1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

DERMATOLOGIC AND OPHTHALMIC DRUGS

ADVISORY COMMITTEE

Friday, August 27, 2004

8:00 a.m.

5630 Fishers Lane

Room 1056

Rockville, Maryland 20852

PARTICIPANTS

Jennifer A. Dunbar, M.D., Acting Chair

Kimberly Littleton Topper, M.S.

MEMBERS:

Paula L. Knudson

William Gates, M.D.

CONSULTANTS (VOTING):

Scott M. Steidl, M.D.

Jeffrey Lehmer, M.D.

Vernon Chinchilli, Ph.D.

CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

OPHTHALMIC

DEVICES PANEL MEMBER (VOTING):

Jose S. Pulido, M.D., M.S.

PATIENT REPRESENTATIVE (VOTING):

Elaine King Miller, Ph.D.

INDUSTRY REPRESENTATIVE (NON-VOTING):

Peter A. Kresel, M.B.A.

FDA STAFF:

Jonca Bull, M.D.

Wiley A. Chambers, M.D.

Jennifer D. Harris, M.D.

C O N T E N T S

Call to Order, Jennifer A. Dunbar, M.D. 4

Conflict of Interest Statement,

Kimberly Littleton Topper, M.S. 5

Introduction, Wiley Cambers, M.D. 7

Eyetech Pharmaceuticals Presentation:

Introduction, David Guyer, M.D. 30

VEGF Overview and Macular Degeneration

Pathophysiology, Antony P. Adamis, M.D. 36

Pegaptanib Clinical Efficacy, David Guyer, M.D. 51

Pegaptanib Clinical Safety,

Anthony P. Adamis, M.D. 79

Pegaptanib Benefit/Risk Profile,

Donald J. D'Amico, M.D. 102

Committee Discussion 114

FDA Presentation, Jennifer D. Harris, M.D. 129

Committee Discussion 153

Open Public Hearing:

Daniel D. Garrett, Prevent Blindness America 192

Ellen Hofstadter 196

Nikolai Stevenson, Association for

Macular Diseases 198

Carl R. Augusto, American Foundation for

the Blind 201

Bruce P. Rosenthal, OD, FAAO Lighthouse

International 207

Bob Liss, OD 210

Committee Discussion 211

Questions 217

P R O C E E D I N G S

Call to Order

DR. DUNBAR: I would like to call the

Dermatologic and Ophthalmic Drugs Advisory

Committee meeting to order to review NDA 21-756,

for Macugen, and I would like the committee members

to introduce themselves. I am Jennifer Dunbar,

from Loma Linda, California, and I would like the

committee members, starting on my left, to

introduce themselves.

DR. GATES: I am William Gates, from

Nashville, Tennessee.

DR. LEHMER: I am Jeffrey Lehmer, from

Bakersfield, California.

DR. PULIDO: Jose Pulido, Rochester,

Minnesota.

DR. STEIDL: Scott Steidl. I am a retina

specialist from the University of Maryland, in

Baltimore.

MS. KNUDSON: Paula Knudson, with the

Texas Health Science Center, in Houston.

DR. CHINCHILLI: Vern Chinchilli, Penn

State Hershey Medical Center.

DR. BULL: Good morning, Jonca Bill,

Director of the Office of Drug Evaluation V, in the

Office of New Drugs here, at FDA.

DR. CHAMBERS: Wiley Chambers, Deputy

Director for the Division of Anti-Inflammatory,

Analgesic and Ophthalmic Drug Products.

DR. HARRIS: Jennifer Harris, medical

Officer, same division.

MR. KRESEL: Peter Kresel. I am the

industry representative, Irvine, California.

MS. TOPPER: Kimberly Topper, FDA, the

Executive Secretary for the committee.

DR. MILLER: Elaine King Miller, Amarillo,

Texas.

DR. DUNBAR: Now we will ask Ms. Topper to

read the conflict of interest statement.

Conflict of Interest Statement

MS. TOPPER: The following announcement

addresses the issue of conflict of interest with

regard to this meeting and is made a part of the

record to preclude even the appearance of such at

this meeting. Based on the submitted agenda for

the meeting and all financial interests reported by

the committee participants, it has been determined

that all interests in firms regulated by the Center

for Drug Evaluation and Research present no

potential for an appearance of conflict of interest

at this meeting with the following exceptions:

Dr. Jennifer Dunbar has been grated a

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

505(n) for her spouse's ownership of stock of the

sponsor. The stock is valued from between $25,001

and $50,000.

Dr. Jose Pulido has been grated a waiver

under 21 U.S.C. 505(n) for his children's ownership

of stock in the sponsor. The stock is valued from

$5,001 to $25,000.

A copy of the waiver statements may be

obtained by submitting a written request to the

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

of the Parklawn Building.

In the event that the discussions involve

any other products or firms not already on the

agenda for which an FDA participant has a financial

interest, the participants are aware of the need to

exclude themselves from such involvement and their

exclusion will be noted for the record.

We would also like to note that Dr. Peter

Kresel has been invited to participate as a

non-voting industry representative. Dr. Kresel is

employed by Allergan.

With respect to all other participants, we

ask in the interest of fairness that they address

any current or previous financial involvement with

any firm whose products they may wish to comment

upon. Thank you.

DR. DUNBAR: Now we will ask Dr. Chambers

to give an introduction of the issues that we will

review today.

Introduction

DR. CHAMBERS: Thank you, Dr. Dunbar. Let

me start with welcoming everybody. Good morning.

I want to particularly welcome the advisory

committee members, and the time that they have

taken both to review the material and to both

travel and attend today.

[Slide]

We are here today to discuss Macugen, and

this is the Dermatology and Ophthalmology Advisory

Committee meeting. Those of you who think you

should be some place else, we would welcome the

open seats if you want to give them up.

My name is Wiley Chambers. I am the

Deputy Director for the Division of

Anti-Inflammatory, Analgesic and Ophthalmologic

Drug Products, and it is our Division within the

Office of Drug Evaluation V that will be reviewing

this application today.

[Slide]

This application, unlike many others--or

at least the section that we will be reviewing

today, unlike many others, is part of the

continuous marketing application Pilot 1 NDA

submission which was part of PDUFA 3, which is the

Prescription Drug User Fee Act that was enacted

into law in 2002. This allowed for the

presubmission of individual modules in different

sections that would then be reviewed, and comments

given back. This would not be a final action but

it would be comments on a particular section, with

the goal of speeding ultimate approval of

particular applications by being able to give

interactive comments early on. The action on the

actual NDA will only be taken after all the modules

are submitted and reviewed.

[Slide]

Today's discussion is clinical only. We

are only dealing with the clinical section. We are

not dealing with the pharm. tox. section. We are

not dealing with the chemistry manufacturing

section. So, no one should expect that we will

take an action on this NDA today, tomorrow or the

next day because there are other modules which are

being reviewed in their own time course.

The expectation is that we will give

comments back to the sponsor of the application

within approximately six months of the time when

the module was submitted, and so we have scheduled

this meeting to deal with the clinical issues and

our clinical feedback. As you will hear later on,

we have particular questions that are geared toward

this application, but we are looking primarily to

see have we missed anything; are there other areas,

while we are still within the review period, that

we should be looking at further, or are there

issues that you think need to be further explored

before an application would be acted on one way or

the other?

[Slide]

I am going to spend some time today going

through basic clinical trial design issues for

products for macular degeneration in general.

[Slide]

The Division gives guidance as trials are

performed on a way to do a particular trial. We

don't believe there is a single method to do all

clinical trials. We have tried to give what we

think is a good way to do trials that will give

answers that we can then interpret. We clearly

recognize that there may be additional ways and

there may be reasons to have variance from what we

recommend. But just so that everybody is in the

same page, I am going to go through what we

generally recommend to sponsors of trials so you

know where there are potential differences, which

you may either agree with or disagree with, but

more for informational purposes.

We ask that trials be parallel on design

trials; randomized by person as opposed to

randomized by eye; double-masked, meaning at least

the investigator and the patient are masked to what

treatment they are receiving; and to try to

incorporate dose ranging within the study

development plan. That does not mean every trial

but it means that there be an exploration to dose

ranging.

[Slide]

The inclusion criteria for at least wet

macular degeneration, using that term as broad as

that is, is that we expect patients to have

choroidal neovascularization documented by fundus

photography and/or angiography. We expect there to

be specific observable features, including

membranes greater than a particular defined size

and with particular diagnostic features such as

leaking on fluorescein, such as leaking on

indocyanine green or ICG, but define a particular

population for which we could then label the

product.

[Slide]

We try to get the trials in total to be as

general as possible while still identifying a

population that the product works for. Patients

with concurrent ocular diseases that may be

associated with choroidal neovascularization we

think should be excluded to avoid any kind of

confounding issues. In this particular case that

generally means excluding people with presumed

ocular histoplasmosis and excluding high myopia,

primarily because these things can also cause

choroidal neovascularization and we want to try and

figure out which disease the product is working on.

[Slide]

We ask for replication. So, we want

safety and efficacy, supported by at least two

independent trials of at least two years duration.

We are looking for robustness in the findings. We

want independent trials, and to that extent we mean

geographically separate so that we know the product

does not just work in Washington, D.C. or does not

just work in Boston or one particular city where

the water supply is unique. These trials conducted

to date were each multicenter trials and so,

obviously, clearly meet that criteria.

Actually, before I go on let me say one

thing about the two-year trial. We have asked for

trials to go on for two years and we have had

discussions at this advisory committee before about

how long trials should go on for. We have

recognized that endpoints may be acceptable at a

one-year time point but we have asked that trials

continue on for two years. So, while you may not

hear two-year data, you can rest assured that the

trial will continue to go on for two years and we

will ultimately have that information which we will

factor into our decision. But we believe that,

because of the age of the population, one year is a

significant portion in the rest of their lives.

Consequently, if the product is showing benefit at

one year we believe we could potentially approve a

product and label it as working for however long it

works for, but we think that duration needs to be

at least one year, but have not been wedded to

anything more than that. If you end up disagreeing

with that, as with anything that I say today,

please feel free to make those comments to us.

[Slide]

The clinical trial program we think should

be able to identify adverse events that occur at

least at a one percent adverse reaction rate.

People may argue that one percent is too low, too

high. It is, for lack of a better figure, what we

have picked. That means you need at least 300

patients studied fully through that to be able to

determine that. We generally recommend at least

500 patients so that we are not dealing with,

"well, I've got 299" or "I've got 298" or "I've got

301." We know in this population, because of the

natural age and normal life span, people are not

going to necessarily survive through the

trial--just not related to the drug but related to

other reasons. So, we start out asking for people

to do trials of 500 patients or more.

We like the concentration to be studied

that is going to be marketed, we like

concentrations that are above what is going to be

marketed to be studied to try and exaggerate

potential adverse events so that we can get a

handle of potential adverse events that may occur,

even if they are not going to occur on the final

product that is approved, so that we have some idea

of what to look for. And, we would like the

frequency of dosing to be at least as frequent as

proposed for marketing. You will see in the trials

we discuss today dose-ranging studies that look at

different concentrations.

[Slide]

The duration, as I mentioned, should be at

least 24 months but, as I also said, the endpoint

could be as short as 12 months.

[Slide]

We do not require multicenter trials. It

is certainly easier to enroll larger number of

patients with multicenter trials. Our preference,

if a company is going to do a multicenter trial, is

that there be at least 10 patients per arm per

center. We have set that number so that we can

look at investigator interaction. Now, that is

frequently a difficult thing, to enroll that many

patients per arm per center, particularly if you

have a multi-arm study and you are doing dose

ranging. That dramatically increases the number of

patients you would have at a particular center.

You need to recognize that if we do not

have that many we are probably not going to be able

to look for investigator interaction at any one

particular center. We will do some other things to

look at that question but to get a true, you know,

is there one investigator that is disproportionate

to other investigators really requires more

patients than you will see in these particular

trials. This is not an uncommon problem that we

have. We don't have a solution. Generally, if you

are able to enroll a large number of patients at

any one center you probably wouldn't do a

multicenter trial. So, again, we welcome

suggestions on how to get around this.

[Slide]

Stratification is not necessary. If there

is a chance of imbalance in factors that someone

believes may influence the results, and in this

case there have been discussions about whether

occult versus classic potentially would influence

the results or whether baseline visual acuity would

potentially influence the results. We have

suggested that people stratify so that they have a

higher chance of having an equal distribution

between the individual groups--again, not required.

The hope is that randomization will take care of it

but stratification frequently helps.

[Slide]

Control agent--we have asked that at least

one of the clinical trials that is performed

demonstrates superiority to a control. We have not

defined what that control has to be. It could be

the vehicle; it could be a sham; it could be a

lower dose; it could be a different product. By

saying at least one trial has to demonstrate

superiority, that means we also potentially would

accept an equivalence trial. In today's discussion

we are going to deal primarily with superiority

trials but, recognize, we potentially would accept

either a superiority trial or an equivalence trial.

We prefer a vehicle control given our

druthers of different choices, and we prefer that

because it minimizes the bias. There is some

animal evidence--we are not aware of any human

evidence to date but there is some animal evidence

that mechanical manipulation may initiate

inflammatory mediators that may help the condition.

Consequently, by not having something that

simulates that same pathway, there may be some

influence going on by the way you deliver the

product, in this case the intravitreal injection,

that may be a positive effect. But there are

ethical issues, and I am sure we will probably get

into some of that, with giving vehicle controls.

One of the most common reasons cited for

not giving a vehicle control is the risk of

endophthalmitis. We recognize that there is a

theoretical risk of getting endophthalmitis in the

vehicle group. The clinical trials that were

performed here had cases of endophthalmitis that

were in the active control group.

I just want to be on record for stating

that, to the agency's knowledge, we have not had a

case of endophthalmitis in the vehicle control

group in any trial that has run that, and there

have been trials that have run it. So, we continue

to think it is not unethical to run a vehicle

control. Should we get an endophthalmitis case,

which I am not hoping for anyone, we may change

that opinion but at the present time we continue to

recommend vehicle controlled trials.

We do reluctantly accept sham controls,

but we have put a condition any time we have

accepted sham controls, and that has been that we

have wanted additional doses, in other words, more

than one dose tested to try to aid in the masking

of the trial. You will see that in the case of

these trials today there are multiple doses, in

addition to the sham, that is conducted. Again, we

recognize that having a sham increases the chance

of bias influence in the results, although just

having a sham does not necessarily create bias.

[Slide]

Dose ranging--we prefer to try and bracket

the dose that will ultimately be marketed, in other

words, study doses that are higher and study doses

that are lower than that which will be ultimately

marketed so we get a better understanding of the

drug product.

[Slide]

Efficacy has been discussed a lot. We

have a number of parameters that we readily accept

as being acceptable. We have other parameters

which we think may in the future be acceptable or

we will be willing to entertain if there is

validation, and validation does not necessarily

need to occur in this particular trial. The thing

that we readily accept as being important is a

change in visual function. So, our guidance to

people when we are having discussions about

clinical trials is that there be statistical

significance in clinical relevance in visual

function at more than one time point. By visual

function we mean visual acuity, visual fields or

color vision.

[Slide]

The evaluations we expect to be carried

out include, obviously, best corrected distance

visual acuity. By that, we generally mean using a

chart that has equal number of letters per line and

equal spacing between lines. The ETDRS is one type

of chart that meets that, and based on the

validation information that was conducted at a four

meter distance so that is our preferred both

distance and test but we are willing to recognize

other equivalent tests of best corrected distance

visual acuity.

We expect best corrected visual acuity to

be measured at every visit, and we expect those

visits to occur no less frequently than every three

months.

We expect to have dilated seven field

fundus photography sometime during the trial. We

expect to have fluorescein or indocyanine green

depending on what exactly is being studied during

the trial, and we have not specified exactly when

that has to be. We expect dilated ophthalmoscopy

to be performed both for evaluation and for safety

at every visit. We expect a dilated slit lamp exam

for the same reason. We expect to have endothelial

cell counts, not necessarily in every trial but

somewhere within the development plan, and have at

least one study that includes it at the beginning

and end of the trial, and the same thing standard

systemic clinical and laboratory evaluations.

[Slide]

Two meters versus four meters has been a

source of a lot of controversy. It is my

understanding it stems primarily from the

practicality of being able to have exam rooms that

are four meters. In my father's day and age, it

would have required 20 foot length and his exam

rooms were set up to do that. That is not the

current trend now. People use exam lanes that are

much shorter. But the subject has been studied.

It was the source of a lot of discussion in the

past, and there is a paper that set out four meters

as a standard that was published in Ophthalmology

in 1996 for exactly the purpose of discussing what

the best distance is.

It does not mean that you can't

theoretically correct. You know, two meters, four

meters--you can use the same distance and make the

charts smaller so you are looking at the same angle

that gets subtended. The issue is the variability

that occurs when measuring at two meters versus

four meters and the potential for any bias if the

patient is allowed to lean. Now, if we would strap

down or lock every patient into an exam seat and

never let them move at all, it probably wouldn't be

an issue but we don't do that. Just so people get

a feel, at a two meter distance 17 inches is equal

to one of one line. Those of you sitting in the

various seats, if you are leaning backward or

leaning forward, just sitting in your same seat can

easily do 17 inches. We don't have any reason to

believe that people are attempting to bias the

results or attempting to lean, and visual acuity is

a very common measure in ophthalmology so everybody

is aware to try to keep people from leaning or keep

that from influencing what goes on. But studies

have been done that show poor reliability at one

meter versus four meters. So, the assumption is

that there is also more variability at two meters

than there would be at four meters. The overall

impact on a particular trial is not known, and the

only way to know that for sure would be to do both

two meters and four meters, which we do not have

data to discuss today.

We think it is more significant for those

trials that have a feature that allows there to be

a potential in masking, such as sham. We think it

is more of an issue in an equivalence trial than it

is in a superiority trial. These trials that we

are talking of today are superiority trials; they

are not equivalence trials. But there are issues.

[Slide]

Our recommended endpoints to date have all

been, as I mentioned earlier, visual function. We

think at some point in the future we will end up

accepting anatomical changes but we have not yet

found anatomical changes that correlate directly

with visual function. So, currently we readily

accept doubling of the visual angle, which on the

ETDRS chart at four meters would be 15 letters or

more; a halving of the visual angle, in other

words, showing improvement in vision; a quadrupling

of the visual angle, which would be 30 letters or

more. These are all looking at percentage of

patients that have this particular finding because

we think a doubling of the visual angle is a

clinically significant difference that would not

occur within the variation of day-to-day visits.

[Slide]

We have also been willing to accept a

difference in the group mean. We do not know

exactly how much of a difference in group mean

would be clinically significant so for

consistency's sake we have said we will readily

accept a mean change of 15 letters. That does not

mean that something less than that may not be

statistically significant. We are just not ready

to accept without question anything less than 15

letters.

[Slide]

Let me just briefly talk about equivalence

trials just so you know the full scope of what we

have talked about with individual sponsors. We

believe it is possible to do comparison with an

active agent which has already demonstrated

repeated success. Visudyne is currently approved

for predominantly classic choroidal

neovascularization in atrial macular degeneration

and a couple of other things. So, for that

particular indication we would accept an

equivalence trials if one wanted to conduct it.

The way we have set up equivalence trials is that

we have asked that at least 50 percent of the

established treatment effect be preserved so that

95 percent confidence intervals be drawn around

those parameters to protect at least 50 percent of

the treatment effect. Again, it is not a

particular issue for this product but it may be an

issue for other products.

The analyses that we ask to be conducted

always include intent-to-treat with last

observation carried forward and per-protocol with

observed values only. We recognize these as

differences in the data available for analysis.

The intent-to-treat last observation carried

forward is the fullest data set we can obtain. It

is everybody that was randomized in the trial and

it is creating a value for everyone whether real of

extrapolated. A per-protocol analysis is the

minimal data set. It is only those patients that

fully met the protocol and only the values that we

have there.

We don't believe that either one of these

two analyses is the best analysis or is the most

proper or is the most representative. We think

they are extremes and we ask that both be conducted

and we look for differences between these two

analyses. If there are no differences between

these analyses we assume that, regardless of how

much inclusion/exclusion, your results are pretty

much the same and you can accept either one. If

there are differences we ask for additional

analyses to try and explore which one is likely to

be telling a better picture or why it is telling a

different picture.

Other analyses which you would have seen

in the briefing package include things like

worst-case analyses where we treat all dropouts in

the control as being successes and all dropouts in

the test product as being failures. This is not a

correct test. This is not an accurate test. We

are making assumptions in the worst direction to

look and see how robust the findings are. We don't

expect the product to win on a worst-case analysis,

but it does give us an idea of what the limits of

potential analysis results could be.

[Slide]

As a general rule, we ask for alphas to be

0.05. This is the common 5 percent for two-tailed.

In other words, p is less than 0.5. We ask for

power to detect a difference to be 80 percent or

greater, and we ask that any time anybody looks at

the data, any kind of look any time during the

evaluation that there be an adjustment in the

statistical plan, in other words, correction for

that alpha for any look that occurs. All of our

analyses that you see in any of our data sets will

include these features.

[Slide]

The last one I want to talk about is

pediatrics. There is an agency initiative to try

and include, when possible, pediatric patients in

the drug development of particular products. So, I

am covering it for completeness. In this particular

case, choroidal neovascularization is rarely seen

in pediatric populations and we have not asked the

sponsor of this application or any of the

applications that just deal with choroidal

neovascularization to include pediatric patients

because the population we don't think is relevant

in this particular case. But as a general rule we

do ask for pediatric patients to be included during

the development.

I am happy to take any questions and,

again, I thank everybody for your time, and look

forward to a fruitful discussion.

DR. DUNBAR: Are there any questions at

this point regarding Dr. Chambers' presentation?

If not, at this point then I would like to open the

forum for the sponsor, Eyetech Pharmaceuticals and

I will ask that the sponsor introduce each of their

speakers within their presentation.

Eyetech Pharmaceuticals Presentation

Introduction

DR. DYER: Good morning.

[Slide]

Today we will discuss the first anti-VEGF

therapy for the eye and the first treatment to

target the underlying biology of neovascular

age-related macular degeneration. Pegaptanib

sodium achieved statistical significance for

clinically meaningful, prespecified primary

endpoint in replicate trials with strong supportive

data in secondary endpoints.

The efficacy was against usual care

controls, and this pharmacological agent also shows

a favorable safety profile and provides a treatment

benefit to many patients for whom no effective

therapy presently exists.

[Slide]

My name is David Guyer. I am from Eyetech

Pharmaceuticals. I previously was professor and

chairman of ophthalmology at the N.Y. School of

Medicine and a practicing ophthalmologist

specializing in macular degeneration.

Also speaking today will be Dr. Tony

Adamis, who was an ophthalmologist on the full-time

faculty at Harvard, and is now with Eyetech. He

ran the ocular angiogenesis laboratory as well.

