interesting information.

286

DR. GIBOFSKY: Dr. Williams?

DR. WILLIAMS: I agree. I think it would

be interesting. I doubt you would have enough

power to make any decisions.

DR. GIBOFSKY: Dr. Hoffman?

DR. HOFFMAN: The type of stones becomes

something of a complicated issue because even

people who wind up having uric nephropathy\--if I am

not mistaken and Bob Terkeltaub may want to

comment\--often have calcium oxalate stones because

the initial crystallization is with urate on top of

which calcium oxalate is laid down.

DR. GIBOFSKY: Other comments on bullet

five? Dr. Hochberg?

DR. HOCHBERG: While I agree that people

with stones and hyperuricemia could be entered into

the studies that we have been discussing, they also

could serve as the population of a completely

separate study which I think would be relatively

easy to recruit from urologists who see patients

with recurrent stones and I am sure measure or at

least could be convinced to measure serum uric acid

287

levels. Allopurinol, if I remember correctly, is

the standard of care for patients with recurrent

stones with any etiology because of the point

brought up by Dr. Hoffman. So, people who are

intolerant of allopurinol would be candidates for

hyperuricemia therapy if they have hyperuricemia

and recurrent stones.

DR. GIBOFSKY: Everyone comfortable with

our discussion of bullet five? Any further

comment? If not, let\'s go on to bullet six, please

discuss inclusion of heart and/or renal transplant

patients, especially those on drugs such as

cyclosporine.

I think we heard from Dr. Terkeltaub this

morning that cyclosporine is going to be a footnote

to the gout story but, nevertheless, there are many

patients still on it. How does the committee feel

about offering input into the inclusion or

exclusion of these patients, who are receiving

transplants whether or not they are on

cyclosporine, for these kinds of studies? Dr.

Cush?

288

DR. CUSH: I would exclude. I think it is

a problem for the transplant world. It is a

relatively small problem compared to the numbers we

are talking about in the issues above that, where

we are trying to include real-world patients. So,

I think that is a second study or post-marketing

study that has true value, but I am not sure it is

necessary for registration.

DR. GIBOFSKY: Are you suggesting that

renal transplant patients don\'t exist in the real

world, Dr. Cush?

DR. CUSH: Not in my real world.

DR. GIBOFSKY: They do in mine, Dr. Cush.

DR. CUSH: Oh, really!

DR. GIBOFSKY: Any other comments? It is

a small subset of patients, granted.

DR. WILLIAMS: I would just agree that I

think studying cyclosporine and uric acid is a

separate study.

DR. GIBOFSKY: Dr. Hoffman, did you want

to comment?

DR. HOFFMAN: I think it is in a sense a

289

separate study but if someone is looking at a new

agent, this is a group of people I think have

fairly serious problems when they do get gout and

they do need to be studied. I would lean more

towards including them as a subset for separate

analysis.

DR. GIBOFSKY: Dr. Finley?

DR. FINLEY: Dr. Calabrese showed a couple

of patients and I think of the one patient that I

took care and his gout predated his

transplantation, and once he got transplanted and

was on cyclosporine his gout was immeasurably more

difficult to care for. I don\'t know that this is a

subtext for how we are discussing this but the

notion that there weren\'t individuals who were gout

patients predating their transplantation ought to

be thought of as we flavor this discussion. I

concern myself with those real-world patients.

Transplants used to be uncommon; used to be not

part of our practices. Now we see patients who

commonly have those.

DR. GIBOFSKY: Dr. Bathon?

290

DR. BATHON: I think the issue with

oxypurinol might be different from other drugs that

we might consider down the road. In general, a

brand-new drug that has not been tested in people

is probably not a drug that you would want to put

into patients who have a renal transplant

initially. So, I would think they would be a

later, separate study for most brand-new drugs that

are being evaluated.

DR. GIBOFSKY: Any other discussion on

bullet six? Dr. Hochberg?