Our risk/benefit section will be presented by Prof.

Don D'Amico, from Mass. Eye and Ear Infirmary at

Harvard.

[Slide]

Neovascular age-related macular

degeneration represents 90 percent of the severe

vision loss from this disease. Many patients note

a loss of independence and inability to read, to

ambulate and to recognize faces of their loved

ones. This occurs because when the disease forms

abnormal blood vessels that leak blood and fluid

waviness or blurred vision can be seen in the

central area that sometimes can lead to a scotoma

or blind area centrally that prevents them from

seeing straight ahead, and in up to a third of

patients clinical depression can be noted.

[Slide]

The devastating effects of this disease

were well summarized in a book by Henry Grunwald,

who was the former editor-in-chief of Time Magazine

and U.S. ambassador. In the book, "Twilight:

Losing Sight, Gaining Insight" Mr. Grunwald said,

"after a lifetime during which reading and writing

have been as natural and necessary as breathing, I

now feel the visual equivalent of struggling for

breath."

[Slide]

Macular degeneration represents a major

public health problem and urgent unmet medical

need. It is the most common cause of irreversible,

severe blindness in developed countries.

Ninety-five percent of retinal specialists believe

that macular degeneration represents an epidemic,

and there are 200,000 new cases a year in the

United States alone, and a prevalence of up to 1.6

million patients with active bleeding. Limited

treatments are available and 85 percent of retinal

specialists are dissatisfied with current treatment

options.

[Slide]

Macular degeneration represents a

progressive disease. Early on in the disease these

whitish-yellow spots, called drusen, occur and

patients can progress to the neovascular form of

the disease which is where pegaptanib is effective.

This is an angiogenic disorder and what happens is

abnormal blood vessels grow behind the retina where

they leak blood and fluid, as depicted here, and,

untreated, they lead to disciform scarring where

fibrovascular tissue destroys and replaces the

normal rods and cones in the retina. At this

point, usually moderate to severe visual loss is

noted.

[Slide]

Let's discuss the therapeutic options

available for patients with neovascular macular

degeneration. In the 1980s, the Macular

Photocoagulation Study Group showed the beneficial

roles of thermal laser photocoagulation. However,

very few patients are suitable for this treatment.

The treatment is most suitable when the abnormal

blood vessel, as seen here on a fluorescein

angiogram, is away from the center of the macula,

in what we call extrafoveal or juxtafoveal

location, because for patients where the blood

vessel is dead center or subfoveal the laser scar

itself can destroy the very tissue we are trying to

save. Unfortunately, most patients with

neovascular macular degeneration have subfoveal

disease where the blood vessel is dead center.

[Slide]

In the year 2000, photodynamic therapy, or

PDT, was FDA approved for patients with subfoveal

predominantly classic angiographic subtype. Thus,

for approximately three-quarters of patients with

neovascular macular degeneration there is no FDA

approved therapy, although there is off-label use,

with some limited CMS reimbursement, presently.

Today we will discuss the first anti-VEGF

therapy for the eye, a pharmacological treatment

that targets the protein VEGF that is responsible

for the hallmarks of all choroidal

neovascularization. Increased levels of VEGF lead

to neovascularization and increased permeability,

which lead to the clinical features of all

choroidal neovascularization, and pegaptanib blocks

VEGF.

[Slide]

VEGF is the common denominator for

neovascular macular degeneration. Numerous peer

reviewed papers have shown that for all

angiographic subtypes, by immunohistochemistry

staining, VEGF is present in both autopsy and

surgical specimens.

[Slide]

Pegaptanib sodium is a pegylated modified

oligonucleotide. It has a selective vascular

endothelial growth factor antagonist to isoform

165. Tony in just a few minutes. It is a sterile

aqueous solution in a single-use, pre-filled

syringe, which is important for safety reasons.

The recommended dose is 0.3 mg of intravitreous

injection administered once every 6 weeks.

[Slide]

We will show you today that pegaptanib met

a clinically meaningful primary efficacy endpoint

with statistical significance in replicate,

well-controlled clinical trials, with a favorable

safety profile.

[Slide]

I will now ask Tony Adamis to discuss a

VEGF overview and macular degeneration

pathophysiology.

VEGF Overview and Macular Degeneration

Pathophysiology

DR. ADAMIS: Thank you, David and good

morning.

[Slide]

In 1971 Judah Folkman first proposed the

targeting of a specific angiogenic factor as a way

to treat disease, and specifically a way to treat

cancer and ophthalmic disease.

[Slide]

It was in 2004, with the completion of

pivotal Phase III trials using Avastin which blocks

VEGF that this theory was in a definitive fashion

proven correct. This drug now was approved this

year as a first-line therapy for colon cancer. So,

we entered this era of biological anti-angiogenesis

therapy.

[Slide]

The target in that trial and in our trial

is VEGF, which is an acronym for vascular

endothelial growth factor. Prior to that it was

called vascular permeability factor. Unlike many

other growth factor names, these two are very

appropriate in the sense that they describe the

central biological functions of this protein. VEGF

makes vessels very leaky and VEGF makes vessels

grow. The leaky aspect of it was discovered in

1983 by Harold Dvorak and then the

neovascularization aspect or biology of VEGF was

discovered by Napoleon Ferrara, who has been a

leader in this area, and Dan Connolly, in 1989.

Since then, if one conducts a MEDLINE

search, there have been over 11,000 published peer

reviewed articles on VEGF. There is a large body

of knowledge concerning this growth factor. I show

you just one example of that here. This is the

protein structure of VEGF. We now can determine

very precise structure-functional relationships.

[Slide]

The disease we are here to discuss, as

David said, is age-related macular degeneration, a

very prevalent disease in our society and a very

complex one scientifically when one begins to study

it. We are beginning to unravel the earlier stages

of the disease, the stages where Bruch's membrane

is altered and gives you those yellow spots, the

drusen that David showed you in a clinical

photograph. We are also starting to understand the

complex interaction of the different cell layers

with the vasculature. But the area or the phase of

the disease, the late phase of the disease that we

are studying is the neovascular phase where vessels

begin to grow up towards the retina. These vessels

are abnormal and leaky, and they leak fluid and

lipid and they damage the photoreceptors which

sense light, and people lose vision and go blind.

This process, the angiogenic process, has been very

well studied.

[Slide]

As David said, the data indicate that it

is biologically plausible that blocking VEGF would

have a beneficial effect in this disease in a broad

population. When one looks at surgical specimens

or autopsy specimens of patients with the disease,

what is seen is that the common denominator is

VEGF. It is present in all angiographic subtypes

and it is present in all active stages of the

disease. So, therefore, the hypothesis that

blocking VEGF in neovascular MD would have a

broad-base effect has some broad biological

plausibility.

[Slide]

But those are not the only data that we

have. There is a large body of preclinical

evidence, roughly 15 years worth, which is

summarized on one slide here. Let me just briefly

walk you through it. In preclinical models of

vessel growth in the cornea, in the iris, in the

retina and in the choroid, if one gives a VEGF

inhibitor you can prevent the growth of vessels and

you can prevent the leak that is associated with

those vessels. So, VEGF seems to be required for

those processes.

Similarly, if one looks at those normal

tissues and now introduces VEGF into the system,

either by injecting the protein or genetically

over-expressing it, VEGF in and of itself is

sufficient to produce the neovascularization or

leak that can occur in these tissues.

Then, so that we have some context in

which to interpret those preclinical data, surgical

specimens and autopsy specimens from humans with

actual corneal neovascularization, iris

neovascularization, retinal and choroidal

neovascularization show that VEGF is expressed at

high levels in those tissues at the time when the

vessels are growing and leaking. So, the totality

of the data supports this approach of blocking VEGF

in specifically the disease under study today,

age-related macular degeneration.

[Slide]

It gets a little more complicated in the

sense that VEGF really refers to a family of

related molecules, and I want to talk about one

specifically, VEGF 165 which is the target of

pegaptanib.

[Slide]

We were faced with the paradox a few years

ago, as we looked at the accumulated data

concerning the role of VEGF in disease and in the

normal state. What we found was that VEGF is

required for the normal formation development of

vessels during development throughout the body. I

am just showing you here two examples. These are

the vessels of the normal colon and these,

obviously, are the normal vessels of the retina.

[Slide]

In the same molecule, VEGF was shown in a

number of definitive studies and laboratories

around the world that VEGF is required for the

abnormal vessels that can grow in the colon, and

this is colon carcinoma, and here is a case of

age-related macular degeneration. So, how is it

that the same protein can cause these vastly

different phenotypes, these different types of

vessels? One set of vessels are normal and they

don't leak and they behave appropriately; another

set looked very different and they behave very

differently.

[Slide]

Perhaps, we thought, some of that

complexity is encoded in these different isoforms.

Let me just explain what those are. There is one

VEGF gene but that gene encodes multiple

transcripts or mRNAs for VEGF that have different

sizes that translate into different proteins. So,

one of those major proteins or isoforms is VEGF

165, which just simply means that it is composed of

165 amino acids. Another major isoform, especially

in the eye, is VEGF 121. We asked the question

could it be that differential expression or

synthesis of these isoforms underlies the

complexity that we see in the vessels in the normal

and the diseased state?

[Slide]

So, in an experiment we conducted and

published last year, we studied the retinal

vessels. We studied the normal retinal vessels

that are developing as the retina forms and we

studied abnormal retinal vessels in a model of

retinopathy prematurity. This is a model where

vessels grow towards the vitreous and leak and are

distinctly abnormal.

What we saw was that when normal vessels

are developing the isoform expression of the two

major isoforms, 120 and 164 which are the rodent

counterparts to human 121 and 165, is roughly equal

during development. But rather strikingly, during

disease when disease vessels are growing there is a

shift to almost exclusive expression of the 164

isoform. So, it was an interesting association

that we saw of 164 with diseased vessels.

[Slide]

But to really get at the causality of 164

in the production of diseased vessels we conducted

the following experiment. In a model of abnormal

vessel growth we gave pegaptanib which blocks just

164 and compared it to a non-selective VEGF

inhibitor which blocks all the isoforms. We saw

that bpth were equally effective in preventing

abnormal vessel growth. Here is the control with

the abnormal vessels, and both are pretty good at

inhibiting that.

We also looked in a model of normal

retinal vessel development and, again, gave

pegaptanib and what we saw was essentially zero

inhibition of normal vessels. We did not affect

normal vessels. Whereas, the non-selective VEGF

inhibitor had a deleterious effect on these normal

vessels in the retina. So, the conclusion we made

was that VEGF 164 may be preferentially associated

with disease and targeting it gives you a much more

selective inhibition in that you are much less

likely to affect normal vessels in the developing

animal. But I will tell you that there has

subsequently been independent support of this,

specifically from UCSF, where this is also perhaps

true in the adult animal.

[Slide]

To be certain of our conclusion because we

used a reagent here, pegaptanib in particular, we

wanted to make sure this conclusion was robust.

So, we created animals genetically that where we

deleted specifically the 164 isoform and these

animals were able to make all the other types of

VEGFs. What we see here is that these animals have

completely normal retinas and normal retinal

vessels and they are no different than animals that

make all VEGF isoforms. In fact, these animals

grow up to a normal age. They can reproduce.

There are no abnormalities we can detect, even

though they cannot make any VEGF 164.

[Slide]

So, how was a drug made that specifically

blocked VEGF 164? Well, pegaptanib is an

oligonucleotide aptamer. It specifically is 28

nucleotide in life. Aptamers are molecules that

will fold in a very specific fashion. They have a

three-dimensional conformation such that they will

bind to the target protein of interest--in this

case it is VEGF--in a highly specific manner, and

in the case of pegaptanib with a very high

affinity. This binding occurs extracellularly.

The drug does not enter the cell. It is all

happening outside the cell, which is where VEGF is

residing. These features make it act very much

like an antibody but there are some important

distinctions, aside from it not being an antibody;

it is an oligonucleotide.

This class of molecules, in the published

literature and it has been our experience as well,

are quite non-immunogenic. In our preclinical and

in our clinical examination of pegaptanib we have

not seen a single instance when an antibody is

raised to it. And, as I alluded to, they have this

remarkable target specificity and this simply

attests to that.

[Slide]

This shows that pegaptanib is very

efficiently binding to human VEGF 165 and murine or

mouse VEGF 164, but there is no significant, or

essentially no binding to VEGF 121 or related

family member of placental growth factor.

[Slide]

So, what we would expect when pegaptanib

is administered to the eye is that you would have

selective VEGF inhibition of 165 which was

associated with pathology and in our animal model

spares the normal vasculature, and we would have

two very important biological responses as a

function of that blockade: vessel growth would be

inhibited, as would permeability, and the thinking

was this would translate to a better visual

outcome.

[Slide]

The last thing I would like to talk about

is how we chose our dose. This drug is

administered to the eye nine times a year, and

there are three doses that we chose.

[Slide]

Let me show you the data that we had in

hand when we were planning these trials. We knew

from our pharmacokinetic experiments that when

pegaptanib is given to the eye via intravitreous

injection it slowly exits the eye and it can be

measured in the plasma. Actually, the plasma

levels mirror the levels that one sees in the

vitreous. So, by sampling the blood you can infer

what is happening in the eye.

The other important thing that we learned

here is that when the drug exits the eye, at least

in this rabbit model, you have thousand-fold less

concentration in the plasma than you do in the eye.

In a more relevant primate model we saw that this

held up in the sense that it was 800 times less in

the plasma than it was in the eye.

[Slide]

We learned from those studies that the

half-life in the primate vitreous is approximately

four days. We also had data that we had collected

in tumor models and in a model of retinopathy

prematurity that when you give pegaptanib

intravenously the amount of pegaptanib that is

needed to inhibit the VEGF is about 1 ng/mL.

We also had another inhibitory

concentration that we had determined in vitro in

tissue culture in various assays of calcium

mobilization and endothelial cell proliferation.

The relevant concentration in tissue culture of

pegaptanib that was required to inhibit VEGF was

significantly lower. It was 0.01 mcg/mL or 10

ng/mL.

When we started out it was not entirely

clear which of these inhibitory concentrations

would be most relevant when you are injecting the

drug into the eye. So, we postulated that if this

is the most relevant inhibitory concentration, then

a 3 mg dose, given every 6 weeks would sufficient

block VEGF for the entire 6-week period. If, on

the other hand, this was the relevant

concentration, the 3 mg dose, the 1 mg dose and the

0.3 mg dose would actually all three be sufficient

to block VEGF for the entire 6-week period, and

perhaps that may translate to a plateau of the dose

response.

[Slide]

To summarize what I have just discussed,

VEGF appears to be an important control point for

neovascularization and vascular permeability, the

pathologies that lead to vision loss in age-related

macular degeneration. Pegaptanib specifically

targets the VEGF isoform VEGF 165, which we believe

is operative in disease. I have shown you data

from ROP but this has also been shown to be true in

choroidal neovascularization, diabetic retinopathy

and other conditions. And, pegaptanib dosing is

based on pharmacokinetic data which were collected

prior to the conduct of this study.

[Slide]

At this point, Dr. David Guyer will return

and David will talk to you about our clinical

efficacy data from the pivotal trials.

Pegaptanib Clinical Efficacy

[Slide]

DR. GUYER: In this section we will show

you that pegaptanib met a clinically meaningful

primary efficacy endpoint with statistical

significance in independent, well-controlled,

replicate trials, with a favorable safety profile.

[Slide]

The macular degeneration program consisted

of 6 trials, 1,281 patients and over 10,000

treatments at 117 sites in 21 countries. The dose

ranges that were studied ranged from 0.25 mg to 3

mg per eye.

[Slide]

These are the six trials. EOP1003 and

1004 are pivotal trials, sham-controlled,

double-masked, randomized trials. There were 622

patients in the predominantly ex-U.S. trial and 586

in trial 1004 in North America. The other four,

smaller trials were pharmacokinetic trials and

open-label single or multiple dosing trials with,

or without PDT, for the total exposed of 1,281.

[Slide]

The Phase I/II program showed that

pegaptanib appeared safe in all tested doses and

regimens with no dose-limiting toxicities. There

were no unexpected retinal or choroidal

abnormalities noted by angiography as read by an

independent reading center. As Tony mentioned,

these trials established the dosing regimen based

on pharmacokinetics.

[Slide]

The study objective of the pivotal trials

was to establish a safe and efficacious dose of

intravitreous pegaptanib sodium in patients with

subfoveal choroidal neovascularization secondary to

age-related disease.

[Slide]

The development of these pivotal studies

was done in conjunction with our expert advisory

panel, whose names are listed on this slide.

[Slide]

The study design was two randomization,

double-masked, sham-controlled, dose-ranging trials

of pegaptanib 0.3 mg, 1 mg and 3 mg and sham. The

treatment regimen was every 6 weeks and the

prespecified time point for the primary endpoint

was 54 weeks. PDT, photodynamic therapy, was

permitted per the FDA-approved label at the masked

investigator's discretion. Since shams could have

PDT, this represented a usual care control group.

[Slide]

Independent monitoring was done both by an

independent reading center that confirmed the

eligibility prior to randomization, and an

independent data safety monitoring committee, or

IDMC.

[Slide]

These were the members of the IDMC. It

was chaired by Prof. Alan Bird, who is here with us

today.

[Slide]

Because of the biology of neovascular

macular degeneration and the mechanism of action of

pegaptanib, we designed a trial with a very wide

range of inclusion criteria which included a broad

range of visual acuities, 20/40 to 20/320, and

broad angiographic criteria including all subfoveal

angiographic subtypes; lesion sizes up to and

including 12 total disc areas in size; greater than

or equal to 50 percent of the total lesion size

needed to be active choroidal neovascularization;

and for minimally classic and occult disease

subretinal hemorrhage and/or lipid and/or recent

change in vision was necessary for inclusion.

[Slide]

Ocular exclusion criteria included

previous subfoveal thermal laser therapy, and to

avoid older chronic cases any subfoveal scarring or

atrophy or greater than or equal to 25 percent of

the lesion being scarred or atrophic. Causes of

choroidal neovascularization other than age-related

diseases were excluded, and if a patient had recent

intraocular surgery or was thought to perhaps need

cataract surgery in the near future, they also were

excluded. Finally, no more than one prior PDT

treatment was allowed.

[Slide]

The general exclusion criteria included a

history or evidence of severe cardiac disease such

as myocardial infarction within the last 6 months,

ventricular tachyrhythmia or unstable angina;

evidence of peripheral vascular disease; or

clinically significant hepatic or renal

dysfunction; or a stroke within the last 12 months.

Our population, however, was very characteristic of

your typical elderly population in that 50 percent

of the patients had systemic hypertension; 25

percent were on statins; and 20 percent had

cardiovascular disease.

[Slide]

Stratification at randomization included

study center, a history of prior PDT use and

angiographic subtype.

[Slide]

Our primary efficacy endpoint, which was

prespecified, was the percent of patients losing

less than 15 letters from baseline to week 54, the

same endpoint that was used for marketing approval

of Visudyne.

This is an ETDRS chart where 5 letters

equal 1 line, and the 15-letter change or 3-line

change represents a doubling of the visual angle

which is a clinically meaningful change to an

individual patient.

[Slide]

Our primary endpoint used in

intent-to-treat, or ITT, population included

patients receiving at least one treatment and a

baseline visual acuity measurement. The last

observation carried forward, or LOCF, was used to

impute missing data. We will also discuss

supportive visual and angiographic endpoints, as

well as exploratory or subgroup analyses.

[Slide]

This table shows the various study visits.

Of note, a telephone safety check was done 3 days

after treatment. Tonometry or measurement of

intraocular pressure was done both before treatment

and 30 minutes after, and fundus photography and

fluorescein angiography was done at baseline and

weeks 30 and 54.

[Slide]

In order to preserve the integrity of the

masking there were two physicians involved in the

trial. One physician administered the study

treatment and the second physician was involved in

any patient assessments or decisions. Patients

were also masked in that the sham procedure was

identical to the active drug procedure except for

the actual penetration into the vitreous. This

meant that they had application of a lid speculum,

instillation of topical medications,

subconjunctival anesthetic, and pressure against

the globe using a needle-less syringe.

The visual acuity examiners were also

masked to both he treatment arm and also to

previous vision assessments, and the reading center

was not aware of the patient's treatment arm.

[Slide]

This slide represents the patient baseline

characteristics for both trials 1004 and 1003.

What we can see in each trial is that the active

doses and the sham are well balanced with respect

to sex, age, initial visual acuity, angiographic

subtype, prior use of PDT and lesion size. The

only difference between the two trials was that

there was slightly more prior PDT use in trial

1004. That was the North American trial, and that

was because Visudyne was approved and reimbursed

earlier in the United States than in Europe. Out

of 9 possible injections, on average all patients,

treated and sham, received 8.5 of the 9 injections,

and overall there was about a 10 percent rate of

discontinuation in the trial.

[Slide]

We prespecified to use a Hochberg

procedure to account for the multiple doses in this

pivotal trial. As per agreement with the FDA, it

was decided to unmask study 1004 first--that was

the trial that was recruited first, thus, the

results were available earlier--in order to

determine which doses to formally analyze in the

study trial study, 1003.

[Slide]

So, we proceeded to unmask the first

trial, study 1004, and we found for the 0.3 mg dose

67 percent of patients lost less than 15 letters

compared to 52 percent of sham. This hit our

Hochberg adjusted p value at 0.0031. Note that the

1 mg dose had a similar response rate, about 66

percent. The p value was 0.0273. The 3 mg

response rate was higher than the shams at 61

percent, however, it did not hit the necessary p

value.

[Slide]

For this reason, prior to unmasking the

second trial, it was prespecified to the FDA that

only the 0.3 mg and 1 mg doses would be formally

analyzed in the second trial. Then we proceeded to

unmask the second trial, study 1003.

[Slide]

This study showed replication of the

findings of the first trial study, 1004, in that 73

percent of the patients in the 0.3 mg dose,

compared to 59 percent of sham, lost less than 15

letters, again hitting our Hochberg adjusted p

value of 0.0105. Again, the response rate in the 1

mg group was similar at 75 percent and a p value of

0.0035, and the response rate in the 3 mg group was

69 percent. The p value you see here, 0.1252 was a

nominal p value because we decided, as we

mentioned, not to formally analyze it.

[Slide]

So, we can look at the combined data and

see that 70 percent of the 0.3 mg group, 71 percent

of the 1 mg group and 65 percent of the 3 mg group

lost less than 15 letters compared to 55 percent of

the shams, and for all of these active treatment

groups we had low nominal p values.

It is important to emphasize that for the

0.3 mg group we were able to show independent

replication in two trials of a statistically

significant effect in a prespecified clinically

significant primary endpoint.

[Slide]

I would like to turn now to some

supportive visual angiographic analyses. There are

a variety of ways of looking at various visual

outcomes that are standard for reassurance that the

treatment effect for showing the primary endpoint

is real. As we will present, all of these analyses

were in favor of pegaptanib which gives us

confidence in this treatment effect. Because the

independent trials had the same protocol and

demographics, and because we prespecified it in our

statistical plan, we will present these as pooled

data.

[Slide]

This graph shows the percent responders

over time. What we can see is that we were able to

show that the active treatment group had a

treatment effect over sham not only at our primary

endpoint at 54 weeks, but at every studied time

point the active treatment group did better than

the sham.

[Slide]

This is a graph of mean change in visual

acuity. Again, the active treatment group is here,

the sham or usual care group showing a progressive

decrease in vision, and the difference at 54 weeks

was approximately 50 percent in favor of the active

treatment group.

[Slide]

This treatment effect was early and

sustained, by as early as 6 weeks, which was the

first visit after the first injection the

pegaptanib groups had already distinguished

themselves from the controls and, as we can see

here, the 0.3 mg and the 1 mg group had done that

with the low nominal p value. This sustained

itself throughout the 54-week course of treatment.

[Slide]

Sham eyes were twice as likely to suffer

severe vision loss than actively treated patients,

as shown in this graph of percent of patients with

severe vision loss. We can see the sham controls

with severe vision loss compared to the

active-treated groups.

[Slide]

At week 54, again, there was a low nominal

p value for the 0.3 mg and 1 mg group compared to

sham, with progression to severe vision loss which

is 30 letters or 6 lines.

[Slide]

This also was seen for legal blindness in

one eye, which is 20/200 or worse. We again can

see that more sham eyes progressed to 20/200 vision

or worse compared to actively-treated groups.

[Slide]

Patients on pegaptanib were also more

likely to maintain and/or gain visual acuity. This

graph shows the prespecified endpoints of

maintaining or gaining vision that is greater than

or equal to zero lines gained, as well as greater

than or equal to 3 lines gained. These other two

endpoints were not prespecified but we can see

again in all cases a treatment effect for

maintaining or gaining vision compared to sham.

[Slide]

The next few slides will show the

distribution of visual acuity change at baseline

and compared to week 54. Let's first look for the

0.3 mg group. This was the range of visual

acuities at baseline. Yellow is the 0.3 mg group

and blue is the sham.

[Slide]

After 54 weeks in the trial we can see

that more patients in the 0.3 mg treated group than

sham had good visual acuities and more patients

with sham than treated patients had poorer visual

acuity. So, the shift in distribution was in favor

of our 0.3 mg group, and the p value for this was

less than 0.0001.

[Slide]

The same is true, as we can see here, for

the 1 mg group. This is the baseline visual acuity

distribution and at 54 weeks again we can see more

1 mg treated patients than sham having relatively

good visual acuities and more shams than treated

eyes having poorer vision. Again, this shift in

distribution is in favor of the 1 mg group had a p

value of less than 0.0001.

[Slide]

Finally, we can see that for the 3 mg

group also. Here is the baseline distribution and

at 54 weeks again more 3 mg patients had better

visual acuities than shams, and more shams had

poorer vision at the end of 54 weeks than the 3 mg

treated patients.

[Slide]

This is a graph of the cumulative

distribution function of vision. What it shows on

the bottom is the change in visual acuity up to

week 54 and the cumulative proportion on this axis.

This shows the robustness of the data as it uses

all of the data points for 54 weeks.

What we can see first is this S-shaped

curve. This is the blue sham patients. You can

see here, for example, at minus 15--that is minus

15 letters which was our primary endpoint, moderate

for vision loss, and we see minus 30 which, as we

talked about, represents severe vision loss, and we

can see the zero or higher time point which

represented maintaining vision. What we can see is

that, whether we are talking about preventing

vision, maintaining vision or gaining vision, there

has been a shift in distribution, a shift in the

distribution of the sham patients in all active

treatment arms to the right, suggesting benefit in

all areas. The area between the lines which

represents this improvement was highly

statistically significant for all three doses, for

the 0.3 mg dose less than 0.0001; the 1 mg dose

0.0001 again; and the 3 mg dose 0.0017.

[Slide]

I would like to now turn to the

exploratory or subgroup analyses.

[Slide]

It is important to emphasize that this

study was powered to test for statistical

significance in the overall study population, that

is, to test for the primary hypothesis or primary

endpoint of all subjects. Nevertheless, it is

important to explore various baseline

characteristics such as lesion composition, lesion

size, baseline vision, age, sex and pigmentation of

the iris.

[Slide]

Despite a reduced ability to draw

statistical conclusions because of decreased sample

size, in some cases as small as 18 patients,

multiple subgroup analyses which can both lead to

false positives and negatives--despite this no one

subgroup drove the overall effect, as we will show

you.

[Slide]

We will first look at the 0.3 mg and 1 mg

doses as was described in the FDA briefing book.

We have also analyzed and prepared the 3 mg dose

and if people are interested later we can show you

that. We will present this using pooled data

because it was prespecified and we will show the

individual trials after.

[Slide]

Here we can see for the pooled data at the

0.3 mg dose that in all cases of all patient

characteristics the 0.3 mg active treated group did

better than sham. This was for sex, age and,

consistent with the biology of this disease and the

mechanism of action of pegaptanib, for all

angiographic subtypes, predominantly classic,

minimally classic and occult, as seen here; also,

initial baseline visual acuity, size of the lesion,

race and pigmentation of the iris.

[Slide]

Here we can see for severe visual

loss--the first graph was moderate visual loss or

primary endpoint, but we can see that the

conclusions we made are supported by severe visual

loss, or 6-line loss, 30-letter loss in this graph.

The blue are the sham so all had more severe vision

loss than actively treated 0.3 mg group for all

patient characteristics. So, this supports our

primary analysis.

[Slide]

Turning to the 1 mg group, we can see the

same thing, that in all patient characteristics the

1 mg group did better than sham. Again, we can see

that this information is supported by severe vision

loss where, again, sham in all cases did worse than

the actively treated 1 mg dose.

[Slide]

Let's now turn to the individual trials.

Individual trials which are under-powered

inherently have more variability. Nevertheless, we

can make the same conclusion, that no one subgroup

drove the overall efficacy. Again, for trial 1004

with the 0.3 mg group we can see the very small Ns,

sample sizes, for some of these groups and, again,

we can see support for using severe visual loss as

another important clinical endpoint.

[Slide]

For trial 1003, with the 0.3 mg dose we

can see the same thing.

[Slide]

For the 1 mg dose, again we can see, in

trial 1004, that in all cases the treated groups

did better than the controls and this was supported

by the severe vision loss in 1004 again.

[Slide]

And, in trial 1003, again, for moderate

vision loss treated patients did better than the

blue shams and support with severe vision loss

where shams did worse than actively treated

patients for progression to severe vision loss.

[Slide]

In order to be sure there were no

important subgroup relationships, we also performed

a multiple logistic regression to identify any

potential factors either influencing the outcome or

modifying the treatment effect. Subgroups and

interactions of subgroups with treatment were

investigated.

[Slide]

These are some of the subgroups that we

evaluated, age, angiographic subtype, use of PDT,

sex, race, lesion size, status of

smoker/non-smoker, subretinal hemorrhage, the

fellow eye vision loss and lipid.

[Slide]

We found for the 0.3 mg dose that no

factors were identified as significant treatment

effect modifiers for 0.3 versus sham, and no

factors except treatment with pegaptanib were

identified as significantly influencing the

response, and this had a p value of 0.0003 in favor

of treatment.

[Slide]

For the 1 mg group we again found that no

factors were identified as significant treatment

effect modifiers versus sham, and for pegaptanib at

1 mg there was a relationship between treatment

with pegaptanib, again at 0.0001, and age which

favored patients with less than 75 years of age.

This is not to say that older patients did not do

better. It just said that there was a favor for

younger patients even both appear to respond.

[Slide]

What can we conclude from these

exploratory or subgroup analyses? First, we have

shown that the treatment benefit appears

well-distributed among a broad patient population.

Second, the efficacy is not consistently

concentrated in or absent from any particular

patient subgroup. No one subgroup drove the

overall efficacy.

[Slide]

The 0.3 mg dose represents the lowest

studied efficacious dose and it met its primary

efficacy endpoint with statistical significance in

independent replicate trials, as we have shown you.

The efficacy was substantiated in every clinically

meaningful endpoint tested. We have seen the

secondary endpoints. And, the 1 mg and 3 mg doses

show no additional benefits over 0.3 mg. Tony will

shortly show you that there was no safety

difference between 0.3 mg and 1 mg as well.

However, theoretically we all know that a lowest

dose yields the lowest systemic concentration. So,

the sponsor advisory board and independent data

monitoring committee endorsed the 0.3 mg dose as a

dose that should be selected.

[Slide]

I would like to turn now to angiographic

findings. We have mentioned to you that we believe

there are two mechanisms of action for pegaptanib,

anti-angiogenesis and anti-permeability. As I will

now show you, we have anatomical confirmation for

both mechanisms of action that support the visual

findings we have shown you today.

Let's first look at the anti-angiogenesis.

Here is a patient in the trial with predominantly

classic neovascularization that showed virtually

complete regression. The white large area is the

neovascularization. You can see it has almost

completely regressed after 54 weeks of treatment.

But this is one case. So, let's look at the whole

group.

[Slide]

What we can see is that there was a

decrease in the lesion size that had a low nominal

p value in favor of active treatment for the 0.3

and the 1 mg dose. So, we have anatomical

confirmation or support for anti-angiogenesis as a

mechanism of action that supports the visual

findings.

[Slide]

The second mechanism of action that we

described was anti-permeability. Here is another

patient in the trial that had significant cystoid

macular edema with neovascular disease. We can see

the cystoid-like patterns here. This is a sign of

a lot of permeability. After 54 weeks of treatment

we can see a great decrease in the permeability.

[Slide]

Again, we can show that leak size over

time was less for treated groups than for shams.

The p values here are noted.

[Slide]

In addition, we can look at the change in

leakage to week 54 as a sign of anti-permeability

action, and we can see that very similar to visual

distribution curves I showed you earlier, we can

see again that there was less leakage noted more

often in actively treated 0.3 mg patients than in

sham, and more leakage noted in shams than in

actively treated eyes. This change in distribution

had a low nominal p value of 0.0004. So, again we

have anatomical confirmation for anti-permeability

as an important mechanism of action that supports

the visual findings.

[Slide]

I would like to now turn to photodynamic

therapy, or PDT. I think it is first important to

have a historical perspective of the use of PDT in

this trial so you can understand some of the

challenges we faced when we were designing this

trial.

At the time of starting the trial PDT was

available primarily in the U.S., and there were

certainly ethical considerations that required that

PDT be permitted in patients with predominantly

classic disease. However, the PDT usage pattern

was not yet known.

[Slide]

So, what we decided to do was to create

very strict rules for the use of PDT in this trial.

What that meant was that patients had to have

predominantly classic disease and the masked

physician--remember, we had two physicians--the

masked physician determined if the patient was

eligible for PDT per the FDA label and then whether

that PDT was recommended for that individual

patient. If so, the treatment was administered per

the FDA label.

Now, to ensure that these strict rules

were being followed, we had a reading center review

the usage pattern and we found that 92 percent of

the time the reading center agreed with the

appropriate use of PDT in this trial.

[Slide]

PDT use could occur three ways: prior to

the study, at baseline, and post-baseline and,

actually, any combination of the three. It is

important to emphasize that overall the use of PDT

was extremely low. Three-quarters of patients were

never exposed to PDT in the study eye at any time

in the time trial.

[Slide]

Let's examine each one of these three

scenarios in detail. First let's talk about prior

PDT which was stratified and was balanced at

randomization. Also, notice the small numbers

again, emphasizing very little PDT use in the

trial, 18-29 eyes in the various subgroups, but it

was stratified and balanced.

[Slide]

Baseline PDT is the second scenario, and

the baseline PDT use was again very similar among

the groups. We can see here that for the active

treated groups 10-13 percent of patients had PDT at

baseline compared to 14 percent for shams and,

again, look at the very small numbers, 31 to 40

patients per subgroup.

[Slide]

Finally, let's talk about post-baseline

PDT use. Now, it is important to mention that a

meaningful analysis of potential post-baseline PDT

effects on efficacy is limited to the inherent bias

in the trial. What I mean by that is, remember,

the patients were never randomized to post-baseline

PDT use. In order to really assess the baseline

PDT use we would have had to design a trial

randomizing patients to PDT and baseline. That

wasn't this trial. As an example of this, what is

called the channeling bias, a patient with a poor

response might be the patient that would be

preferentially channeled to get PDT. What this

really means is that post-baseline PDT is an

outcome variable. So, for this reason, we must

treat post-baseline PDT in a different way, as I

will show you now.

[Slide]

We need to ask was there increased PDT use

in pegaptanib patients relative to sham that could

suggest that some of the pegaptanib efficacy was

derived from PDT?

[Slide]

The answer to this question was no. As we

can see, there was no higher use of post-baseline

PDT in active treated patients compared to sham.

[Slide]

The second important question about

post-baseline PDT use is was there an increase in

the average number of PDT treatments in pegaptanib

patients relative to sham?

[Slide]

Again the answer is no. As we can see

again, there was no higher post-baseline PDT use in

active treatment eyes compared to sham.

[Slide]

The third important question, which will

be addressed in detail in Tony's safety section, is

was there evidence of any adverse events with the

co-administration of photodynamic therapy and

pegaptanib that could lead to a drug-to-drug

interaction? The answer is no--more on that in

just a few minutes.

[Slide]

In summary, pegaptanib met a clinically

meaningful primary efficacy endpoint with

statistical significance in replicate, independent,

well-controlled clinical trials.

[Slide]

I will now ask Tony to come up and discuss

our clinical safety database.

Pegaptanib Clinical Safety

[Slide]

DR. ADAMIS: This is the entire safety

database. This includes the patients from the

earlier Phase I/II trials. What you see here is

that the total clinical experience to date includes

over 1,200 patients in over 10,000 treatments, of

which 7,500 are intravitreous injections that we

can monitor for the safety. There is a slight

imbalance that you will see in that there are more

patients receiving 3 mg than 1 mg of 0.3 mg. That

is because that was the dose that was used

throughout most of the Phase I/II program. In

addition, we gave doses of 0.25 mg and 2 mg in

those earlier programs as well.

[Slide]

The overall safety is shown here. As

regards any adverse events, you can see it is

balanced between all treatment arms and sham.

There is an imbalance in the serious adverse

events. These are largely injection related, and

we will talk about those in depth in a moment.

The discontinuations, you will note, due

to adverse events are low. They are one percent in

both the treated and the sham arms. Similarly, the

death rate is balanced to two percent.

[Slide]

Looking at the death rate just a little

more closely, we can see that there is no evidence

here of a dose response.

[Slide]

Let's look at the most frequent non-ocular

serious adverse events. This is a busy slide but

the thing to note here is, first, that there is

good balance between the treated and the sham arms

and, secondly, there is no clustering within a

system organ class. This is rather diffuse. These

conditions are age appropriate. The mean age of

this population is 77 years old that we studied.

These people had a number of concomitant illnesses.

Fifty percent of them had hypertension; 25 percent

were on statins; 20 percent had cardiac disease.

So, we believe it is representative of the

population.

[Slide]

We looked particularly for VEGF

inhibition-related adverse events as these have

been reported with other non-selective inhibitors

given intravenously at higher doses. We were happy

to see that there were no signals here. The most

sensitive signal, the one that has been picked up

with other non-selective inhibitors in smaller

trials than ours, less powered but nevertheless it

was evident, was hypertension. You can see here

that the rate of adverse events is 10 percent both

in the treated and in the sham arms--no signal

there for that very sensitive signal of VEGF

inhibition. Thromboembolic adverse events are

similarly balanced, as are ischemic coronary artery

disorders, heart failure and serious hemorrhagic

adverse events.

[Slide]

Why is it that we did not see any of these

VEGF inhibition-related phenomena? There is a

number of reasons. Some of these are theoretical,

some are real but in aggregate they provide I think

an argument. Pegaptanib is, as I said, selective

for VEGF 165 so the other major isoform 121 is

never blocked. So, all VEGF is never blocked with

pegaptanib, even if you gave it at very large

concentrations. It just does not bind to VEGF 121.

Secondly, the concentrations that we see

when we put 0.3 mg in the eye are many orders of

magnitude less in the plasma and those

concentrations are below the inhibitory

concentration that our models have told us both for

in vitro and in vivo inhibition of VEGF. So, we

believe that these are levels that are below the

ability of pegaptanib to affect VEGF levels in any

sort of substantive way.

Third, as I just said, there was an

absence of sensitive VEGF inhibition signals, the

most sensitive being hypertension which I showed

you but also in our 1006 trial, where we looked

carefully at proteinuria, again there is no

evidence that this drug is inducing proteinuria in

either our clinical population or in our

preclinical models.

Then, the report recently of

thromboembolic adverse events occurring in cancer

patients on chemotherapy and receiving Avastin--we

think there are a couple of very different things

about our population and that population that was

studied. Number one, cancer in and of itself

predisposes patients to thromboembolic phenomena.

They have indwelling catheters; they are bedridden;

and the cancer itself alters the clotting system.

Secondly, some chemotherapy has been shown to be

vascular toxic, to be prothrombotic. There is a

published literature on that.

So, add these two hits to the vasculature

and then block all VEGF to prevent the endothelium

from healing itself, one can have a theoretical

basis for understanding now why thromboembolic

phenomena may be more prevalent in a population

with cancer and chemotherapy. That is not age

related macular degeneration. This is a very

different population that is not, by and large, on

chemotherapy and do not have cancers.

[Slide]

Let's look at the ocular adverse events.

Again, this is a busy slide but we will talk about

these events in a little more detail. They are

listed here, those that occurred greater than or

equal to 10 percent of patients on either

pegaptanib or sham. You can see that there is a

slight imbalance in eye disorders, and we will talk

about these, and you see a number of various

adverse events listed here.

[Slide]

Let's talk about them in more detail,

number one that was listed on the previous slide

being eye pain. These patients receive nine

intravitreous injections over the course of a year.

It is rather remarkable actually that two-thirds of

them never reported a single instance of pain. Of

those patients, approximately the one third that

did report pain, it was mild or moderate in

character in 99 percent of them, and only one

patient exited this trial describing an adverse

event of pain.

The other important thing to note here is

that the eye pain in the sham arm, at 28 percent,

was significantly higher than what is seen in the

fellow eye, 2 percent. So, some of this mild pain

that these patients experienced--one conclusion you

can draw is that it may be due to the preparative

procedure prior to the injection of the drug. As

you recall, these patients have a speculum placed

in the eye. They have povidone-iodine scrub. They

have a subconjunctival anesthetic injection. These

things may have contributed to the lion share of

the reports of pain which, again, was mild. Then,

obviously, there is a difference here. The

remainder of it here can well be ascribed to the

actual intravitreous injection itself.

Of those patients who reported pain, it

was in a minority of their injections, two in both

the treated and the sham arms, and the median time

to resolution was two to three days which is the

time of the follow-up phone call.

[Slide]

With regard to vitreous floaters, there

was more than an imbalance here. It was 33 percent

in the treated arms versus 8 percent in the sham.

Again, there is a slight difference, 8 versus 1,

between the sham eye and the fellow eye so some of

this may be due to the preparative procedure but a

large portion of it, the majority of it, is very

likely due to the act of giving an intravitreous

injection itself. When giving a 90 mcL volume

injection into the eye, in the average human a

volume of 4 mL, you are displacing the vitreous and

it is perhaps not surprising that as a function of

that you are going to induce floater. These

floaters never were severe. All of them were

characterized as mild to moderate. No patient left

the trial because of floaters. It was in a

minority of injections, 1 to 2 injections, that

these were reported, if they ever were reported,

and the median time to resolution was 3 days in the

treated arms versus 7 days in the sham arms.

[Slide]

We looked at cataract very carefully. We

specifically looked at cataract in only the aphakic

eyes. One-third of these patients approximately

were pseudophakic. What we saw was that across all

treatment arms there was a slight imbalance, with

30 percent of the eyes having an adverse event of

cataract versus 26 in the sham arm. This slight

imbalance may be partially explained by the fact

that the phakic fellow eye also had a slight

imbalance, 17 percent in the treated versus 15

percent in the sham arms.

But we looked at this a little more in

depth. The type of cataract that one would expect

if this was due to a drug toxicity, the type that

has been amply described in the literature, is

posterior subcapsular cataract. So, when we looked

for that specific type of cataract grading, you can

see there is zero difference. It is 11 percent in

both the treated and the sham arms.

[Slide]

Nuclear cataract was similarly well

balanced. In fact, if you remove the eyes that

were vitrectomized, which we will talk about in a

minute, vitrectomy can cause a nuclear sclerotic

cataract to accelerate. This is 18 percent in both

arms and there is, indeed, a slight imbalance in

cortical of 18 versus 15 percent.

One piece of objective data we have is

that the vast majority of these patients came in at

baseline with cataract and only 3 patients

underwent elective cataract surgery over the 54

weeks of the trial in the treatment arms.

[Slide]

Anterior chamber inflammation was another

adverse event. You can see here that there is an

imbalance slightly with 14 percent occurring in

study eyes versus 6 percent in the sham eyes, and

there were zero reports in the fellow eyes. None

of these cases of anterior chamber inflammation

were characterized as severe. All of them were

mild to moderate and we believe they were largely

due to the active intravitreous injection and not

to the drug itself. The reports of inflammation

were all moderate and self-limiting and did not

increase during the course of the trial. In fact,

there was a slight trend to decrease, arguing that

there wasn't a sensitization to the molecule here,

in fact, supporting that this was due to the

injection itself. The median time to resolution

was 8-9 days, and no patient left the trial because

of inflammation.

[Slide]

We looked at interaction potentially with

PDT and specifically at ocular adverse events. You

can see here that the majority of patients did not

have the combination of PDT and pegaptanib, but of

those who did we looked very carefully at the event

rates and the important thing to consider here is

the event rate difference in the sham arms

plus/minus PDT, and does that difference change in

any sort of meaningful fashion when the PDT is

given together with pegaptanib. The answer is that

from these data there doesn't appear to be a

difference in those two measures. The same is true

with vitreous floaters. There is a slight

difference here and there is really no difference

here in the treatment arms.

[Slide]

But let's look at it another way. This

assessment is looking to see if there was a report

of an adverse event at any time during the 54

weeks. For instance, if the patient had PDT at

baseline but had an adverse event at 54 weeks it

would be captured and presented in these data. We

thought we would try to look at this a little more

carefully and see if there was a better temporal

relationship. So, now we are looking at data of

patients who had PDT plus/minus 2 weeks around an

injection of pegaptanib. These events may more

likely signify some sort of interaction and, again,

there are no alarming signals here.

When one looks at eye pain there is very

little difference here and there is very little

difference here between the sham and the treatment

arms. The same is true for corneal epithelium

disorders. For these two specific adverse events

one can postulate a mechanism as to why that is.