DR. HOCHBERG: I would agree that patients

post-transplant should represent a separate

population for studies. Another consideration is

also because of the adverse events which would be

much higher in the population because of the co-therapy, the

potential risk of infection, etc.

which would be difficult to interpret if post-transplant

patients are intermingled with patients

who have primary gout in a large population and may

not be evenly distributed.

DR. GIBOFSKY: Any other comments?

291

\[No response\]

I think we have adequately discussed all

of the materials presented to us in appropriate

depth and detail. However, are there any issues

that we either haven\'t discussed that any of the

members of the panel would like to bring up, or any

of the bullets that we have discussed that any

members of the panel would like to made additional

comments on or go back to for further discussion?

Dr. Geis?

DR. GEIS: Would it be useful to just talk

for a few minutes about the definition or

identification of patients with chronic gout?

Because if we don\'t have that right in the

inclusion-exclusion criteria we will be in trouble

regardless of what we measure.

DR. GIBOFSKY: The question for us is the

issue of a definition of chronic gout. Do we want

to offer some suggestions as to what the term

\"chronic\" should mean in this setting? I think we

have considered frequency of attacks. We had a

brief discussion on severity of attacks. But do we

292

want to offer a little bit more guidance? Dr.

Felson?

DR. FELSON: I actually wanted to bring up

a different issue but it is not unrelated to Dr.

Geis\'. I think it would be reasonable, since we

are talking about therapy for people who can\'t take

allopurinol but for whom allopurinol would

otherwise be indicated, to use the same definition

that is published and accepted for allopurinol use.

I think Bob Terkeltaub went over it earlier today

and I am not sure I remember all the details, but

it is a particular uric acid level, but I think you

need three attacks per year as sort of the criteria

that are out there. That would seem like the right

thing to do, with some kind of good documentation

that there have been attacks.

What I wanted to raise, I have sort of

been thinking about how one would evaluate subjects

in trials or participants in trials and it wasn\'t

clear to me how you would get the number of

attacks. Would you see a patient every three

months and say how many attacks have you had since

293

we last saw you? Or, do you have them come to see

you with every attack, creating some chaos in your

practice, so you can document those attacks?

I am also mindful of the fact that we are

involved in an Internet study where we are finding

that people actually have attacks much more often

than they necessarily see doctors with. So, I am

not sure exactly what the answer to that question

is, but I think it is something worth discussing

and considering. If serum uric acid is a primary

outcome, then that is easy. You can just have them

come every three months and get a serum uric acid.

But if it is number of attacks in the interim, then

if you have them come every six months or three

months and ask them to remember, their memory may

not be all that accurate. You may want them to

come in with every attack if you want to have a

document or attack list. So, I don\'t know exactly

how that would occur.

DR. GIBOFSKY: Dr. Cush?

DR. CUSH: Tomorrow I was going to make

the proposal about what is an acute attack. I have

294

not read a really good definition of that but I

think we were all taught it in medical school,

using gout as an example of the four cardinal signs

of inflammation\--redness, warmth, pain and

swelling\--and that an acute attack could be three

our of four, two out of four. Hence, the ideal

situation would be that as defined by a healthcare

provider on direct examination, although it might

be interesting to also ascertain whether patients

could make the same judgment using the same rules.

I think we are all impressed that patients

who have gout often do return to the clinic and

say, \"well, I had an attack last month\" or \"I\'ve

had five attacks since I last saw you,\" but they

have no joint swelling and you find out it was just

that they had a little more pain in the instep.

They just jump on it with prednisone or colchicine

or something. You are not sure if it was a true

attack but they define it as an attack. It is

certainly not like those first few attacks where

they couldn\'t walk and they were on crutches, and

they were in the emergency room and the sheet was

295

bothering me\--you know, the classic gouty thing. I

think sticking to the four cardinal signs of

inflammation as a measure of attacks makes most

sense.

DR. GIBOFSKY: Dr. Cush, how would you

deal with or how do you deal with the frequent

coexistence of gout with pseudo-gout in terms of

defining what the etiology of the inflammation was?