There is, you know, the povidone-iodine prep for

the injection which can affect the epithelium and

perhaps cause pain. On top of that is a near

temporal relationship the placement of a contact

lens for doing the PDT, and one could understand

why there might be a slight increase here. Again,

no patients dropped out because of any adverse

events related to a combination of PDT and the use

of pegaptanib.

[Slide]

Now let's concentrate a bit on ocular

serious adverse events. The three most common we

are going to discuss in detail here are

endophthalmitis, retinal detachment and traumatic

cataract. The ones below occurred at a very low

event rate. When the narratives in the cases were

looked at in depth there really did not appear to

be an association with the use of pegaptanib so we

will not discuss them further here unless you wish

to discuss it later in the question and answer

session.

Endophthalmitis occurred in 12 patients

over 54 weeks. That translates to a relative risk

of 1.3 percent of patients developing

endophthalmitis over the course of one year of

therapy. So that we could compare our rate to the

published literature this was converted to a per

injection rate of 0.16 percent. What we learned is

that the rate that we saw is not an outlier; it is

within the published norm and reported norm in

cases of endophthalmitis in patients receiving

intravitreous injected therapeutics.

As important as the rate is what happened

to these patients, what was the outcome. One

patient lost severe vision in this trial as a

function of their endophthalmitis, 1/12, which

translated to a rate of 0.1 percent over the course

of the year. Seventy-five percent of the patients

who developed endophthalmitis elected to stay in

the trial.

Traumatic cataract--you can see there were

five cases of it and there were five cases of

retinal detachment, of which three were

rhegmatogenous in nature.

[Slide]

I show you here the specific details of

all 12 cases of endophthalmitis. What you can see

here are the starting visions, the visions prior to

the event, and the change in vision from just prior

to the event which probably most accurately

captures the visual loss related to the

endophthalmitis itself. What you can see is the

one patient who lost 11 lines as severe vision

loss.

Let me just tell you anecdotally what

happened. It was a protocol violation. It turns

out this patient had an active lachrymal sac

infection prior to the development of the

endophthalmitis and the injection of the mediation,

and had an active lachrymal sac infection after the

event of endophthalmitis. The patient should never

have been enrolled because that was an exclusion

criterion.

The other patients, as you can see, were

treated aggressively and their visual outcomes tend

to be perhaps a bit better than what you would

expect for a case of endophthalmitis. In fact,

there are some patients here who gained one or two

lines of vision.

[Slide]

How were these patients diagnosed, and

were we able to identify the endophthalmitis

relatively early? This slide shows you exactly

what happened. Three patients were identified in

their follow-up phone call at days three-four post

injection. Eleven patients presented to their

physician's office with complaints, and this

happened between days two and five. Two patients

came in and were diagnosed in a routine follow-up.

The endophthalmitis cases I am describing here are

the 12 in the first year and the ones that have

occurred subsequent to that which I am going to

talk about.

[Slide]

We have been following the endophthalmitis

issue very carefully and I would like to provide

you with an update on where we are beyond the

54-week time period. As I just said, in the first

year 0.16 percent of injections, or 1.3 percent of

patients, developed endophthalmitis. In the

second, and now some patients have entered the

third year of this trial, there have been five

additional cases as of July 31st of this year, and

there has been one case in our Phase II diabetic

macular edema trial. So, if you look at the total

now, it is 18 cases of endophthalmitis with a

denominator of over 14,500 injections, and the rate

now is reduced somewhat to 0.12 percent per

injection.

In the first half of this trial when we

saw the case reports of endophthalmitis we convened

an expert panel of ophthalmologists and retinal

specialists who work in the endophthalmitis area

and we decided that we needed to heighten the

awareness of the need for strict adherence to an

aseptic protocol when one is giving an

intravitreous injection. In fact, there was a

letter sent to IRBs and a formal protocol

modification mandating the use of a sterile drape,

of a speculum, of the use of povidone-iodine. When

we did these things and we analyzed what the

potential effect could be, what we saw was that

prior to that protocol modification being adopted

at all sites between August of 2001 and May of 2003

the rate was 0.18 percent, and after that protocol

modification the rate has now fallen to 0.03

percent.

Can we ascribe the decrease in the rate to

the change in the protocol? Not necessarily.

There was more than one variable that was changing

here. At the same time that we instituted this

protocol modification and heightened awareness

about the aseptic technique there was a dramatic

uptake in the number of intravitreous injections

being given for off-label use in diabetic macular

edema with steroids, triamcinolone in particular.

So, the knowledge base and the experience of retina

physicians increased rather dramatically at the

same time that we saw a drop in our rates.

[Slide]

The visual outcome for the cataract cases

is shown to you here. For the one patient who lost

7 lines of vision, it was ascribed to progression

of macular degeneration. All of these patients, in

fact, had successful cataract surgery.

[Slide]

The visual outcome of the retinal

detachment cases is shown here. All of these were

successfully repaired and you can see the cases of

rhegmatogenous detachment which most likely were

injection related. The visual outcomes were quite

good.

[Slide]

Intraocular pressure was examined. As I

said earlier, it is not surprising if one injects

90 mcL into a 4 mL closed space that you will see a

transient rise in pressure. In fact, in

ophthalmology it is common with almost all

procedures that pressure spikes tend to occur.

Well, they occurred here and the transient rise in

mean intraocular pressure at the first prespecified

measurement, 30 minutes, was 2-4 mm across the

treatment arms.

It is important to note that the mean

intraocular pressure returned to pre-injection

levels one week following the injection, which was

the next visit, and that 90 percent of patients,

approximately 90 percent of patients, never had a

spike above the prespecified threshold of 35 mm and

any patient who did have a spike was not allowed to

leave the physician's office till the pressure was

below 30 mm.

Very importantly, there was no evidence of

a persistent increase in intraocular pressure over

one year. The drug did not seem to alter the

outflow of the eye in any way. In those patients

who did have a spike, the question was if you had a

spike was it because somehow the drug was altering

the outflow mechanisms, and if that was the case

you would expect to see an increased incidence

during the course of the trial as it progressed.

As the data show you here, that is not the case.

It doesn't appear to increase over time and, in

fact, may have been dropping slightly.

[Slide]

This slide simply shows the mean

intraocular pressure values over time for all three

treatment arms and sham, again giving us some

confidence that the drug is not inducing a rise in

chronic IOP.

[Slide]

We have a safety update for you regarding

angiography. Colored photographs and angiograms

were looked at in the independent reading center at

the University of Wisconsin. We have looked at up

to 97 percent now of our month 18 angiograms and 92

percent of our two-year angiograms to get a sense

of is there any evidence of cumulative toxicity.

The results are that there is no evidence

whatsoever of alterations in the normal retinal or

100

choroidal vasculature as a function of the drug

being in the eye now for up to two years, nothing

that deviated from the natural history of

age-related macular degeneration and no alterations

in the normal vessels.

[Slide]

The safety update, which was just

concluded in the past week by the independent data

monitoring committee, has reviewed 100 percent of

the patients through month 18 of this trial and 97

percent through month 24, and there have been no

deviations from sort of the pattern of adverse

events, the ones that we saw in the first year of

the trial. There have been no new safety concerns

except perhaps for a slight increase in the number

of retinal detachments. There were 6 that were

reported in the second year of this trial.

[Slide]

To summarize the non-ocular safety, there

was a very low discontinuation rate due to adverse

events. It was one percent and it was balanced in

the treated and the sham arms. Non-ocular serious

101

adverse events appeared to be similar in rate and

character between pegaptanib and sham, and the

mortality rate, as you saw, for the 77 year-old

population was similar between pegaptanib and sham.

[Slide]

As regards ocular safety, I think what we

can conclude is that the majority of the ocular

adverse events were judged to be procedure related.

They were transient and mild in character and

largely self-limiting. There was a low

discontinuation rate due to ocular adverse events

and the serious adverse events were infrequent.

They were rarely associated with severe vision loss

and were mostly procedure related. Finally, there

were mild transient and predictable, manageable

increases in intraocular pressure but no evidence

of a long-term rise in intraocular pressure.

[Slide]

At this point Prof. Don D'Amico, who is a

practicing retinal specialist at the Massachusetts

Eye and Ear Infirmary, will come and discuss the

risk/benefit profile for pegaptanib.

102

Pegaptanib Benefit/Risk Profile

DR. D'AMICO: Thank you, Dr. Adamis. Dr.

Dunbar, members of the advisory committee, ladies

and gentlemen, with your permission I would like to

introduce myself a little more fully and my

perspectives so that you can have the clearest

context in which to place my remarks.

[Slide]

With regard to this study, while it was in

progress I was invited to be a member of the safety

committee and later became its chair. At the

conclusion of the study I was asked to be a member

of the scientific advisory board. I perform a

virtually identical role for the Alcon Corporation,

chairing their safety committee in the evaluation

of their anecortave product. I also advise them on

surgical themes and instrumentation as well.

Finally, I am a consultant to the Iridex

Corporation serving as a member on the safety

committee for the transpupillary thermotherapy

trials and their PTAMD or laser for drusen trial.

I hold no equity in any of these companies nor any

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of their competitors.

[Slide]

I would like to also share four

perspectives that will inevitably influence my

remarks and may be helpful to you also in your

evaluations. First, of course, I was a member of

the pegaptanib safety committee. Secondly, I have

had a career-long laboratory, as well as clinical,

interest in endophthalmitis and the effects of

administration of intravitreal medications. I am,

as introduced, an academic in the field of retinal

diseases and therapy. But perhaps most importantly

and most germane is that I have a very active

retinal practice at the Massachusetts Eye and Ear

Infirmary and care for many patients with macular

degeneration.

[Slide]

As has been said, neovascular AMD is quite

a source of human suffering. At the 20/40 level of

visual acuity driving privileges frequently become

impossible for a patient. At 20/80 or worse

difficulty is even present in trying to read large

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print. And, 20/200 or worse is a commonly accepted

level of definition of legal blindness at which it

is difficult to recognize faces and independent

function is threatened.

[Slide]

How extant is this problem in the world

today? In a very careful meta-analysis of the most

comprehensive studies recently reported by the Eye

Diseases Prevalence Research Group, they looked at

studies in the United States, Western Europe and

Australia over an 11-year period.

[Slide]

Based on their analysis, it is the leading

causes of blindness in U.S. adults in patients aged

40 years or older. You see that slightly over half

are due to age-related macular degeneration.

[Slide]

They then applied their model to the U.S.

Census data for both 2000 and projected to the

future. In a morning filled with numbers, I will

spare you all the numbers here, but using a

definition of 20/200 or worse as blind and 20/40 or

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worse as visually impaired, there are 3.3 million

Americans with visual impairment today. In the

future there will be approximately 5.5 million

American with visual impairment at some level,

again slightly over half, due to age-related

macular degeneration. So, it is clearly a problem.

[Slide]

As such, it merits our highest attention

as physicians, researchers, etc. to try to find

treatments and even cures. This slide is color

coded and it lists the candidate therapies for

neovascular subfoveal age-related macular

degeneration. Therapies which have demonstrated

effectiveness in replicate clinical trials are

shown in yellow. We have laser photocoagulation,

photodynamic therapy with Visudyne and the data you

have just heard on pegaptanib. The great majority

of interventions are listed in white, which

indicates ongoing study with various degrees of

promise, and it includes surgical options, as you

see here and a variety of other laser treatments,

as well as other pharmaceuticals, many of which are

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nearing the end of their clinical trials. There

are also some abandoned therapies that were

ineffective and combination strategies, as you see

in the lower right, are becoming of increasing

interest.

[Slide]

Looking at the established therapies,

there are two. One is photocoagulation with

thermal laser which has been effective in

extrafoveal, juxtafoveal and subfoveal lesions.

However, in subfoveal lesions this therapy has been

abandoned due to the immediate destruction of

central vision following treatment and is no longer

in clinical use. Photodynamic therapy with Visudyne

is approved for subfoveal predominantly classic

lesions.

[Slide]

In addition, evolving clinical practice,

in a hope to provide improved care for patients

with macular degeneration, has led to a new

accommodation therapy which has become widespread.

That is the combination of a PDT treatment with

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Visudyne in association with an intravitreous

induction of triamcinolone in the peri-PDT period.

This treatment has had some very promising early

pilot results but the literature is quite minimal

at present. Nevertheless, it has become a common

treatment in clinical practice.

[Slide]

Intravitreous injections are quite common

in my world as a retinal specialist. They were

employed and were actually the pathway to great

success in the therapy of endophthalmitis, and are

still continued widely in use for that indication.

We also utilize intravitreal injection as a

treatment of retinal detachment, as well as

administering agents for CMV retinitis. However,

there has been great expanded use recently in

office practice of intravitreal injections as

regards the use of triamcinolone acetodine for

diabetic macular edema, retinal vein occlusions,

uveitis, as I have just mentioned, in association

with photodynamic therapy.

[Slide]

108

Pegaptanib represents the potential for a

new approach, a pharmacotherapy, and what are the

advantages of pharmacotherapy? They are both

general and specific. In general, pharmacotherapy

offers the prospect of treatment at a molecular

level with improved targeting of the disease

process and, more importantly, limitation of the

collateral damage that invariably occurs with

larger scale interventions such as surgery or

laser.

Pegaptanib quite specifically is based on

very extensive basic science into the most widely

accepted, central disease processes in AMD, namely

neovascularization and leakage, with consistency

across multiple experimental models and studies.

[Slide]

As a member of the safety committee, we

looked for three specific areas in great detail.

One, were there any potential systemic side effects

from receiving an anti-VEGF medication? Secondly,

were there intraocular drug-related side effects

from this VEGF medication? Thirdly, were there any

109

mechanical side effects or complications from the

intravitreal injection procedure itself?

[Slide]

We did find serious ocular adverse events

related to the injection procedure. As you have

heard, there were 12 cases of endophthalmitis.

This incidence rate is quite comparable to that in

published series for intravitreal injection with

the other forms of intravitreal injection therapy

that I have mentioned previously. One of these

patients had severe visual loss. Nine of the

patients continued in the study and elected to

continue receiving study medication. Finally,

after protocol modifications, the incidence is

clearly trending downward.

There were five cases of retinal

detachment, which were repaired and some were

related to the underlying macular degeneration

itself. Traumatic cataract was seen in five cases

and all were surgically repaired without sequelae.

[Slide]

So, in these 22 serious ocular events, we

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considered them in the context of 7,545

intravitreous injections performed in 1,190

patients by 117 centers worldwide, and many of

those centers had more than one injector. We felt

that this denominator indicated substantial safety

for this procedure.

We also found no evidence of systemic side

effects, no evidence of ocular drug-related side

effects, and the majority of other adverse events

were mild and transient within the eye. The

serious ocular adverse events were infrequent and

manageable. So, we concluded that there was a very

favorable safety profile that, in addition, may be

further improved by education and additional

training.

[Slide]

If we look at severe vision loss, again to

understand the context of these adverse events, if

a patient presented to the trial and received sham,

that is, usual care, there was a 22 percent risk

per year of suffering severe visual loss. When

they were enrolled in the pegaptanib group that

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risk was reduced to 9.5 percent per year.

[Slide]

In the endophthalmitis, retinal detachment

and cataract serious ocular events that we saw, the

risk of severe vision loss, that is 6 or more lines

of vision, was 0.1 percent, indicating substantial

order of magnitude less risk from endophthalmitis

than from the real problem here which is the

macular degeneration itself.

[Slide]

Regarding efficacy, you have heard a

detailed presentation and I will just summarize.

There was significant reduction in moderate and

severe vision loss compared with sham. There was

promotion of vision stability and gain in a

proportion of patients. There was efficacy with

broad-based entry criteria including a range of

subfoveal neovascular AMD lesions. And, the

benefit of intravitreous pegaptanib therapy was

early and sustained.

[Slide]

As we have seen, in this slide baseline

112

visual acuity is on the left. Sham is indicated in

purple and pegaptanib in grey. At 54 weeks there

is a definite shift in the 0.3 pegaptanib group to

preservation of better vision on the left of this

chart compared to the visual acuities observed with

sham.

[Slide]

I am not a biostatistician but I will try,

for myself and for all of us, to place these

results in some kind of a wider context. What

could this mean? No one knows exactly how many new

subfoveal neovascular lesions occur a year, but

120,000 per year of new treatment-eligible patients

is probably a reasonable estimate. If those

patients were to behave similar to the gathered

group enrolled in this trial, we could make some

statements, and here they are:

Pegaptanib potentially prevents severe

vision loss, that is a loss of 6 or more lines of

vision, in 15,000 additional patients per year in

the United States compared with usual care, based

on a 57 percent reduction in the rate of severe

113

vision loss with pegaptanib.

[Slide]

Secondly, reaching a level of 20/200 or

worse within the treated eye, we could call that

blindness in the treated eye. Pegaptanib

potentially prevents treated-eye blindness in an

additional 22,800 patients per year in the U.S.,

again compared with usual care, based on a 38

percent reduction in the rate of treated-eye

blindness with pegaptanib.

[Slide]

In conclusion, from the perspectives

available to me and now available to you, I have

concluded that pegaptanib will have a significant

impact on AMD in regard to both individual patients

with AMD lesions that would become amenable to

treatment and, secondly, in its effects on visual

function and its preservation in the aging U.S.

population.

The positive results in this trial

indicate the beginning, and not the limit, of

pharmacotherapy for AMD. I agree with the

114

sponsor's recommendations that the benefits of

pegaptanib therapy for AMD strongly outweigh the

risks. Thank you.

Committee Discussion

DR. DUNBAR: Thank you to the sponsor and

Drs. Guyer, Adamis and D'Amico. At this point I

would like to open the floor for discussion and

questions for the sponsor from the committee

members, and ask that you will speak your name into

the microphone as you ask each question. Are there

any questions from the committee members? Dr.

Chinchilli?

DR. CHINCHILLI: Yes, I don't know much

about the disease and the patients that were

recruited for the two trials so, please, bear with

me. Could patients have AMD in both eyes? I mean,

roughly what proportion of patients that were in

the trials had that situation?

DR. GUYER: In general, for neovascular

age-related macular degeneration usually one eye

becomes active at a time. If the patient lives

long enough, they often will get it in the second

115

eye. In this particular trial the investigator

would choose--in a very few number of cases where

there would be active disease that was eligible for

the trial, the doctor would make that decision. If

we look at slide D-82--

[Slide]

--here we can see some of the baseline

characteristics. In two-thirds of the patients

this was the worse eye that was treated. Again, no

patient was treated in both eyes at the same time.

But in the lifetime of a patient there could be

some overlapping times where they have an active

lesion and the second one becomes active. Some

patients are fortunate enough not to get it in

their second eye but, unfortunately, if they live

long enough many will.

DR. CHINCHILLI: Thank you.

DR. DUNBAR: Dr. Pulido?

DR. PULIDO: A superb presentation; very

interesting results. Just two questions. Number

one, glaucoma was not an exclusion criterion in the

study. So, some of the patients had glaucoma and

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AMD. Do you have any data as to the effect of

chronic injections on the small subgroup of

patients that had glaucoma?

DR. GUYER: I will let Tony answer that.

DR. ADAMIS: We were interested in that

question as well. Slide OS-31.

[Slide]

We looked specifically at patients with a

history of ocular hypertension and/or glaucoma, and

then followed their pressures throughout the entire

54 weeks. What we saw was that there was no change

in their intraocular pressure as a function of

treatment.

DR. PULIDO: The other question probably

is to you as well. There are some recent

articles--here is one from Nature, May: VEGF

delivery with retrograde transported Lentivector

prolongs survival in a mouse ALS model. Here is

another one: mural protection of ischemic brain by

VEGF is critically dependent on proper dosage.

Here is another one. So, we have gone under the

assumption that VEGF and VEGF 165 is specifically a

117

cytokine for angiogenesis, but there is more data

to show that there is an independent effect

directly on neural tissue, separate from its

angiogenic effect. ERG was not a part of this

trial. You did some ERGs on some dogs, from what I

saw here. I don't know how many, how long, etc.

So, considering the neuroprotective

effect, from your data--it is wonderful--that the

angiogenesis is important, critical to take care of

this significant problem in patients. But my

concern is the long-term chronic dosaging

considering that there is an independent effect of

VEGF as a neuroprotective agent.

DR. ADAMIS: As always happens in science,

what seems very straightforward becomes more

complex, and what you quote is absolutely correct.

I think that is Peter Carmeliet's paper in Nature.

But what has been learned in about the last five

years is that neural cells have VEGF receptors and

VEGF may be neuroprotective for certain tissues.

Certainly, in the ALS model that is the most

convincing story to date. Whether the effect is

118

direct or not is still being debated in the

scientific world, but it may well be direct because

of the VEGF receptor on the neural cells.

We were interested in this as well. Even

before we got into the scientific question as part

of our preclinical safety testing, there was a

9-month dog study where the dogs received 3 mg

injections every 2 weeks bilaterally. Then they

had ERGs done and there were no abnormalities seen

there. So, that gives us a little bit of comfort

but, more importantly, recently we examined this

issue and looked specifically at the isoform story.

We presented a paper at ARVO last spring where we

showed that in a model of retinal ischemia if one

gives a pan-isoform, non-selective VEGF inhibitor,

you can in fact induce some neural apoptosis. But

when we gave pegaptanib in the exact same setting

there was no induced apoptosis. So, again getting

at this thesis, the important thing with pegaptanib

I think is that you are sparing some VEGF to allow

it to have its physiological or perhaps these

rescue functions that can occur in the eye. So,

119

that gave us an additional measure of comfort that

we are not going to have neural toxicity.

DR. PULIDO: But the question still arises

have you done long-term ERG studies on these

patients?

DR. ADAMIS: Oh, I am sorry, no, we have

not done those in these patients.

DR. DUNBAR: Mr. Kresel?

MR. KRESEL: My disclaimer is that I am

not a statistician and so I am not sure if this is

even an appropriate way to ask this but I am going

to ask it anyway. You did a great job of looking

at endophthalmitis which, you know, obviously is

one of the things that people have concern about,

and referred to a decrease in patients that was

only five cases in years two and three. My

question is how many patients continued therapy

that far? So, did the number of patients decrease

and, therefore, the percent not go down? Because

what we saw is a cumulative number that, of course,

did go down.

DR. ADAMIS: It is a fair question. The

120

number of patients was decreased in the second

year. That is why the metric we used was on a per

injection basis. That accounts for any loss of

patients and those were the rates that I presented

to you today. So, on that basis it does go down.

Slide 129.

[Slide]

Just to show you the data, you can see

that prior to the amendment on a per injection

basis it was 0.18 percent, and then post the

amendment it was 0.03 percent but with that

additional confounding variable of a lot of

off-label steroid injections going on.

DR. DUNBAR: Dr. Gates?

DR. GATES: In the context of the cases of

endophthalmitis, could you expand on the initial

injection technique versus some of the changes that

you made secondarily? Because draping oftentimes

means different things to different people.

DR. ADAMIS: Correct. The details of the

injection procedure are on a slide but let me see

if I can recite them from memory for you, the

121

changes. There was a requirement for the

installation of an antibiotic drop or dilated

povidone-iodine prior to the amendment. Then,

after the amendment the drape that was specified is

a clear plastic one that adheres around the lids

and the lashes, and then the placement of the

speculum, and then also asking for a

povidone-iodine flush to be done, and then patients

received postoperative antibiotics. So, what we

tried to instill there was a sense of uniformity in

the procedure. There was more latitude prior to

that. Those were the changes, to the best of my

memory, that were instituted.

DR. DUNBAR: We have more than one-year

data, but would you anticipate that the patients

will continue every six-week intravitreal

injections for the rest of their lives?

DR. ADAMIS: That is an important

question. It is one of the questions we ask in the

second year of the design. We want to know,

obviously, about the safety in the second year and

then an important question was do people need to be

122

on this for the second year. So, the trial design

is one of randomized discontinuation to try to get

to an answer as regards that very important

question, do people need another nine injections?

DR. DUNBAR: Dr. Lehmer?

DR. LEHMER: I noticed in the data that

most of the p values were significant, at least in

the graphs and the tables, for the 0.3 mg and the 1

mg doses, and for the higher dose there was less

incidence, at least in the tables and graphs, of

statistically significant levels. Are there any

conclusions you have drawn about that? Is more not

better, etc.?

DR. GUYER: It is a great question and

obviously one we spent a great deal of time

analyzing. There really is no definite answer to

why the 3 mg, as you mentioned, perhaps appeared

not to do as well. Slide E-51, please.

[Slide]

There is one possible explanation that we

have looked at. This shows the mean change in

vision over time for each individual trial. On the

123

left is study 1004, on the right is study 1003.

What you can see is that in one of the trials,

1004, this is the 3 mg dose, this is the 0.3 mg and

1 mg dose, going head-to-head pretty throughout.

Of course, here is the usual care sham. It seemed

that the 3 mg dose in one of the trials didn't seem

to do quite as well as the other two active

treatments--still doing better than the sham. In

1003 you can see that actually all three doses

seemed to do equivalently.

So, one possibility is, you know, six

different events, three doses, two trials, one out

of six times by chance, it is possible that the 3

mg dose didn't do as well. Of course, as you

mentioned, all of these clinical parameters,

secondary parameters, etc., are all dependent on

the other. That is one explanation.

The thing that we do know, however, is

that the 0.3 mg dose, which represents the lowest

efficacious studied dose, clearly hit the primary

endpoint in replicate trials and showed consistent

behavior throughout the trials. Because of safety

124

issues, theoretical safety issues, we believe that

the 0.3 mg dose has met the requirements to be an

effective treatment here.

DR. DUNBAR: Dr. Miller?

DR. MILLER: Thank you. In terms of the

number of patients that have been in the trials,

are you comfortable or is the model sufficient

enough to tell us that there are no adverse risks

related to the population? For example, with Vioxx

we now know that after a period of time there are

now people that are coming up with cancer, that it

is causing cancer in some of them. Have you given

it to enough patients so that you would know if

there were rare cases where other problems would be

caused?

DR. ADAMIS: The population studied was

large in that it was 1,200 patients, large for an

ophthalmology trial. But for very rare events, and

this is a problem faced with all clinical trials,

that show up in patients on the order of one in

every 10,000 or so, you just don't have the power

in these types of trials to detect in a very

125

air-tight manner those signals.

That being said, with the power we have,

and we do have some significant power according to

the guidelines Dr. Chambers talked about earlier,

we were happy to see with all three doses that

there wasn't any evidence of toxicity, either

systemically or in the eye, related to the drug.

But we will never know with absolute certainty for

those very, very rare events.

DR. MILLER: Thank you.

DR. GUYER: Also as Dr. Chambers

mentioned, Dr. Miller, the fact that we had a

higher dose, 10 times higher than the dose that we

believe is the correct dose, gives us some comfort

that a dose 10 times higher has been studied in

many patients. So, that gives us more comfort than

in many other trials.

DR. MILLER: Thank you.

DR. DUNBAR: Ms. Knudson?

MS. KNUDSON: I was just curious about the

necessity for pregnancy tests and two forms of

birth control when your animal data indicated no

126

problems and you are dealing with a very elderly

population. What was the necessity for this?

DR. ADAMIS: That is the miracle of modern

medicine. There are people over age 50 having

babies. It happens rarely but, you know, in this

case one can't be overly cautious so that was the

reason for that.

MS. KNUDSON: Two forms of birth control?

DR. ADAMIS: That is the standard protocol

in clinical trials.

[Laughter]

MS. KNUDSON: Did you pay for them?

DR. ADAMIS: I don't know. I will find

out.

[Laughter]

DR. DUNBAR: Are there any additional

questions? Dr. Steidl?

DR. STEIDL: Thank you for a superb

presentation. I think I understand some of the

rationale behind the 15-letter vision loss, the

primary endpoint. I understand the comparison to

PDT. Most of my patients, when I say "you have

127

only lost two lines of vision; this is a success,"

you know, they are not too happy with that, nor to

they agree with me.

I guess one of the things that I really

wanted to know, there was, I guess as far as I

could see, only one paragraph devoted to quality of

life. Of course, if a patient has one bad eye they

may notice more in the treated eye than if the

other eye is 20/20, but I am just curious what your

feelings are, your comfort is with this. As

physicians, we often think it is good for the

patient but, you know, in terms of the patient's

perspective on this what have you gotten from your

trial?

DR. ADAMIS: Sure. First, I would also

mention that this difference, as we mentioned

earlier, is against a usual care control and

actually provides for approximately three-quarters

of patients the only positive one-year data. So,

we think that that is very, very important, in

addition to the fact that the primary endpoint was

supported by every secondary visual angiographic

128

endpoint that we saw. So, that gives us great

confidence in our endpoint. Slide number Q-2,

please.

[Slide]

We agree that it is very important to look

at quality of life measurements, and we did using

the NEI-VFQ25 which, as many of know, is a

validated measure. It was only measured in one of

the trials, in trial 1004 which was the North

America trial. Because validated foreign language

versions were not consistently available we did it

in just the one trial. For that reason, we were

significantly under-powered. We could not pool the

data. The results were not statistically

significant but there were trends that favored

pegaptanib treatment. As I said, it was

under-powered really to detect the small but

potentially meaningful differences between groups.

Slide Q-3.

[Slide]

We can see some of these differences. It

is important to mention that a 5 or more difference

129

in the LS mean is considered potentially to be

meaningful. So, anything between 0 and 5 is

probably not meaningful. What you can see here are

5 data points that hit that 5 level for the 0.3 mg

dose, and this has to do with color vision,

peripheral vision, distance vision, social

functioning and role limitations. So, these strong

trends, despite a very under-powered sample, give

us some confidence that the QOL, very much as the

angiography and the other secondary visual

endpoints, also supports the primary endpoint, and

we are getting significant benefit for these

patients, not, as you say, just measuring on an eye

chart, but actually benefit that is important to

them in the real world to help them get around.

DR. DUNBAR: Thank you very much. At this

point we will take a 15-minute break and begin

again at 10:30.

[Brief recess]

DR. DUNBAR: We will begin the agency

presentation by Dr. Jennifer Harris.

FDA Presentation

130

DR. HARRIS: Good morning.

[Slide]

I am Dr. Harris and I was the primary

medical reviewer for Macugen.

[Slide]

I am not going to repeat everything that

the sponsor has presented to you; I am just going

to try and bring up the salient points to try and

give you an idea of how we went through the

application and what we thought was important to

present this morning.

I will go briefly over the study design;

the efficacy results for each individual study so

you can see what replicated itself and what did not

replicate itself; conclusions about the efficacy; a

safety overview of the combined study, the pooled

study overview. There are a couple of specific

safety concerns that we want to talk about a little

bit more and the sponsor discussed a little bit

this morning but we just wanted to go over those

again. Then conclusions about the safety and then

we are going to briefly go through the questions

131

that we are going to pose to the advisory committee

and, of course, you will see them again after

lunch.

[Slide]

Again, there were two Phase III studies,

1003 which was an international study, and 1004

that was done predominantly in North America.

[Slide]

Both trials were randomized,

double-masked, sham-controlled as you have heard,

dose-ranging, multicenter trials. Within the

trials patients received intravitreous injections

of either 0.3, mg, 1 mg or 3 mg every 6 weeks for

54 weeks. These trials were actually 2 years in

duration. The data that we will be looking at

today is only from the first year of the trial. At

the 54-week time period these patients were

re-randomized.

[Slide]

This is just a little schematic, just to

show you where we are. We are at week 54 and this

is the data that you will be seeing. The two-year

132

data is probably sometime soon I think, this month

or next month. This is not the data you will see

today.

[Slide]

Subjects that were enrolled in these

trials were over the age of 50. They had subfoveal

choroidal neovascularization secondary to AMD. The

total lesion size was less than 12 disc areas, and

greater than 50 percent of the lesions had to be

active CNV. The best corrected visual acuity had

to be between 20/40 and 20/320. These patients, as

you have heard, were allowed to have PDT before

entering into the trial and they were also allowed

to have PDT during the trial. Prior to the trial

they could not have had anymore than one prior

photodynamic therapy treatment, and the patients

could not have had any previous subfoveal laser

treatment.

[Slide]

The primary efficacy endpoint, again, was

a proportion of patients who lost less than 15

lines of visual acuity from baseline at 54 weeks.

133

Those are considered responders. Secondary

efficacy endpoints were the proportion of patients

gaining greater than 15 letters of vision,

proportion of patients gaining more than zero

letters of vision, and a mean change in visual

acuity.

[Slide]

Just to give you an idea of the subject

disposition, there are approximately 612 patients

in the 1003 study that were randomized to

treatment. Approximately 53 percent of these

patients discontinued. As you can see, it was

pretty well distributed. The treatment groups were

consistent, with approximately 10 percent or so of

patients discontinuing in each of the treatment

groups.

[Slide]

For the second study, 1004, we see the

same thing. The distribution of patients enrolled

was approximately the same in each treatment group,

including sham and, again approximately 10 percent

or so of the patients discontinued therapy.

134

[Slide]

I am showing you this, not that I think

that you can probably read it but just to give you

an idea of who was enrolled and to show you really

that the groups were well balanced. They were very

well balanced between all three active treatment

arms, including the sham. The demographics of

patients that were enrolled in the 1003 trial were

consistent with patients who actually had the

disease.

I also wanted you to note down at the

bottom that patients with all subtypes of

neovascular AMD were enrolled. There was a

substantial number of patients with predominantly

classic and occult lesions that were enrolled in

the trial.

[Slide]

The same thing can be seen for study 1004

where the groups, again, were well balanced, were

representative of the population in which the

disease was seen and, again, all three subtypes of

neovascular AMD were represented.

135

[Slide]

Now I will go into the efficacy results.

Before we go to the efficacy results I want to just

put up this slide to show you how corrections were

made in the p value. As we went into the Phase III

trials we did not go into these trials with one

optimal dose and, therefore, you know if you have

one optimal dose, one time point, you look at the

0.05 value and you can determine whether the drug

works or not. We went into the Phase III trials

and we had three different doses so we had to find

a way to correct for that. A decision was made to

use the Hochberg procedure to actually control for

these multiple comparisons.

With the Hochberg procedure, each of the

treatment groups was compared to sham and if all

three of the p values were less than 0.05, then we

were considered to have three active doses. If

not, if two of the p values were less than 0.025,

then we had two active doses. Or, if one of the p

values was less than 0.0167, then we had one active

dose. If none of these criteria were met, then we

136

had no active doses. So, as you go through the

results you may see some 0.05 or even 0.025 and

that may or may not mean that that was actually

statistically significant.

[Slide]

This is the primary efficacy result for

study EOP1004. As you will see, at month 12 for

the 0.3 mg dose there was approximately 67 percent

treatment effect versus 53 percent of the sham

group. This was a statistically significant

result, with a p value of 0.016. Again, the actual

treatment effect is about 14 percent over sham.

The 1 mg group did show that there was a 67 percent

treatment effect versus 53 in sham. However, this

did not meet our pre-required p value.

[Slide]

For study 1003 we have similar results

and, again, the 0.3 mg group shows approximately a

73 percent treatment effect versus 60 percent of

sham, with a p value of 0.01. In this trial it was

also seen that the 1 mg group was also

statistically significant with a 75 percent

137

treatment effect versus 60 percent.

So, it appears that both the 0.3 mg and

the 1 mg group have approximately a 15 percent

treatment effect over sham, with the 0.3 mg

replicating its results in both trials and the 1 mg

dose did not replicate these results.

[Slide]

You have seen this graph before. This

shows you what was happening to the patients'

visual acuity in study 1004 throughout the first

year of the study. What we see is that all

patients continued to lose vision in all treatment

groups, including sham, throughout the first year

of the study. That being said, it does appear that

the patients in the sham group lose vision at a

higher rate than those in the other three active

treatment groups.

[Slide]

In study 1003 we see the same thing. All

patients continued to lose vision throughout the

first year of study on active treatment and in

sham, but those patients in the sham group appeared

138

to lose vision at a faster rate than those in the

Macugen treatment group.

[Slide]

We have a chart similar to the sponsor's

in that we looked at a subgroup analysis. The

reason why we do that is to make sure there isn't

one particular group that is actually driving the

results. As we see in this chart for study 1004,

if we look at all the subgroup analyses that were

done, the type of AMD, color of the irises, the

lesion size, baseline demographics and male/female,

what we see is that for each subgroup analysis the

0.3 mg group shows a higher response rate than the

sham group in each of the subgroups.

[Slide]

This was repeated in study 1003 where,

again, the 0.3 mg group shows a higher response

rate in all of the subgroup analyses over sham.

[Slide]

We also wanted to take a look at lesion

size, basically because of the proposed mechanism

of action of Macugen, and that is to inhibit

139

endothelial cell growth. So, we wanted to see

whether that was, indeed, happening. What we

noticed was that actually the total lesion size for

patients, as well as the total size of the CNV and

the total leak size, continues to increase for all

treatment groups. Even in patients receiving

Macugen, lesion size does increase but it does

appear that it increases to a lesser degree in the

0.3 mg group than in sham. However, it is noted

that it does increase in size.

[Slide]

The same thing was seen in the 1003 study

where, again, the total lesion size for all

treatment groups did increase in size, however, for

the 0.03 mg group it does seem to increase to a

lesser degree than in the sham group.

[Slide]

As you have heard, patients who entered

the trial were allowed to get photodynamic therapy,

which is an approved therapy for AMD. So, our

question became were we really seeing an effect of

Macugen or were we just really seeing the effect of

140

patients receiving an already approved therapy?

So, we took a further look at this and the first

chart you see here is the number of patients who

actually got on-study photodynamic therapy

treatment in study 1004. We see that approximately

the same amount of patients actually received

photodynamic therapy in all treatment groups,

including sham.

Another thing that we did note is that

while the protocol specified that only patients

with predominantly classic should have been allowed

to get photodynamic therapy, there were many people

who had occult or minimally classic CNV who also

received photodynamic therapy.

[Slide]

The same thing was seen in study 1003

where approximately the same amount of patients

across the treatment groups received photodynamic

therapy, with some occult patients and minimally

classic patients, again, receiving photodynamic

therapy. What was also interesting was that the

1003 study was an international study and you can

141

see that there were approximately half as many

patients who received PDT in the international

study versus the American study. That could be

based on practice patterns across the ocean.

[Slide]

We also wanted to look at not so much what

percentage of patients got photodynamic therapy but

were more patients in one group or the other

receiving more treatments? As we look at this

chart for study 1004, we are looking at the total

number of photodynamic therapy treatments. We see

that there is substantially less number of

treatments that were given in the 0.3 mg group

versus that given in the sham group.

[Slide]

For study 1003 the results are similar.

While there is not that big of a difference between

wham and the 0.3 mg group, the point is that there

were less photodynamic therapy treatments given in

the 0.3 mg treated group.

[Slide]

Lastly, we wanted to look at the results

142

and say, well, it looks as though the same

percentage of patients were receiving photodynamic

therapy; it looks as though the same number of

treatments were given. Well, did that make any

difference in terms of the responder analysis, the

primary efficacy endpoint?

So, what you are looking at here is the

responder analysis at month 12 for four different

groups, the first group being the group that

received no photodynamic therapy either before the

trial or during the trial. The second one are

those patients who only received pre-study PDT.

The third is a group that received on-study

photodynamic therapy only. The fourth group are

those patients who received pre-study and on-study

photodynamic therapy. The last line here is for

reference so you remember what the primary efficacy

results were for all patients that we just looked

at.

What we noted, which was good, is that the

majority of the patients who entered the trial

never had any confounding or problems with

143

photodynamic therapy, and that their results

actually were pretty consistent with the overall

results. In terms of the number of patients who

received photodynamic therapy either before or

during the trial, or both before and during the

trial, those numbers were so small that we really

can't make any conclusions about whether receiving

photodynamic therapy before or during the trial has

any effect on the efficacy results.

[Slide]

Similar results were seen for study 1003,

where we looked at the number of patients who

actually received photodynamic therapy. They are

extremely small and no conclusions can be drawn

from using concomitant PDT therapy. The results

for those patients who received no photodynamic

therapy, again, were consistent with the overall

efficacy results.

[Slide]

We were curious, I mean, our primary

efficacy endpoint is really those patients who lose

less than 15 lines of vision. We know, based on

144

the disease process, that patients will continue to

lose vision so those patients who lose less than 15

lines, that is probably a good thing for them. But

we wanted to know was there any possibility that

you could actually gain vision if you use this

drug. So, we looked at the number of patients who

gained greater than 15 letters of vision.

If you look at study 1004, actually there

is a statistically significant increase in patients

who actually gained vision in the 0.3 mg group and

the 1 mg group as compared to sham. However, those

results were not replicated in the 1003 study where

you see no statistically significant gain in

vision.

[Slide]

So, in terms of our efficacy conclusions,

we believe that Macugen 0.3 mg does reduce the risk

of vision loss in patients with neovascular

age-related macular degeneration. But keep in mind

that there is only approximately a 15 percent

treatment effect over sham, and that there is no

clinically meaningful increase in vision seen in

145

patients during the first year of using Macugen.

[Slide]

The sponsor has presented all of the

safety results. I am not going to go back through

all of them. I just want to say that we agree that

similar events were seen in all treatment groups

and no dose-dependent adverse events were seen.

Most of the events, we think, were related to the

act of giving an intraocular injection itself and

no so much to the drug. The majority of adverse

events, things like eye pain, superficial punctate

keratitis, floaters, iritis are those things that

we commonly seen with intraocular injections of any

drug.

[Slide]

But there are two safety concerns that we

want to talk about a little bit more. That is,

endophthalmitis again and also a little bit about

systemic VEGF inhibition and what that could mean.

[Slide]

In the database we had there were 16 cases

of endophthalmitis. What we heard this morning is

146

that actually there are 2 more cases. I guess

there is a total of 18 now. Of those 16 cases, all

of those 16 cases occurred in the pegaptanib sodium

treated patients, and none of the cases were in the

sham treated patients. All 16 cases occurred

within one week of injection.

[Slide]

So, I took a look at what kind of

organisms were actually coming out of the

endophthalmitis samples. We see that of the 16

cases, the overwhelming majority are those types of

organisms that are commonly seen around the lid or

around the ocular area--coagulase negative Staph.,

Staph. epi. There were about 6 cases that were

actually negative on the samples. So, it stood to

reason that maybe the problem was with the

injection procedure and the sponsor did take a look

at that and made some changes.

[Slide]

The original procedure called for the

patients to get 2-3 drops of 50 percent saline

diluted, 10 percent povidone-iodine or they could

147

receive 1 drop of topical antibiotic.

[Slide]

An amendment was made in the protocol

after I think 12 cases of endophthalmitis, and it

was changed so that patients would undergo a more

sterile preparation procedure, similar to most

intraocular surgeries, and patients would be

prepped and draped similar to intraocular surgery

and patients would receive either pre-injection

topical antibiotics for 3 days prior to injection

or 5 percent povidone-iodine flush immediately

prior to injection.

[Slide]

So, what happened to the endophthalmitis

cases? Well, we saw in the database that actually

13 of the 16 cases occurred before the protocol

amendment. Three of those 16 cases occurred within

3 months after the protocol amendment. This is

actually wrong now because I guess there have been

2 additional cases since that time. Based on the

data that we had, there had not been any new cases

of endophthalmitis 3 months after the protocol was

148

amended.

[Slide]

I just want to touch a little bit on

systemic VEGF and what that could or could not mean

in terms of this. Obviously, having VEGF is a good

thing in some instances and it is a bad thing. It

is a bad thing in the eye. We want to inhibit that

in cases like AMD. But we want it in the systemic

circulation, mainly because it plays an active role

in cardiac angiogenesis. This is important in

collateral blood vessel formation in patients with

myocardial ischemia. It is also an important

vasodilator and it helps to maintain coronary

artery blood flow and helps maintain patency of

coronary arteries.

[Slide]

So, what we did is we looked at the whole

database and we said, well, are there any events

within the database, the adverse event database,

that could possibly in any way be related to VEGF

being inhibited in the systemic circulation?

Of all the things that we came up with--

149

arrhythmia; atrial fibrillation which could be an

early indication of myocardial ischemia;

bradycardia; chest pain; coronary artery disease,

not just those cases where patients obviously came

into the study with a known diagnosis but those

patients who were diagnosed with coronary artery

disease during the trial; and myocardial

infarction--and we looked at the database and said,

well, is there a problem? Could we actually have

these systemic anti-VEGF effects based on the

intravitreal injections? What you see here on the

chart is that actually all the numbers are pretty

small across all the groups, and there is no real

indication that the intravitreal injection of

pegaptanib will have any systemic anti-VEGF

effects.

[Slide]

Just for completeness, in terms of the

death rate, there were approximately 25 patients

who did die during the study, approximately the

same in each study, and the majority of causes were

actually things like cardiovascular events,

150

malignancies and they were pretty typical of the

age of the population that we were studying. So,

we think those events were really due to the

population and not actually to the drug.

[Slide]

In terms of safety, similar events were

seen in all treatment groups. The most frequently

occurring adverse events related to the intraocular

injection itself and not to the drug. The risk of

endophthalmitis appears--and I have to emphasize

"appears" since there may be more cases that we

haven't seen--to be minimized by sterile technique

and there does not appear to be an apparent

increase in the risk associated with systemic

anti-VEGF activity.

[Slide]

We will just go over the questions

briefly. You are going to see the questions again

this afternoon but just so you can start thinking

about them. The questions that we would like to

have discussion about are, one, based on the

inclusion and exclusion criteria, are there

151

patients excluded from the studies that you believe

need to be studied?