DR. CUSH: Well, I think it depends on the

nature of the therapy that is used to treat that

individual. You could discount the fact that they

could exist together, as could septic arthritis be

in the mix there as well. I think if my therapy

wasn\'t working when it should be, that is when I

start the existence of another background condition

such as pseudo-gout. But talking about uric acid

lowering therapies, theoretically they should not

be effective in preventing attacks, whereas

colchicine and non-steroidals and steroids would

certainly have effect on both conditions.

DR. GIBOFSKY: But the question implicit

in Dr. Felson\'s statement is what would the gold

296

standard be for identifying those attacks. Should

it be the physician observation, the patient self-report?

If it is the physician observation, should

there be a demonstration of uric acid crystals in

the fluid each time?

DR. CUSH: No, my suggestion is that it

should be by direct examination by a physician or

someone in the trial to assess the patients on a

PRN basis as it arises. I don\'t think crystal

identification is necessary. Again, I threw out

that maybe patients could ascertain this having

some very defined rules about what a true attack

was, but that would be a study for someone to do to

show patient-derived variables compared to

physician-derived variables, hopefully, with the

idea of coming away with easier ways of doing long-term

trials in the future.

DR. GIBOFSKY: Dr. Williams, you have a

comment?

DR. WILLIAMS: Jack covered much of it but

I am a little concerned about self-reported attacks

of gout because I have gout patients who tell me

297

they had an attack that lasted several hours or a

day and without treatment went away, and I suspect

those really weren\'t attacks of out. I think if

you are going to use that as one of your measures

you have to have them evaluated by an investigator.

DR. GIBOFSKY: Any other comments from

members of the panel regarding the information we

have covered today, or any other topics you would

like to raise in this context? Dr. Hochberg?

DR. HOCHBERG: Well, just for completeness

sake in this context I guess, there is the push and

pull here. While it would be nice to have subjects

who would call in to the study nurse, let\'s say, at

the time that they are having an attack of gout so

they could be seen in order to have a health

professional concur that this is, in fact, an

attack of gout, that may impact on recruitment and

retention, particularly for a study where if you

are looking for people who are intolerant of

allopurinol, let\'s say, they may be widely

dispersed; they may not live necessarily close to

the individual physician. Or, if we are going to

298

recruit in general from a large population in the

VA healthcare system we may have problems getting

those individuals in.

So, there are validated criteria which

have been published for survey purposes to validate

a diagnosis of acute gout by the American

Rheumatism Association, now the American College of

Rheumatology. So, sponsors may want to think about

using those in conjunction with some type of

telephone monitoring on a frequent interval in

order to eliminate the problem of recall over three

months between visits, let\'s say, with monthly

telephone monitoring\--\"have you had an attack of

gout in the past month?\" If the answer is yes, try

and collect some information about it. If not,

\"thank you very much. We\'ll call you in another

month and we\'ll see you for your uric serum acid

monitoring visit in three months.\"

DR. GIBOFSKY: Any further discussion or

comment? If not, let me thank you all for your

participation. Dr. Witter, Dr. Harvey, did you get

the input that you were looking for from the group?

299

Dr. Harvey, any concluding remarks?

DR. HARVEY: I think that there has been a

lively and a thoughtful discussion on all of the

topics by the committee, and I think there is a lot

here for FDA to think about and I would like to

thank the committee for all of your work and

especially thank the Chairman today. Thank you.

DR. GIBOFSKY: Thank you all very much for

your input and hard work and making my role here

particularly easy. Tomorrow morning we will begin

at 8:00 sharp. Please bring your luggage with you

if you are staying at the hotel. It will be stored

here in the FDA offices, and we will depart from

here tomorrow evening to our respective homes or

wherever else we are sojourning. The hotel shuttle

should be here momentarily to take those of us who

are staying at the DoubleTree back there. This

concludes the formal part of the meeting. I will

see you all tomorrow morning.

\[Whereupon, at 4:50 p.m., the proceedings

were recessed until 8:00 a.m., Thursday, June 3,

2004.\]