Visual acuity measurements were conducted

using the ETDRS scale at 2 meters. The validity of

the ETDRS scale was established based on ratings at

4 meters. Are the visual acuity findings

sufficiently robust to overcome the potential bias

introduced by visual acuity measurements taken at 2

meters?

[Slide]

Has sufficient data been submitted to

evaluate the efficacy and safety profile of

pegaptanib sodium for the treatment of the

neovascular form of AMD? If not, what additional

data are needed?

Are additional analyses of the current

data needed to understand the efficacy or safety of

pegaptanib sodium for the treatment of the

neovascular form of AMD?

Has the concomitant use of PDT therapy

with pegaptanib been explored sufficiently? Are

there concerns with using this predictive

152

concomitantly with PDT?

[Slide]

Do the route and/or frequency of

administration of the drug raise any concerns that

are not addressed by the studies?

Endophthalmitis was observed in

approximately 2 percent of patients in the studies.

What is the optimal follow-up needed to minimize

the impact of potential endophthalmitis cases?

Are there any other adverse experiences

that are of particular concern for this product?

VEGF has been shown to be an important

component in the development of collateral vessels

in ischemic heart disease. Inhibition of VEGF in

the systemic circulation could present a

theoretical increased risk of symptomatic

cardiovascular disease in the target population of

elderly patients with AMD. Has the adverse event

profile of the two randomized Phase III trials

raised any concern over the possible systemic

effects of this therapy? Is there additional

monitoring that should be in place for patients on

153

pegaptanib sodium therapy? Thank you.

Committee Discussion

DR. DUNBAR: At this point I would like to

open the floor for questions for either the agency

or for the company. Dr. Pulido?

DR. PULIDO: Thank you. Two questions,

the first one is you said the treatment effect was

15 percent. That is because you took the 67 minus

50. Again, I am not a statistician; I am a

clinician--shouldn't it be the difference divided

by 50 to give you 25 percent as the treatment

effect? So, the delta of 15 over the baseline

which is 50?

DR. CHAMBERS: There are obviously lots of

different ways to look at it. What we have been

doing for ease of description is just to describe

what the percentage difference is between the two

different modes of therapy, and we thought that

easiest to be described as just a 15 percent

difference in the percentage of people who have

lost 3 lines of vision.

DR. PULIDO: The other question I had, and

154

maybe it would be better answered by the company,

when one looks at the serum levels, is that the

total amount of the drug that is being measured or

is that the unbound free form that is being

measured?

DR. ADAMIS: It is the total level.

DR. DUNBAR: Dr. Lehmer?

DR. LEHMER: Are there known levels for

VEGF or VEGF inhibition that are clinically

significant from the cardiovascular current

literature?

DR. ADAMIS: The short answer is no in

humans. The longer answer is that the most

sensitive signal of systemic VEGF inhibition is

hypertension. In the Avastin trials they picked it

up in their colon cancer, the renal study, their

lung cancer study, and some of those were much

smaller studies than ours and there was no evidence

of hypertension as a function of use of pegaptanib

in our study. So, I guess whatever that level

is--and it hasn't been determined--we are probably

well below that.

155

DR. DUNBAR: I have a question for the

agency about the duration of use of the drug. I

would like to know who will decide when to stop

therapy, the agency, the sponsor, or the patient's

physician? Is this something that will be

specified by the agency in relationship to the drug

approval process? Would it be included in the

labeling? Or, is this something that we won't know

for many years and would be addressed in further

labeling decisions?

DR. CHAMBERS: The most accurate answer is

that I think we will not know for a number of

years. The answer that everybody would like to

know is probably best studied by a 10-15-year study

of giving a particular product. We obviously run

into the difficulty of not having a therapy that is

potentially valuable available during the time that

we are doing that so we have chosen to take a path

where, if everything else looks good--and I will

repeat that decisions have not been made on this

particular product and there are lots of other

parameters that still need to be reviewed, but if

156

this product otherwise looks fine we would

potentially label it based on the information we

have available.

As you have heard, the sponsor presented

that as of their latest data safety monitoring

committee they have 90-some odd percent of the

information for the two years. To the extent that

we have two-year data, we will list two-year data.

If we don't, we will list one-year data and as more

data becomes available we intend to amend the label

to reflect what we know.

DR. BULL: I have one thing to add to

that. There is the opportunity for the committee

to make recommendations if you are uncomfortable

with the degree of follow-up, things such as Phase

IV commitments. I mean, there are a number of

options that can be systematically required of the

sponsor to do to look at the long term.

DR. GUYER: I think in answer to your

question, also clinical judgment of the

ophthalmologist will decide much of it until, as

Dr. Chambers mentioned, we do have the answer from

157

continuation of trials. If a physician sees a

patient that is, for example, scarred down and

realizes there is no further benefit of treatment,

we would expect that the physician would stop that

treatment, whenever that is and. Similarly, if the

physician sees active bleeding going on they might

continue it. So, I think a lot of it will be in

the clinical ophthalmologist's hands, at least in

the beginning.

DR. DUNBAR: That was my concern, that a

patient with a quiescent, scarred lesion was

vulnerable, worried about their blindness and might

subject themselves to very frequent injections for

a long period of time. Dr. Lehmer?

DR. LEHMER: We are certainly in the era

of implantable sustained release drug delivery

devices. At what point time-wise, if therapy is

determined to need to continue past a year or past

two years, should a recommendation for conversion

of this drug to an implantable device become

necessary?

DR. ADAMIS: It is an area that we are

158

very interested in, in the laboratory of the

sponsor. So, we are working on alternative

formulations to see if we can get an extended

release profile in implantables of that sort. I

think ultimately that may end up being an

improvement.

DR. DUNBAR: Ms. Knudson?

MS. KNUDSON: I just don't seem to

understand why the DSMB permitted the trial to

continue with the sham arm when at every point it

appears the sham arm is inferior to every drug dose

that was given. This is a disease, as I understand

it, which continually advances and one should treat

patients.

DR. ADAMIS: Yes, the data safety and

monitoring committee, their charge was to monitor

for safety. But the point you raise is a very

important one. So, in this randomized,

discontinuation trial design we actually allow

people who discontinue the drug and lose two lines

of vision to go back on so patients are not forced,

by and large except for a very small group, to stay

159

on sham for two years.

DR. DUNBAR: I have a question for Dr.

D'Amico. I was interested in Dr. Harris'

presentation that 6/16 endophthalmitis patients had

sterile endophthalmitis. I wonder, with your

experience with endophthalmitis, if you could tell

us do you think that these patients had infectious

endophthalmitis that were culture negative, or do

you think that that may be more of inflammatory

response?

DR. D'AMICO: Yes, in the trial, looking

for both of those things, that is inflammation

after injection or specifically infections, we

found really no evidence of a widespread

inflammatory effect at all. In studies of

endophthalmitis in general, for example after

cataract or other forms of ocular surgery,

invariably large studies always find that

approximately two-thirds will be culture positive

and one-third are, inexplicably, culture negative.

Now, what are those one-third? Well, some of them

will be organisms that have just not been

160

successfully collected by the culture technique.

Perhaps the specimen was too small; perhaps the

laboratory didn't plate it properly, or something

of that nature. Some of them may be fastidious

organisms that are difficult to culture. But

clinically I think we treat those cases as presumed

infectious. The patients had acute presentations

and they were invariably managed with TAP and

antibiotic injection. So, I think that they mirror

my clinical experience with endophthalmitis cases,

except somewhat for their outcomes which were

surprisingly somewhat better. They suggested

somewhat better visual outcomes than we might see

in clinical cases that, for example, would occur in

another context, after cataract or something like

that. Have I answered your question?

DR. DUNBAR: Thank you. Dr. Gates?

DR. GATES: Any conclusions as to that?

Is it a smaller bacterial load perhaps with this

injection?

DR. D'AMICO: Well, it is a new

phenomenon. Certainly, these patients were

161

extremely well followed and they included, you

know, contact with the patient and education to

inform patients about side effects, etc. So, the

patients were promptly detected, but it could be

that the load that is introduced in an intravitreal

injection is lower and, consequently, it has a less

fulminating presentation, but I don't know.

I will raise it because someone will, it

also may be that there is some interaction between

a VEGF medication and a profound inflammatory

infection in an eye. But that remains completely

speculative but it is something interesting, as a

scientific point of view, for further research.

DR. ADAMIS: Just to follow on Dr.

D'Amico's comments, there are data in the

laboratory now that VEGF can be pro-inflammatory,

and in models of ocular inflammation VEGF levels

come up and it is associated with the vitritis and

flare, and we have published, and others have, that

if you block VEGF in that sort of instance you can

decrease the inflammation as well as the leak. So,

it is speculation, as Dr. D'Amico said, but it is a

162

plausible hypothesis that it may be having somewhat

of an anti-inflammatory effect as well and you get

less standard damage that occurs when neutrophils

rush in in a case of endophthalmitis, but it is a

theory.

DR. DUNBAR: Dr. Chinchilli?

DR. CHINCHILLI: Yes, I have a question

for the agency. In the briefing document you

showed the results from the worst-case analyses. I

notice that in your presentation you really didn't

discuss that. Is there a reason you didn't present

them today? I mean, how do you feel about--well, I

will tell you that I think you shouldn't do them

but I was wondering why you didn't present them but

they are in the briefing document, or am I reading

too much into that?

DR. CHAMBERS: We do a large number of

analyses, which are neither shown in the briefing

document nor shown in the presentation, to try to

look at the robustness of the findings. We thought

it instructive to give what potentially is a bottom

lower limit and include it in the briefing document

163

just to try and frame people's idea of what the

magnitude could be of inclusion or exclusion of

different findings, but since it does not

necessarily represent an accurate finding we didn't

think, from a time perspective, that it was worth

continuing to present in a presentation.

DR. CHINCHILLI: Well, I think it is

highly inaccurate. I know you try to look at the

bounds but I think they are highly inaccurate

bounds. Later today--I don't know if you want to

get into this now, but I do have some

recommendations about analyses, endpoints and

things like that. So, I don't have to get into

that now.

DR. CHAMBERS: We don't disagree with you.

We don't think either of the analyses are

necessarily the most accurate; we could do

something in between.

DR. DUNBAR: Is there additional

discussion for the agency presentation at this

point in time?

[No response]

164

Now we have a decision about our agenda

because we have significantly more time with our

morning session than we expected. It is imperative

that we start the open public hearing as it is

scheduled at 1:00 p.m. so that the public can have

their voice in this matter. We have two options.

One is that we can take a longer lunch period and

then start the agenda for the afternoon as

previously published. Or, we can begin to answer

some of the FDA questions now and start our lunch

closer to the scheduled time and then have the

public hearing at 1:00 p.m.

So, let's begin to answer some of the FDA

questions now and then we will, of course, begin

the public hearing at 1:00 p.m.

DR. CHAMBERS: We would like to hear some

general discussion as opposed to just going through

the questions. So, that may be a better use of

some of the time this morning, just a general

discussion of the different topics that are on

there and then specifically go through questions

later.

165

DR. DUNBAR: Then we will start with Dr.

Chinchilli in terms of general discussion from the

committee.

DR. CHINCHILLI: Well, I mentioned this in

my previous question and I would like to talk about

the endpoint that is used and the analysis. I

don't quite understand why the analysis was done

this way, and then looking at the briefing

documents I see that this is the way the FDA

recommends the analysis be done. But there is

interest in less than 15-letter loss. I think it

would be better to reverse the definition, to look

at someone who fails, someone who is a treatment

failure who has 15 or more letter loss and then

look at the time to occurrence of that event. This

way you would better handle the dropouts and the

censoring that occurs.

Now, I realize the subjects in these

particular studies come into the study every six

weeks so you don't have a nice continuum for

determining when this treatment failure takes

place, but at least you can have more of a discrete

166

failure time process. It would just get away from

looking at these extreme cases, the worst-case

scenario that the agency likes to look at in terms

of bounding the results. It just seems to me that

that would be a better approach to the analysis,

that is, to reverse the definition and talk about

treatment failure and look at time until treatment

failure occurs, and doing time to event analyses.

That would be a much more accurate analysis, I

feel. I don't know how the agency feels about that

or if they would consider that. I don't know if

there is some reason I am missing that that is not

a good approach. And, maybe the company would like

to comment on that as well.

DR. CHAMBERS: We are certainly open to

looking at a number of different types of analyses

and different ways of doing it. The general

recording of visual acuities has been every three

months, not every six weeks. Consequently, you

have set fixed time points when you are getting the

information. So, time to event, when you are fixed

at every three months, we have not thought as being

167

particularly meaningful.

Whether you look at it on either side of

this coin, whether it be the people that improve or

the people that fail, we have generally thought as

being relatively similar. There are certain biases

that go in as far as the dropouts and which way

they are treated. Obviously, if you are assuming

that somebody is going to drop out and they never

get seen again, they don't get counted as a loss.

That accounts for some of the reason for doing a

number of the analyses that we do.

But, as I said, we do a large number of

different analyses looking at these things to try

and look for the robustness of the findings. In

this particular case, any way you look at it you

have very similar results. So, we did not stress

how it needed to be presented for this particular

case.

DR. CHINCHILLI: I agree. I mean, the

dropouts in these two trials was between 10-12

percent so that is not extreme. But I think you

are going to have trials where you may see more

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dropouts, a higher rate than that, and all these

cases that you are proposing for analysis all

involve some form of data imputation. If you look

at the treatment failure approach and time to event

analysis, you know, you account for that censoring

and you are not imputing data the way you do in the

current methods. You know, I think I am getting

off the tangent here, but it just doesn't sit well

with me the way the outcome is constructed and all

these analyses are performed that involve some form

of data imputation. Again, I agree. I don't think

it makes a bit of difference with these two

particular trials here but in general it is not

really good methodology.

DR. CHAMBERS: We certainly are interested

in additional comments you have along that,

although I am not aware of any method that doesn't

have some type of bias and some type of assumptions

in the way it is presented, including the methods

you are discussing.

DR. DUNBAR: Dr. Lehmer?

DR. LEHMER: I just want to make sure I

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understand correctly that, with regard to the

analyses, the intent-to-treat is what has been

presented, being the most inclusive; the

per-protocol analysis being the most exclusive. As

I understand from the briefing, when the two were

compared there were no significant differences and,

therefore, that is why we are using the

intent-to-treat because we want to be as inclusive

as possible to get the safety data. Is that a

correct interpretation of why we are using the

intent-to-treat analysis?

DR. ADAMIS: The safety data population is

even a little bit larger. Everybody was randomized

and received one treatment. The intent-to-treat

was the folks who had one baseline vision as well.

DR. GUYER: Can I have slide E-101, please?

Maybe we can just summarize this.

[Slide]

This shows the definition of the various

populations that we looked at, and it shows that

the all-randomized group were those that received

an actual randomization number. In this case it

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was 1,208 and that represents the largest

number--as you said, one extreme. The safety group

received study drug, and that was 1,190, slightly

fewer. The intent-to-treat were patients, by the

sponsor's definition, that received study drug and

had an observed baseline vision. That was 1,186.

The per-protocol was all of the ITT patients that

had an observed post-baseline vision and no major

protocol violation. So, as you mentioned, it is a

much smaller group because they observed the

protocol perfectly and also had an observed time

point at week 54. That brings you down to 1,144.

Then you have a week 54 observed which are the

actual patients who received the study drug and had

a baseline vision and also a week 54 vision, and

that is 1,085.

[Slide]

Just to illustrate further maybe some of

the differences, E-102 shows again, starting with

the all-randomized where you start with 100 percent

of your population, going down to week 54 where you

get 92 percent of the data, at least for the 0.3

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mg.

[Slide]

Finally, if we go to slide E-103, this

again shows just the two extremes, so to speak, the

all-randomized with an LOCF, which is in the FDA

briefing book, and the intent-to-treat where study

medication and baseline visual acuity occurred,

which is in our briefing book. Very importantly,

you can see that they are all the same. Slide

E-113.

[Slide]

We can see that on the left we have the

ITT population using an LOCF, which is in the

sponsor's briefing book, and we have the

all-randomized LOCF when there is a true ITT, in

the FDA briefing book. Then we have some of the

extremes, the per-protocol observed and the week 54

observed. Then you can see that we have very

robust data and that the sensitivity analysis and

different analyses all show, for the 0.3 mg dose, a

statistically significant change. So, any way you

look at it, either extreme, we see robustness of

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the data.

DR. DUNBAR: Dr. Pulido?

DR. PULIDO: Ms. Chairwoman, your question

had been do we have general comments at this point,

and I would just like to state that I think the

data at this point looks very favorable. I would

say that my concerns about systemic complications,

from the data, appear very small.

My only concern is the long-term use and

the fact that there is the second aspect of VEGF

that only recently we are learning about, and I

would like to see some long-term follow-up using

ERGs and possibly visual fields in a small group of

these patients to make sure that there are no

long-term consequences of long-term use of this

drug. Otherwise, I am very impressed.

DR. DUNBAR: Are there any other general

comments from committee members? Dr. Steidl?

DR. STEIDL: You can correct my thinking

if I am wrong here, but it looked as though the

lesions continued in general to grow, maybe at a

slower rate, in the treated group. With the

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half-life of, I guess, about four days and

effective vitreous concentrations that are weeks,

it would seem with that trend that it is quite

possible that this may be needed for a while beyond

the study time period. You know, somebody

mentioned the 0.16 percent per injection in

endophthalmitis rate. If you multiply that times

nine it gets pretty close to what was seen. I

don't know if it is valid to extrapolate that, but

then if you start thinking about doubling the time

and getting maybe to 3-4 percent, from my point of

view, it is getting pretty scary.

I don't tend to view those, from a retina

point of view, as sterile endophthalmitis because

in our lab we get a third to a half of clearly

infectious cases that don't come back positive. I

am wondering if that seems like a logical

assumption, that if this is to carry on we could

assume that the endophthalmitis rate would grow

proportionally.

DR. ADAMIS: Yes, I think your

interpretation of the data is correct and,

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obviously, the cumulative risk increases as a

function of time. What our goal is, and we take

this responsibility seriously, is to make sure that

the injection procedure, which may be a modifiable

risk--that the risk gets down as low as possible.

We were fortunate in the second year after the

amendment to actually see that rate go down and,

subsequent to the amendment that occurred last May,

it is down to 0.03 percent per injection.

The other aspect of it that is equally

important is the visual outcome. That is, if this

event happens, are these patients being diagnosed

rapidly and being treated appropriately, and then

doing everything you can to preserve the vision as

a function of getting the infection. I think our

investigators did a rather superb job in the sense

that everybody was diagnosed within a week.

Everybody got intravitreal antibiotics. Over half

of them had vitrectomies and you saw the visual

outcomes. I will tell you that the visual outcomes

in the second year with the additional cases are

the same, if not better, than what you saw in the

175

data presented today. But your thesis is correct

that the more you use the drug, there obviously is

an incremental risk over time that increases.

DR. DUNBAR: Dr. Pulido?

DR. PULIDO: So, yes, there is a risk of

using intravitreal injections, but the alternative

is the present forms of treatment or systemic

medication that also increase the risk. It is a

small risk but I would rather take that risk than

give something that has systemic effects.

DR. ADAMIS: A point well taken. As Dr.

D'Amico said, I mean, it is important to take it in

the context of the potential benefit. So, the

reduction in severe vision loss is greater than 50

percent and the severe vision loss we saw as a

function of endophthalmitis was 0.1 percent. On

balance, at least in this first year, it looks like

the benefit outweighs the risk.

DR. DUNBAR: Dr. Lehmer?

DR. LEHMER: I agree with Dr. Pulido. The

data are very impressive. Along the lines of what

should be looked at in the future--the PDT impact.

176

Obviously, we are not able to really assess that

based on the numbers, but taking this information

forward, seeing what are the clinicians going to do

with this data, in other words, who do we apply PDT

to, what kind of population--a patient comes in

with macular degeneration, do we use Macugen? Do

we use PDT? Do we use both?

I suppose if patient recruitment were

going to start now we would see a much larger

percentage of the European community using PDT

since it has been approved there and there has been

some expanded use of PDT. So, I guess as far as a

future analysis--I don't know if that is already

under way--I would like to see more data on the

impact of PDT.

DR. GUYER: I think that is a very

important point. One of the things that was

important to us when we designed this trial was to

try to make it as much of a real-world trial as

possible. That is why we allowed photodynamic

therapy in it. Showing the data, we can't say a

lot about combination use or anything like that,

177

but I agree with you that certainly future trials

will be able to address those issues and it is

important.

DR. DUNBAR: Mr. Kresel?

MR. KRESEL: I guess being the pragmatic

industry representative, I will ask the question

the way I look at things, which is that we had a

lot of discussion about endophthalmitis and I think

you gave a really good answer as far as how the

patients were treated and how they were followed

up. But they were in a clinical trial where, you

know, they came back to see the physician at these

intervals. So, would you recommend in labeling

that kind of a follow-up so that those patients are

tracked and, in fact, appropriately diagnosed and

treated?

DR. ADAMIS: The optimal follow-up I think

still remains to be determined. One of the things

we have done is we have given grants to specialists

who are experts in this area to try to come up with

a preferred practice recommendation. The only

thing we can say is what we did and what the

178

results were. I think it is still an open question

as to which variables that we changed, and we

changed multiple and, as I said, the steroid

injections were taking place at the same time in

another population--which of those factors is the

most important still remains to be determined and I

think a lot more work needs to be done in that

area.

So as regards to what we will recommend,

it is still being decided. Until we hear back from

the experts we obviously will tell people what we

have been doing and the results that were

associated with that.

DR. GUYER: I also want to comment--many

of the retina people in the room know this--but in

the last three or four years there has been a

tremendous experience in the retinal world with the

use of off-label intravitreal steroids because

there is such an unmet medical need not only for

this disease, macular degeneration, but also for

diabetic macular edema. So, I actually think there

was a tremendous learning curve for retinal

179

physicians learning the best way to do intravitreal

injections. That occurred. We talked about the

protocol amendment and we hope that that had some

effect. But I think also equally important may be

that the retinal doctors had a very, very good

experience of the best way to practice intravitreal

injection administration.

As Tony mentioned, we did sponsor a

roundtable to try to get the thought leaders

together on the best way, and Dr. D'Amico was at

that and maybe he would like to comment on a few of

the findings from that that could help guide us.

DR. D'AMICO: Yes, under an educational

grant a roundtable was convened to look at the

growing use of intravitreal injections in

ophthalmic practice, and to try to assemble the

best available information on what we know about

how to make this procedure as safe as possible. In

this roundtable there were experts from the point

of view of infectious disease, from the point of

view of vitreal-retinal surgeons, people who deal

with antibiotic levels within the eye, and also

180

substantial representatives across industry who

have pharmaceuticals that are used by intravitreal

injection. While all I can tell you is that an

article is in preparation that will be ultimately

submitted to peer review literature, we have

initial plans to submit that article to the journal

Retina. It includes things such as the premise of

using povidone-iodine which emerged as an

incredibly important central aspect of using a lid

speculum. We were finding that, in many casual

surveys, people would do injections and allow the

lid margins, etc. to contaminate the needle, and

probably most importantly, to treat this as a

sterile intraocular procedure.

I was present. I was asked to be a part

of that committee and, if you wish, I have details

about who was there, etc. But I feel that this

document will be very valuable in helping the

evolution of the understanding of intravitreal

technique. So, it will become something that I

think we can go forward with. We can look at

various modifications now to make this safer and

181

safer.

But having participated in both the data

safety committee and also this panel, I am quite

convinced that the protocol modifications had a

very real effect on reducing the incidence of

endophthalmitis, and I am confident that incidence

can be kept low and probably be even further

reduced with appropriate education of both patients

and physicians, as well as appropriate training.

DR. DUNBAR: Dr. Pulido?

DR. PULIDO: Dr. D'Amico, there was a

recent article I believe in The American Journal of

Ophthalmology. It included people from Baskin

Palmer, looking at the incidence of endophthalmitis

following intravitreal triamcinolone injections,

and the incidence was double that of this, wasn't

it?

DR. D'AMICO: Correct. You know, it could

never have been known when these trials were begun,

but intravitreal injections have become quite

commonplace in retinal practice now with off-label

use of triamcinolone and the incidence which has

182

been reviewed shows that it is substantially

higher. Although I believe that that incidence, in

fairness, is decreasing as physicians treat the

injection technique with additional seriousness and

care. But, actually, a detailed review has been

made available to this review committee and showed

that the rate of endophthalmitis following

intravitreal injection with pegaptanib was well

within the range, and at the low end of the range,

for intravitreal medication administration across

the board.

DR. DUNBAR: Ms. Knudson?

MS. KNUDSON: The only thing that confuses

me a little is that you say that no patients

receiving the sham treatment had endophthalmitis.

Doesn't it seem that it is the drug then that was

causing it?

DR. D'AMICO: Well, the sham patients did

not receive the penetration of the eye with the

needle so that explains why it is that event which,

presumably, allows bacteria to gain entry into the

eye.

183

DR. DUNBAR: Recently several of the

comments reflected not so much concerns about the

statistical significance of the efficacy of the

drug but, rather, concerns for the future.

Previously Dr. Bull mentioned that the committee

can make Phase IV recommendations for plans for the

future, for future studies. What is the mechanism

for this? And, perhaps this is an appropriate time

for the committee to discuss some of these future

concerns.

DR. BULL: That would fundamentally fall

under recommendations for additional studies. If

these are data deficiencies that you might see as

impacting marketing of the product, it would argue

against whether or not you feel the data is

sufficient at this point in terms of the efficacy

assessment. If these are data needs that need to

be obtained in a systematic way, they can certainly

not hold up marketing of the product if you feel

there is sufficient efficacy in terms of what you

have seen.

We realize this is an incomplete data set

184

and I think that that needs to be kept in mind,

given the earliness of where we are in this

submission. In fact, there are modules in the NDA

that have not come in and have not been vetted by

the agency yet. So, I have to say that, you know,

we haven't seen the data, as has been mentioned, in

terms of the re-randomization. There are a number

of sort of outstanding assessments here that I

think certainly have significant implications for

further work. But I think things that need to be

looked at systematically certainly have the

potential of being addressed in Phase IV.

DR. DUNBAR: Dr. Pulido?

DR. PULIDO: Just for clarification, that

could be a postmarketing surveillance. For

instance, study ERG could be postmarketing,

following marketing approval surveillance in that

regard.

DR. BULL: You mean is post-approval?

DR. PULIDO: Yes.

DR. BULL: Potentially but, again, as I

said there is a huge caveat here that we are still

185

very early in the review of this application and

there are a number of other aspects, particularly

from chemistry manufacturing issues, that will need

to be addressed and other things that will impact

the totality of our assessment of the data.

DR. DUNBAR: Dr. Chambers and then Mr.

Kresel.

DR. CHAMBERS: Let me just clarify, the

range of different options includes additional

Phase III trials, additional Phase IV clinical

trials, as well as postmarketing commitments,

postmarketing monitoring. There is going to be a

certain amount of postmarketing monitoring that

automatically goes with any new drug product. But

what you are describing would probably more

accurately be done as actual controlled clinical

trials because you want, obviously, a baseline as

well as continued follow-up in order to look for

any potential changes. That is probably better

done with a control group and making sure you have

everybody in your trial.

DR. DUNBAR: Mr. Kresel?

186

MR. KRESEL: I guess my question isn't

really a question--well, it is but it is for the

rest of the committee because it is not one for me

to decide. But if I were in the sponsor's shoes,

and I have heard people commenting on how long can

we use this drug and what are the consequences, I

guess I would like to hear the committee weigh in

on how much follow-up post-approval the committee

thinks is appropriate, for planning purposes. That

is, you know, the sponsor is going to have two

years of data pretty soon. How much data does the

rest of the committee think is appropriate to

continue follow-up?

DR. DUNBAR: Dr. Pulido?

DR. PULIDO: Trying to answer your

question and Dr. Chambers' at the same time, I

don't know whether it is necessary to do a

randomized, controlled trial for the results of

ERG. One possibility is that there hasn't been any

change whatsoever so that if you take the patients

that already have been in the trial for a year and

do ERGs in a small group of them and compare it

187

even to the fellow eye and there is no difference,

well, that tells you volumes. That decreases the

chances of having to go ahead and do another

randomized, controlled trial and slow the

acceptance of this drug into the marketplace.

DR. DUNBAR: Dr. Chambers?

DR. CHAMBERS: Let me just ask don't you

think there is likely to be decreased ERG in

patients that had macular degeneration compared to

the other eye?

DR. DUNBAR: Dr. Pulido?

DR. PULIDO: Not necessarily because

macular degeneration is such a localized area that

is involved that the ERG overall may not be

affected. We know that macular disease does not

affect a large part of the ERG. So, my only

concern, again, is, is this affecting a broader

area of the retina than what we are measuring by

doing visual acuity measurements? If that is not

the case, I don't think we should delay it.

DR. CHAMBERS: I don't know that we are

talking necessarily about delaying it, but I guess

188

the question still in my mind is interpretation.

If you don't see anything, yes, that is great. If

you do see something, is that necessarily the drug

product or is that the disease going on? And you

don't know the answer to that.

DR. PULIDO: Then you would have to do the

trial you were considering.

DR. DUNBAR: Taking a step back to Mr.

Kresel's question, I would like to ask the other

committee members if there is any sense among the

committee to build a consensus of how long the

company should study the drug for the future after

this they finish this planned two-year period. Not

so much requesting additional data such as the

visual field and ERG that Dr. Pulido mentioned, but

just to continue the clinical trial, is there any

sense among the committee? Dr. Lehmer?

DR. LEHMER: In the PDT studies there was

a physical endpoint of no leakage. Is there a

similar endpoint with regard to this study looking

for that type of endpoint or stabilization of

vision? I think we have to have some kind of

189

clinically meaningful endpoint on which to base the

answer to that question of how long do we carry the

study for and, therefore, how long do clinicians

expect to carry on the treatment.

DR. GUYER: In the photodynamic studies

there was continued leakage. When they decided to

retreat they would do a fluorescein angiogram to

determine that. But over the course of the year,

similar to what we have seen, there was still

leakage occurring and that us the disease, and Tony

can perhaps give us some hypothesis for why.

So, for that reason, I think the two-year

data will be very, very important in the sense that

we will learn more about two years of therapy

versus one year of therapy. Until that data, as we

mentioned earlier, I think what is nice about the

eye is that you can look in and see the disease and

a patient who has significant disease with large,

scarred, poor vision obviously wouldn't be

necessarily a good candidate to continue treatment.

Someone that might not have any leakage, as you

say, could be used as a clinical endpoint for

190

perhaps stopping treatment, and people who are

actively bleeding would continue.

But it is important to say that really the

only recommendation we can make is this clinically

important finding is based on one year or 54 weeks

of treatment. So, we really can't say anything

more and it would be dangerous to try to speculate

that less treatment could give the same effects.

So, we believe that clinical judgment would be

very, very important in determining long-term

treatment.

DR. DUNBAR: Dr. Pulido?

DR. PULIDO: The other thing that I think

is important is the fact that even with one-year

follow-up--what was the mortality rate in this

group of patients? Wasn't it 10 percent or

something?

DR. ADAMIS: It was two percent in treated

and sham alike.

DR. PULIDO: Right, so I mean you are

already getting to a point where there is a certain

mortality in these elderly patients. To continue

191

it more than two years, I think you are going to

find a higher mortality rate and I don't know

whether we are going to find more than what we are

already finding.

DR. DUNBAR: Is there any additional

discussion at this time? If not, at this point

let's break for lunch and we will reconvene at 1:00

p.m. for the public discussion.

[Whereupon, at 11:45 a.m., the proceedings

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

192

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

Open Public Hearing

DR. DUNBAR: We are beginning the

afternoon session of the Dermatologic and

Ophthalmic Drugs Advisory Committee on Macugen with

an open public hearing.

Both the Food and Drug Administration, the

FDA, 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, FDA believes that it is

important to understand the context of an

individual's presentation. For this reason, FDA

encourages you, 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 sponsors of any products

in the pharmaceutical category under discussion at

today's meeting. For example, this financial

information may include the sponsor's payment of

your travel, lodging, or other expenses in

193

connection with your attendance at the meeting.

Likewise, 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.

At this point of the open public hearing,

I will ask speaker number one to please come to the

podium. Each speaker will have seven minutes to

present.

MR. GARRETT: Hi. My name is Dan Garrett

and I am with Prevent Blindness America. My

organization paid for my own travel to come here

today and I personally do not have a financial

relationship with any of the companies pertaining

to this drug.

I mentioned I am with Prevent Blindness

America. We are the second oldest voluntary health

agency in the country. We represent organizations

throughout the country that primarily focus their

efforts on screening, training, advocating,

194

researching and educating people on the importance

of good vision care. We also advocate for

increased research funding and increased funding to

the Centers for Disease Control in Washington, and

we try to impact public policy as it relates to

saving sight and vision loss.

The reason I am here today is not to

endorse this product but to encourage the committee

to make the right decision as it relates to the

science behind this drug. It might suggest that

this could prevent further vision loss for people

with AMD. That is why I am here today. My

organization does not endorse the product of

discussion today.

A few thoughts and figures, and I wasn't

here earlier today so forgive me if these are

repetitive. It is important to point out that

nearly 1.7 million Americans aged 40 and older have

AMD, and if nothing is done by the year 2030 the

number of blind and visually impaired could

possibly double. So, we are talking about a fairly

significant population. It is very important that

195

this committee consider this drug because it has

the potential to potentially stop vision loss.

Unfortunately, there is not a miracle drug out

there yet that prevents AMD but, hopefully, with

all the science and research that is going on that

will be in the near future for us.

Another interesting statistic, and this

could particularly hold for people with AMD because

they are the ones that have most low vision, vision

impairment is the cause of 18 percent of hip

fractures, and most people that have AMD are living

on their own and they have lost their central

vision so it is very difficult for them to navigate

their way around their home. If only one in five

of those hip fractures were prevented, more than

440 million dollars could be saved annually so that

is significant. So, any type of AMD drug that

could prevent further vision loss is certainly a

welcomed addition to the marketplace for patients.

My organization, again, advocates

advancements in treatment of AMD, and I just want

to say to the committee that I am sure you will

196

make the right decision on behalf of all the older

Americans in this country for the people that have

AMD. Anything that can prevent further vision loss

should be welcomed. That is all I have to say.

Thank you.

DR. DUNBAR: Thank you. At this point I

will ask speaker number two to come to the podium.

MS. HOFSTADTER: Good afternoon. I am

Ellen and I am 81 years old. I do not have any

financial ties with the drug company except my stay

in the hotel and my travel.

I was diagnosed with AMD two years ago. I

belong to an HMO. The HMO doctors checked me and

told me "you can go home; there's nothing we can do

for you." But I didn't take no for an answer. I

called the Jewish Eye Clinic and asked if there was

a doctor who could see me. The girl says, yes, and

in two weeks I have an appointment. I got Dr.

Schwartz. I had an eye test, an angiogram and he

looked my eye over and he said, "don't drive, but

do not sell your car because we might can help

you."

197

So, I took some lasers, some Visudyne in

my left eye but it didn't help. So, my left eye is

legally blind. Then I was approached by Dr.

Gonzalez who asked me if I would like to step into

a clinical trial with Macugen shots. Well, it was

very heavy for me because when I was a young girl I

was sent to Auschwitz and I was experimented on by

the infamous Dr. Mengele. So, I had really a

choice to make.

I didn't think long about it and I thought

I want my sight. So, I told them I would. So, I

got into the clinical trial and I got a Macugen

shot in my right eye. It sounds very scary but

really 20 minutes of discomfort is a small price to

pay. After the third shot I gained my sight back

to 20/20 and could read seven lines below. I had

altogether 12 shots and three weeks ago I had my

lost one and my sight is 20/20 in one eye.

And I really want to thank the researchers

who worked so hard to find a drug like Macugen to

help us for this dreadful disease. Thank you.

DR. DUNBAR: Thank you. Next I will ask

198

speaker number three to come to the podium.

MR. STEVENSON: My name is Nick Stevenson.

I am the president of the Association for Macular

Diseases. It is the only national support group

that is solely concerned with both the practical

and the emotional problems confronted by

individuals and families endeavoring to cope with

our particular type of eye disorder. To do that,

we publish a newsletter which advises our members

what is going on in the world of research, what is

not. There is an increasing number of scams and

frauds which are proliferating now not only in

numbers but in funding as well, and we maintain a

members hotline where members can always call in

and we can act as a link between them, their

problems and the problems that they may face.

I, myself, have been legally blind from

the wet type of macular degeneration for 26 years.

I have no financial interest in this pharmaceutical

company or actually any, except that they did pay

my travel and expenses to come down here. But what

I would like very much to emphasize for all of you

199

is something that many of you, I can understand,

have already experienced, how difficult and

understandably difficult it is for a fully-sighted

person to fully appreciate the enormous subtraction

from life that loss of vision represents, for some

far more than for others but, nonetheless, it is

not something that any of us foresaw in earlier

years of our lives. We may have thought of

disasters overtaking us, such as being struck by an

automobile or some disease attacking us in a way

that we found ourselves to be vulnerable. But the

loss of vision is something that few of us have

ever contemplated. We felt that there was a

warranty issued on our eyes and we had the full use

of our eyes for as long as we needed them. Then we

find that we don't and an entirely different set of

circumstances appears.

Now, it must be admitted that macular

degeneration varies widely in the degree of

severity with which it affects individuals. But

for those with more severe type, such as this drug

addresses, they have the problem of not recognizing

200

the faces of their friends, or their enemies if

they have them. Also, they are not able to drive

in a society where an automobile is as automatic a

feature as a horse once was out West, or even

almost an appendage of oneself--the automobile--is

taken away.

In addition to that, the inability to read

to varying degree, whatever it might be, is also a

very serious detraction from quality of life. That

blue sign over there; it is that entrance right

there past the blue sign--of course, you can see

it. And does this bus go to Amherst? Well, the

drive is too busy to answer you so he nods and you

don't see him nodding--these are not major events

but they have a cumulative effect and what is very

difficult for a great many of us to understand

fully, because we don't choose to, is that macular

degeneration is a progressive disease. As the

years go by; the eyes do get worse whether we have

the dry type or whether we have the wet type.

So, it seems to me high time that some

action was taken to try to avert the further

201

incidence of macular degeneration in its various

forms for the people who follow behind us. It has

been said of older people that, as they think of

their lives, the days grow longer and the years

grow shorter. So, as the years grow shorter, all

of us hope that somewhere--like Dr. Jonas Salk

finding the cure of polio back in 1954--something

may appear that will give us some surcease from the

anxiety, and the apprehensions, and the limitations

of macular degeneration. Thank you.

DR. DUNBAR: Thank you. Now I will ask

speaker number four to come to the podium.

MR. AUGUSTO: Good afternoon. I am Carl

Augusto, president and CEO of the American

Foundation for the Blind, an organization that is

dedicated to expanding the rights and opportunities

of people who are bind or visually impaired in this

country. Like Helen Keller before me who devoted

44 years of her life to the American Foundation for

the Blind and its causes, I am always grateful to

speak to governmental officials, corporate America

and the general public on how we can improve the

202

lives of people who are blind or visually impaired.

In my 30-plus years working as a

rehabilitation counselor and as an administrator in

agencies serving the blind and visually impaired, I

have seen first-hand the many difficulties faced by

those who are losing their vision as a result of

AMD, age-related macular degeneration. After

living most of one's life, relying heavily on the

sense of sight, not seeing well enough or seeing at

all can certainly turn the world upside down for

those people and their families. Add to that other

physical ailments, physical disabilities, personal

and social hardships that older people, many of

them, experience the emotional and the functional

adjustment to vision loss is very, very difficult.

Ordinary daily activities become

challenging, if not impossible. If you can imagine

not having the opportunity or not having the

ability to read the morning newspaper, to drive to

supermarket to get your groceries, to do your

personal business, to read your personal mail, to

cook for yourself--this is what is happening with

203

so many people losing their vision in this country.

Moreover, it is difficult to adjust emotionally and

functionally to a certain level of visual loss if

that vision worsens next month.

One of the first clients that I had as a

rehabilitation counselor was a gentleman suffering

from age-related macular degeneration. He was

about 50 years old and his deterioration rate was

steady over the course of time, and he was really

overwhelmed by this. His name was Jack. Jack had

lost confidence in his capabilities. He felt that

he couldn't do his job any longer. And, one of the

things he said to me was, "just when I think I'm

beginning to adjust, I lose more vision and the

despair sets in again."

Well, his visual loss forced him to retire

from his job long before he should have. It was a

financial hardship to his family. He was staring

at the walls every day and not feeling productive

at home. It took an emotional toll on the family.

His wife couldn't handle it any longer and she left

and now he was on my doorstep, wanting answers to

204

how to live independently.

I remember thinking that, gee, if I had

seen him a little earlier, or if the progression of

his sight loss was not as significant I might have

been able to help him realize that he could do his

job still using alternate techniques or technology.

But he lost his vision much too quickly and he did

give up.

Now, my blindness is caused by a recessive

gene disorder and it started when I was very young.

When I was eight years old I started losing my

vision and my loss was very gradual over the course

of time. I became totally blind at about age 45.

Some days I think I haven't reached 45 yet but that

is just a couple of years ago. But that gave me an

opportunity to learn the skills that I needed to

function independently at home and on the job. I

had an opportunity to tackle the emotional hurdles

that inevitably arise with severe vision loss, and

I truly believe I live a life that is as normal and

satisfying as anyone's.

Now, AMD is the leading cause of severe

205

visual loss in our country, and this visually

impaired population will continue to increase as

the baby-boomers reach old age. Simply stated, we

are outliving our eyes and delaying the effects of

AMD or stopping the effects of AMD would give

millions of people more time to adjust emotionally

and functionally, to locate rehabilitation

facilities, and to develop the skills that are so

critical in helping them to function independently.

If we can do this, any kind of slowing of the

deterioration would be a blessing.

There are services for people who are

blind or visually impaired. Low vision services

that are delivered by specially trained eye care

professionals enhance the remaining usefulness of

your vision when you do have vision remaining.

Other rehabilitation services are available from

private and public agencies throughout the country

to help you with personal management skills and

also vocational skills. And, assisted technology

is revolutionizing the way blind and visually

impaired people function.

206

However, there are two problems. Many

people with age-related macular degeneration and

other visual loss don't even have a clue that these

programs are available and they may not be in their

own communities. Secondly, we don't have the

funding in this country, federal or otherwise, to

support sufficient services to meet the growing

need for services for the increasing population of

blind and visually impaired people. So, anything

we can do to reduce the numbers of this population

would be helpful in that regard.

In closing, blind and visually impaired

people can live and work with dignity and success

alongside their sighted peers. People can adjust

and learn new skills and also to live

independently. But many of them need time to

develop. Many of them are not adjusting when their

vision continues to deteriorate, and without a

chance to learn to cope with vision loss gradually,

I am afraid that too many people will be like Jack

and will give up on themselves before they realize

that there is help out there that could help them.

207

Thank you.

DR. DUNBAR: Thank you. Now I want to

request that speaker number five come to the

podium.

DR. ROSENTHAL: I am Bruce Rosenthal,

Chief of Low Vision Programs at Lighthouse

International, New York City and Mount Sinai

Hospital. My organization paid my expenses.

However, in the past I have had an unrestricted

educational grant from Novartis for a booklet on

vision function.

Over 75 percent of the visually impaired

patients I have examined for the past 30 years have

a diagnosis of age-related macular degeneration. I

have been witness to how the devastating effects

that progression severe vision loss, especially

from the neovascular form of the disease, impact on

an individual's day-to-day activities. I have seen

how severe vision loss affects an individual's

quality of life, impacts on their independence,

lowers their self-esteem, and results in

depression. In fact, clinical studies have shown

208

that over 57 percent of people with retinal disease

have depression.

As a clinician, I am very concerned with

retaining visual function. Neovascular AMD has the

effect of destroying vital components of visual

function. We are all familiar with visual acuity,

as well as the importance of preserving it. But

other vital components of vision are also

irreparably destroyed by the effects of AMD. They

include contrast sensitivity, and in lay terms that

is how much a pattern must vary in contrast to be

seen, and has become increasingly recognized as an

important factor in influencing the quality of

life. We are also interested in retaining usable

visual field, color perception and stereo-acuity,

just to name a few.

The medical advances, as we all know, that

have taken place in the past 30 years have been few

and far between. However, thermal laser as well as

PDT have really helped to slow the progression and

maintain visual function, and one example that I

will give to you as a clinician is that the early

209

patients I was seeing with low vision would go from

20/800 down to light perception. My patients now

usually fall in the end stage between 20/200 and

20/400. Yet, serious vision loss continues despite

these interventions, as we know.

As Carl Augusto mentioned, we seem to have

an impact, however, with vision rehabilitation. As

a low vision clinician, I have seen that

individuals with AMD who have access to the latest

treatments benefit more from vision rehabilitation

services as well. These individuals have a greater

success rate in the use of low vision optical

prescriptive devices, absorptive lenses, as well as

high tech and electronic aids. These people can

continue to be employed, travel independently,

manage their own affairs, maintain their own

residence and perhaps even drive. Again, I

recommend that you consider the treatment that will

help preserve visual function and its benefits to

society.

DR. DUNBAR: Thank you. This concludes

the five members of the public that have registered

210

to speak at the open public hearing. However,

there are some additional members of the public

that have approached us requesting to speak and,

time permitting, they will be allowed to come to

the podium and give two-minute presentations. So,

I will ask if there are any other members of the

general public that wish to come forward at this

time. Thank you. We have someone coming forward.

DR. LISS: I am Bob Liss. I am an

ophthalmologist in practice, retinal diseases, in

Baltimore. I congratulate the sponsors and

certainly hope that this is approved.

I did want to comment that I am concerned

about the problem of endophthalmitis in terms of

the fact that the drug is very broadly applicable

drug that covers all subtypes of choroidal

neovascularization so it will be used much more

widely, and the people using it in the community,

whether they are retinal specialists or

ophthalmologists who are not retinal specialists,

because of the more broad range of the indications,

are selected different than the investigators. The

211

investigators, as much as the sponsors, have wanted

to have a real-world test of the trials. The

investigators are trained extensively and

controlled much better than the outside area. So,

I do think that control of complications,

particularly endophthalmitis, is important.

The second thing is a comment about the

quality of life. There was just a discussion about

contrast sensitivity and visual fields, along with

the early discussion about ERG and I think these

types of things should be included in future

evaluations. Thank you.

DR. DUNBAR: Thank you. Are there any

additional members of the public that wish to come

forward?

[No response]

Committee Discussion

At this point then we will open up for

general discussion among the committee members,

taking into account the presentations we have heard

from the public. Are there any comments at this

time? Dr. Lehmer?

212

DR. LEHMER: I was going to mention

earlier, and I was glad one of the public speakers,

Mr. Rosenthal, mentioned about contrast

sensitivity. A lot of my patients who have the

same level of visual acuity function very

differently on similar behavioral tasks in the

office and when we test their contrast sensitivity

it varies greatly. So, it seems like I would

second the motion of including that as a measure.

DR. DUNBAR: Dr. Chambers?

DR. CHAMBERS: The agency certainly agrees

they would like to be able to use contrast

sensitivity as a measure and certainly believe it

is a measure of visual function. The difficulty

with using contrast sensitivity in an assay is

figuring out which contrast sensitivity is the most

appropriate, and if you find a difference in one

frequency versus a different frequency what does it

mean? If you have any guidance on which

frequencies are more important than other

frequencies, we would love to hear those comments.

DR. DUNBAR: I am interested in the

213

comments about off-label use of the drug. I think

this is insightful because once the drug is

available to doctors--for example, would a doctor

perhaps instill it into the anterior chamber for a

patient with rubeosis? And, this is a conceivable

possibility. Do we know anything about endothelial

cell toxicity? This is a question actually for the

sponsor.

DR. ADAMIS: The question is an important

one. We did not look specifically at endothelial

cell counts. We didn't do any specular microscopy.

All we can report is that over the 54-week period

there did not appear to be an increased incidence

of corneal edema.

DR. DUNBAR: Is there any preclinical data

that might guide us about this question?

DR. ADAMIS: In the preclinical animal

studies there was no finding of corneal edema as a

function of the use, but in the animals as well, to

my knowledge, specular microscopy was not done.

DR. GUYER: Just as far as a comment on

other uses, the sponsor right now is presently

214

looking at other important diseases in trials. We

finished our Phase II program of diabetic macular

edema and actually, hopefully in the fall, we will

be talking with the agency about putting together a

Phase III program. As you mentioned, there are a

lot of conditions in the eye but today, you know,

we are specifically talking about the indication

for age-related macular degeneration.

DR. DUNBAR: As a pediatric

ophthalmologist, I am interested in retinopathy

prematurity. Do you have any comments about its

use in that situation?

DR. ADAMIS: Theoretically it is a drug

that I think may prove useful in retinopathy

prematurity but the data that I showed you is that,

you know, VEGF is required for normal vessel

formation and the conundrum has always been, well,

how can you block the bad vessels and leave the

good vessels alone? But it look like by targeting

165 we may be able to do that. So, that is

something we would consider doing in the context,

obviously at some point in the future, as a

215

clinical trial. We wouldn't recommend off-label

use at this point.

DR. GUYER: Also, in addition to

retinopathy prematurity to look at in the future,

and we mentioned the diabetic program also, we are

also presently in a Phase II program for retinal

vein occlusions and the macular edema that comes

from that. In fact, if we could just go to E-158

for a second, it just lists a couple of the trials,

if anyone is interested.

[Slide]

In addition to the diabetic program, we

presently are studying, as I said, retinal vein and

also we have a small program with Emily Chiu, of

the National Eye Institute, on von Hippel Lindau

tumors because of the increased permeability of

those lesions. We are considering, but have not

started yet, trials for pathological myopia and

histoplasmosis where, again, choroidal

neovascularization is associated; sickle cell

retinopathy; iris neovascularization, as was

earlier mentioned; and proliferative diabetic

216

retinopathy. Those are presently under

consideration.

DR. DUNBAR: Are there additional comments

from the committee at this time, especially

pertaining to the public hearing?

[No response]

Now I would like to shift our emphasis

once again to the general discussion that we began

this morning and see if there are any other

comments in general from the committee before we

move on to the questions. I will poll the

committee members one by one.

Dr. Chinchilli, do you have any additional

comments?

DR. CHINCHILLI: No, I do not.

DR. DUNBAR: Ms. Knudson?

MS. KNUDSON: No, I do not.

DR. DUNBAR: Dr. Steidl?

DR. STEIDL: No, I don't.

DR. DUNBAR: Dr. Pulido?

DR. PULIDO: No, I do not.

DR. DUNBAR: Dr. Lehmer?

217

DR. LEHMER: No, I don't.

DR. DUNBAR: Dr. Gates?

DR. GATES: None.

DR. DUNBAR: I have no additional

comments. Dr. Miller?

DR. MILLER: No.

DR. DUNBAR: And Mr. Kresel?

MR. KRESEL: No, I do not.

Questions

DR. DUNBAR: At this point then let's move

on to a discussion of the individual questions

posed by the FDA. I will read the individual

question and open up the question for general

disease and at the end of the discussion poll each

member.

The first question reads, has sufficient

data been submitted to evaluate the efficacy and

safety profile of pegaptanib sodium? Excuse me, I

was operating from an older list.

Back to question number one, based on the

inclusion/exclusion criteria, are there patients

excluded from the studies that you believe need to

218

be studied? Is there any general discussion about

the inclusion and exclusion criteria? I am going

to go ahead an poll each member. Dr. Chinchilli?

DR. CHINCHILLI: No, I don't have any

comments.

DR. DUNBAR: Ms. Knudson?

MS. KNUDSON: No, I don't have any

additional comments.

DR. DUNBAR: Dr. Steidl?

DR. CHAMBERS: Can I interrupt? Besides

saying you don't have any comments, if you think it

was appropriate--it is at least somebody saying you

think they were appropriate as opposed to just no

comments. Thank you.

DR. DUNBAR: Let's start back again with

Dr. Chinchilli.

DR. CHINCHILLI: Well, I am not that

familiar with ophthalmological clinical trials, but

the criteria seem appropriate to me.

DR. DUNBAR: And Ms. Knudson?

MS. KNUDSON: I think the criteria are

appropriate and in terms of sufficient data, my

219

only concern is what we have expressed before,

long-term use.

DR. DUNBAR: Dr. Steidl?

DR. STEIDL: I don't believe that there

were patients excluded that need to be studied.

DR. DUNBAR: Dr. Pulido?

DR. PULIDO: I agree with Dr. Chinchilli

and the other members so far.

DR. DUNBAR: Dr. Lehmer?

DR. LEHMER: I agree that the criteria

seem appropriate.

DR. DUNBAR: Dr. Gates?

DR. GATES: I am satisfied with the

inclusion/exclusion criteria.

DR. DUNBAR: I concur with the rest of the

committee. Dr. Miller?

DR. MILLER: I concur.

DR. DUNBAR: And Mr. Kresel?

MR. KRESEL: I agree with what the rest of

the committee has said.

DR. DUNBAR: We will move to question

number two, visual acuity measurements were

220

conducted using the ETDRS scale placed at 2 meters

from the patient. The validity of the ETDRS scale

was established based on readings at 4 meters. Are

the visual acuity findings sufficiently robust to

overcome the potential bias introduced by visual

acuity measurements at 2 meters? Dr. Chinchilli?

DR. CHINCHILLI: We haven't discussed this

although it was mentioned by the agency. You know,

the fact that there is a control group, the sham

group, and that you still see differences is

encouraging. The question is whether or not there

is some sort of interaction. I mean, would the

sham group not have a bias when it is done from 2

meters whereas the dosed groups would? You know, I

don't know if there is any logical explanation for

something hypothetical like that happening. It

doesn't seem like a major issue but I would like to

hear the ophthalmologists talk about this issue.

DR. DUNBAR: Then I will open this up for

general discussion before polling each individual

committee member. Dr. Lehmer?

DR. LEHMER: I was just going to say I

221

wanted to hear what the statisticians had to say

because when we are talking about robustness of

data, you know, I wouldn't know where to draw the

line on are these numbers robust enough to overcome

that difference. But I hear what you are saying,

that this is a comparison between groups that were

tested under the same conditions so my assumption

would be that the relative difference would still

hold up whether it is 2 meters or 4 meters.

DR. DUNBAR: Dr. Chambers?

DR. CHAMBERS: I will just clarify a

little bit. There are some differences in other

areas such as adverse events which might lead

someone to recognize which group they were in even

if they were not able to tell from the actual

procedures, such as some of the floaters, such as

some of the other many adverse reactions which may

lead them to, either appropriately or

inappropriately, believe they were in a group. The

concern is that there may be potential unmasking

because of some of the adverse events that then may

lead to differences, and the issue that there is

222

more variability with measurements at 2 meters

versus 4 meters, although we don't have good

quantitation on what that is.

DR. DUNBAR: Dr. Pulido?

DR. PULIDO: So, Dr. Chambers, is this a

possible way of getting around this problem? I

feel the data is good enough right now at 2 meters.

Because there is a concern, could future studies be

requested to be at 4 meters from the start for the

small chance that there may be a problem?

DR. CHAMBERS: It is the agency's

recommendation that they be at 4 meters to avoid

the issue even coming up. Were we talking about a

single letter we probably wouldn't be asking this

question either. We would say, well, that is

definitely within what the variation is. You may

choose to believe, well, it takes 16 meters before

you even get one line; this is a three-line change

so we think there is enough robustness in the

findings and robustness in differences in visual

acuities that, while we would have not like to have

had it, it is still okay. Or, you may say there

223

just is no way to go and tell and the agency needs

to deal with it as best they can.

DR. DUNBAR: Dr. Pulido?

DR. PULIDO: Though it would have been

nice if it had been done at 4 meters, there appears

to be enough robustness of the data that I accept

it at 2 meters. Is that a good paraphrase of the

way you had said it?

DR. CHAMBERS: I did not want to put words

in anyone's mouth. I was trying to put out

examples of the type of information we are looking

for in comments.

DR. PULIDO: That would have been the way

I would have said it without you having said it.

[Laughter]

DR. DUNBAR: I have a question for the

agency. Was this an agreed upon aspect of the

protocol prior to commencing the clinical trials,

or was this a point that came up in the analysis

later on?

DR. CHAMBERS: The agency, having had the

ETDRS done under an IND, is fully aware of how the

224

protocols were written for ETDRS and has always

assumed that if someone wrote ETDRS that they meant

that they would do visual acuities at 4 meters. We

have come to find out since that time that that is

not the interpretation necessarily in the whole

community and so there were clinical trials that

were started using the charts but moving them to

different distances and people continued to call it

ETDRS even though it does not meet the technical

protocol of ETDRS. In this particular case we were

aware of the difference after the trials had

started. To the extent we were aware of them

before the trial start, to the extent that we were

aware of them during the trials, we have made those

comments but in some cases we are aware that there

were trials that started before we were able to

comment on it. Then you would be caught with the

equal question of do you change the protocol in

midstream or do you run the protocol the way it was

started, even if you would have preferred to do it

a different way?

I will let the sponsor comment on their

225

own but it is my understanding the choice--and we

do fully understand it--is to continue the

protocol, at the point that you recognize there is

a difference, the way it was written so that you

don't raise further questions about, okay, you have

changed the protocol. What would have happened had

you not changed the protocol? So, we are left with

the data that we have. We obviously don't

encourage it in the future but this is what we

have.

DR. DUNBAR: I have a question for the

sponsor. Was every center done at 2 meters? Were

they all uniform throughout the protocols?

DR. GUYER: Could I have slide 14 up,

please?

[Slide]

First, yes, they were all standardized. I

think Dr. Chambers summarized very nicely in the

morning the difficulties with 2 meters versus 4

meters. When we started the trial our thought

process was, first, that historically other trials

were done at 2 meters, most of the other trials

226

were for this condition. Part of the reason was

that in order to be able to read all of the letters

on the chart, some patients would not be able to do

that at 4 meters. So, our thought was we could get

more patients to see at the baseline visions and at

week 54 on the chart and not have to move up to 1

meter.

But certainly the FDA has presented very,

very good information why 4 meters should be

considered as well. There is no perfect testing

distance. I think Dr. Chambers also, on his slide,

said it very well, that the key factor is if

masking is good and if you have some kind of rigid

way of making sure that the patient didn't lean or

move, then 2 meters is certainly a good testing

parameter. The real potential biases at 2 meters

have to do with two things. One is accommodation

which, obviously, in this population because of

presbyopia is not an issue. The second is the

leaning that Dr. Chambers mentioned.

Now, we have randomization which certainly

helps. So, we would hope that good randomization

227

and masking should be equal between sides. But we

also have some very important quality control

information.

[Slide]

We had very vigorous training and

monitoring of the visual acuity examiners before

the trial and during the trial. In fact, we had

over 450 audits performed in all of the centers

throughout the world. And, one of the questions

that was looked at was, was proper patient

positioning, such as leaning, prevented by the

acuity examiners? You can see that in these 469

audits, 98.3 percent of the examiners did use

proper patient positioning, which comforts us that

at least based upon this quality control we don't

believe that the patients were leaning forward.

We also have good evidence of proper

masking. All groups, the active groups as well as

the shams, all got 8.5 of the 9 injections. So,

that suggests that masking was good. Similarly for

discontinuation rates and reasons, which you can

see in the FDA briefing book.

228

[Slide]

Actually, when we did a trial for macular

degeneration a number of years ago we devised this

measuring stick which also must be used at every

examination. Here you can see a visual acuity

examiner to actually remind the visual acuity

examiner always to be sure that the patient is at

the right distance and that the patient doesn't

lean forward. This, I think combined with the

quality control, helps us.

Also, in Dr. Chambers' questions about

masking and floaters, which is a very good

question, we actually have looked to try to give us

some comfort that there was no difference in the

responder rate of patients who had floaters and

didn't have floaters.

[Slide]

This shows that whether the patients had

floaters or didn't have floaters we see an active

treatment effect for both. So, we tried to look at

the data from as many possibilities of potential

unmasking and did not see anything. So, we have

229

some comfort I think by the quality control and by

the good masking in the trial that 2 meters was

probably not an issue. But we certainly share with

the agency that in future trials 4 meters are

preferred. We wish more study centers, as Dr.

Chambers mentioned, had 4-meter testing which has

also been part of our thought process, that it is

difficult to get 117 centers with rooms that big.

But we are working in other trials to do 4-meter

testing after these discussions.

DR. DUNBAR: Thank you. Are there any

other general comments for discussion before

individual polling of the committee members? If

not, I will ask each committee member to answer the

question are the visual acuity findings

sufficiently robust to overcome the potential bias

introduced by visual acuity measurements at 2

meters? Dr. Chinchilli?

DR. CHINCHILLI: Yes, I believe the data

are reliable even though the measurements were

taken at 2 meters. I was comforted by some of

these quality control issues that the sponsor

230

addressed and was prepared to address.

DR. DUNBAR: Ms. Knudson?

MS. KNUDSON: I will echo what Dr.

Chinchilli said.

DR. DUNBAR: Dr. Steidl?

DR. STEIDL: Yes, given the significance,

the audits presented and randomization, I am

comfortable with them.

DR. DUNBAR: Dr. Pulido?

DR. PULIDO: I am comfortable with the

robustness of the data.

DR. DUNBAR: Dr. Lehmer?

DR. LEHMER: I am comfortable with the

robustness of the data.

DR. DUNBAR: Dr. Gates?

DR. GATES: I am also satisfied. In

examining patients on a day-in and day-out basis I

always ask them to lean forward for these different

tasks, and with this randomization not picking on

any particular segment of the patient population, I

know some will and some won't even if they are

physically able or not able. So, with this

231

randomization I am very satisfied with the

robustness.

DR. DUNBAR: I concur with the other

comments to this point. Dr. Miller?

DR. MILLER: Based on what Dr. Chambers

and also the sponsor has had to say, I concur.

DR. DUNBAR: And Mr. Kresel?

MR. KRESEL: I agree with the rest of the

committee.

DR. DUNBAR: We move to question number

three, has sufficient data been submitted to

evaluate the efficacy and safety profile of

pegaptanib sodium for the treatment of the

neovascular form of AMD? If not, what additional

data are needed? I would like to open this for

general comments and discussion.

[No response]

Then I will begin by polling Dr.

Chinchilli.

DR. CHINCHILLI: You have to start over

there next time--I am kidding! Well, based on the

discussions we had this morning, it sounded to me

232

as if some of the committee members want to see

more data on long-term safety and use and

continuation, you know, how long is it necessary to

continue. I mean, I have no idea how long of a

period of time we need to have data to assess

long-term efficacy and safety. So, I am not going

to make a judgment on that but it seemed like it

was a concern to many of the committee members.

DR. DUNBAR: I will ask you to address

each part of the question, the first being has

sufficient data been submitted to evaluate efficacy

and safety profile?

DR. CHINCHILLI: Yes, I sort of glossed

over that. Yes, I believe it has.

DR. DUNBAR: You mentioned the additional

data part as well. Any further comments on that?

DR. CHINCHILLI: No, I don't have anything

else.

DR. DUNBAR: Ms. Knudson?

MS. KNUDSON: I think from what I have

read and heard that sufficient data is available,

and additional data I would like to see is how long

233

would a patient need to use this; how much safety

is there after several years of use. Those are my

concerns.

DR. DUNBAR: Dr. Steidl?

DR. STEIDL: Well, there is a lot of

additional data I would like to see but I don't

think that additional data is required ultimately.

DR. DUNBAR: Dr. Pulido?

DR. PULIDO: Yes, I believe that

sufficient data has been submitted to evaluate the

efficacy and safety profile, and it appears to me

very efficacious and safe. I do believe that

postmarketing surveillance for ERG, visual field

and subsequent vision would be worthwhile in a

subgroup of patients.

DR. DUNBAR: Dr. Lehmer?

DR. LEHMER: I feel that there is

sufficient data to show the efficacy and safety

within the parameters of the study, and would echo

the comments of Dr. Pulido.

DR. DUNBAR: Dr. Gates?

DR. GATES: I also believe sufficient data

234

has been submitted for efficacy and safety.

DR. DUNBAR: I concur with the comments of

the rest of the committee about sufficient data for

efficacy and safety, and I concur with Ms. Knudson

that some type of postmarketing surveillance for

long-term efficacy be continued. Dr. Miller?

DR. MILLER: I concur with regard to the

data for efficacy and safety, however, I am really

concerned, as you have also mentioned, with regard

to how long a patient should be taking this

particular medication.

DR. DUNBAR: Mr. Kresel?

MR. KRESEL: I think sufficient data has

been submitted to evaluate efficacy and safety for

one year, and I will leave it to my ophthalmology

colleagues to determine if longer-term data is

needed.

DR. DUNBAR: Question number four reads,

are additional analyses of the current data needed

to understand the efficacy or safety of pegaptanib

sodium for the treatment of the neovascular form of

AMD? Dr. Chinchilli?

235

DR. CHINCHILLI: I mentioned this, this

morning, about the time to treatment failure. I

don't think it is going to have an impact on this

particular situation here but, you know, it would

be interesting to see Kaplan-Meier survival curves.

I think there was one point where the sponsor had

flashed a slide up there and then took it off

because they were addressing some other issue with

that question. But I think the agency in

particular should consider this for future studies

for future sponsors. I mean, the disease is one

that is progressive so you are going to reach the

point where it has progressed to the point of

concern which, everybody has been telling me, is

greater or equal to 15-letter loss from baseline.

So, I think it should be analyzed in that

manner. As I said, I don't think it is going to

affect this particular situation with this

particular drug. So, I don't see the need for

additional analyses now but I think the analyses I

am proposing would be more accurate and not rely so

much on data imputation.

236

DR. DUNBAR: I wonder if this can be the

answer to our question about how long the drug

should be taken. It seems like this type of

analysis might answer that question. DR.

CHINCHILLI: That is possible, yes.

DR. DUNBAR: Dr. Pulido?

DR. PULIDO: Point of clarification, there

is a question on board by Dr. Chinchilli. I don't

think it is going to make a difference. I don't

think it is going to change what we have found but

since the question is out there to either the FDA

or to the sponsor, do they have the answer to it?

DR. DUNBAR: Will you repeat the question?

DR. CHINCHILLI: Do you have the

Kaplan-Meier survival curves?

DR. CHAMBERS: We have not chosen to ask

for it because we have information, not on this

drug but on other drugs, that time-to-event is not

indicative of what you see at year one and at year

two. So, we have not pushed for this type of

analysis. In fact, we believe that what you see at

month three and month six is frequently in the

237

wrong direction for what you see at one year and,

consequently, have not asked for the time-to-event

analysis because we see them reverse.

DR. CHINCHILLI: But you can use the

Kaplan-Meier survival curve to get a more accurate

indication of what is happening at one year. I

agree if you think three months and six months is

too early, but you can use the curve, the survival

curve to get a better estimate of what is happening

at one year because it accounts for all the

censoring, the dropouts and the terminations that

occur.

DR. CHAMBERS: You are right, if we don't

take people out as a single event and allow them to

either come in or come back out as they go through

that endpoint, I absolutely agree. I am just going

through the reason why we have not in the past used

that because we did not want an answer that

happened to be less--we didn't know exactly where

the point is that is potentially confusing. We

know three and six is not. We have not known about

nine months. In some cases with some drugs it

238

hasn't made a difference. With this particular

drug you don't see reversals. So, what you learn

early on does appear to be continuing later on.

That is just not true of every particular product

so we have not known ahead of time when to use it

and when not to. But I absolutely understand what

you are talking about. We just have not looked at

those particular analyses and I don't know if the

sponsor has or has not.

DR. GUYER: We have. Would you like us to

show it?

DR. CHAMBERS: By all means.

[Slide]

DR. GUYER: This is the Kaplan-Meier

estimate of the first observed loss of 15 letters

of vision with ITT and, again, it is consistent

with the other endpoints we showed you earlier

today, that the active treatment groups at all of

these data points with time show a treatment effect

compared to the sham.

DR. DUNBAR: Dr. Pulido, do you have any