DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
DERMATOLOGIC AND OPHTHALMIC DRUGS
Friday, August 27, 2004
5630 Fishers Lane
Rockville, Maryland 20852
Jennifer A. Dunbar, M.D., Acting Chair
Kimberly Littleton Topper, M.S.
Paula L. Knudson
William Gates, M.D.
Scott M. Steidl, M.D.
Jeffrey Lehmer, M.D.
Vernon Chinchilli, Ph.D.
CENTER FOR DEVICES AND RADIOLOGICAL HEALTH
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.
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
Bob Liss, OD 210
Committee Discussion 211
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
DR. GATES: I am William Gates, from
DR. LEHMER: I am Jeffrey Lehmer, from
DR. PULIDO: Jose Pulido, Rochester,
DR. STEIDL: Scott Steidl. I am a retina
specialist from the University of Maryland, in
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,
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
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
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
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
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.
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.
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
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.
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
I am going to spend some time today going
through basic clinical trial design issues for
products for macular degeneration in general.
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
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
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
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.
We ask for replication. So, we want
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,
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.
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
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
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.
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.
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.
Control agent--we have asked that at least
one of the clinical trials that is performed
demonstrates superiority to a control. We have not
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.
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
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
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
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
We expect best corrected visual acuity to
be measured at every visit, and we expect those
occur no less frequently than every three
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.
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
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
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
equivalence trials. But there are
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.
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
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
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
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
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
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.
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.
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
particular case. But as a general rule
do ask for pediatric patients to be included during
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
DR. DYER: Good morning.
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
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.
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
Neovascular age-related macular
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.
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
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
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
normal rods and cones in the retina. At this
point, usually moderate to severe visual loss is
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.
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 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
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.
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
I will now ask Tony Adamis to discuss a
VEGF overview and macular degeneration
VEGF Overview and Macular Degeneration
ADAMIS: Thank you, David and good
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.
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
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
biological functions of this protein.
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.
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
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
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
in neovascular MD would have a
broad-base effect has some broad biological
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
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
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.
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
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
during development throughout the body.
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.
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
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
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?
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
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
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.
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
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
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.
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.
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
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.
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.
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
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.
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.
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
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
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
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.
At this point, Dr. David Guyer will return
will talk to you about our clinical
efficacy data from the pivotal trials.
Pegaptanib Clinical Efficacy
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.
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.
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
single or multiple dosing trials with,
or without PDT, for the total exposed of 1,281.
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
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
The development of these pivotal studies
was done in conjunction with our expert advisory
panel, whose names are listed on this slide.
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.
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
These were the members of the IDMC. It
was chaired by Prof. Alan Bird, who is here with us
Because of the biology of neovascular
macular degeneration and the mechanism of action of
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.
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
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
Stratification at randomization included
study center, a history of prior PDT use and
Our primary efficacy endpoint, which was
prespecified, was the percent of patients losing
less than 15 letters from baseline to week 54, the
that was used for marketing approval
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
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.
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
angiography was done at baseline and
weeks 30 and 54.
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.
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.
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.
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
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.
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
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.
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.
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
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
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
vision, and the difference at 54 weeks
was approximately 50 percent in favor of the active
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.
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
At week 54, again, there was a low nominal
p value for the 0.3 mg and 1 mg group compared to
progression to severe vision loss which
is 30 letters or 6 lines.
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.
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.
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
baseline. Yellow is the 0.3 mg group
and blue is the sham.
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.
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.
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
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
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.
I would like to now turn to the
exploratory or subgroup analyses.
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
Despite a reduced ability to draw
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
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.
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,
classic and occult, as seen here; also,
initial baseline visual acuity, size of the lesion,
race and pigmentation of the iris.
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
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.
Let's now turn to the individual trials.
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.
For trial 1003, with the 0.3 mg dose we
can see the same thing.
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.
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.
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
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.
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
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.
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
The 0.3 mg dose represents the lowest
studied efficacious dose and it met its primary
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.
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
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
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.
Again, we can show that leak size over
time was less for treated groups than for shams.
The p values here are noted.
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.
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
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.
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
pattern and we found that 92 percent of
the time the reading center agreed with the
appropriate use of PDT in this trial.
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.
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.
Baseline PDT is the second scenario, and
the baseline PDT use was again very similar among
groups. We can see here that for the
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.
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
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?
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.
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?
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.
The third important question, which will
be addressed in detail in Tony's safety section, is
was there evidence of any adverse events
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.
In summary, pegaptanib met a clinically
meaningful primary efficacy endpoint with
statistical significance in replicate, independent,
well-controlled clinical trials.
I will now ask Tony to come up and discuss
our clinical safety database.
Pegaptanib Clinical Safety
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
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.
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.
Looking at the death rate just a little
more closely, we can see that there is no evidence
here of a dose response.
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
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 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
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
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
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.
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.
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.
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
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.
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
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.
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
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.
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.
Anterior chamber inflammation was another
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
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.
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
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
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
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
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
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.
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
Let me just tell you anecdotally what
happened. It was a protocol violation. It turns
out this patient had an active lachrymal sac
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
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.
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.
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
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
In the first half of this trial when we
saw the case reports of endophthalmitis we convened
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
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.
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.
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
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
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.
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
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
alterations in the normal retinal or
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.
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.
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
and the sham arms. Non-ocular serious
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.
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.
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
profile for pegaptanib.
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.
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
of their competitors.
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
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
even present in trying to read large
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.
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.
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.
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
20/200 or worse as blind and 20/40 or
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.
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
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
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
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
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.
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.
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
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.
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
VEGF medication? Thirdly, were there any
mechanical side effects or complications from the
intravitreal injection procedure itself?
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.
in these 22 serious ocular events, we
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
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
enrolled in the pegaptanib group that
risk was reduced to 9.5 percent per year.
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.
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.
we have seen, in this slide baseline
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
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
vision loss with pegaptanib.
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.
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.
The positive results in this trial
indicate the beginning, and not the limit, of
pharmacotherapy for AMD. I agree
sponsor's recommendations that the benefits of
pegaptanib therapy for AMD strongly outweigh the
risks. Thank you.
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.
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
they often will get it in the second
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--
--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
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.
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
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
that VEGF and VEGF 165 is specifically a
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
story to date. Whether the effect is
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
functions that can occur in the eye. So,
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
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.
ADAMIS: It is a fair question. The
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.
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
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
important question was do people need to be
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
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.
There is one possible explanation that we
have looked at. This shows the mean change in
time for each individual trial. On the
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
throughout the trials. Because of safety
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
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
types of trials to detect in a very
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
when your animal data indicated no
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.
MS. KNUDSON: Did you pay for them?
DR. ADAMIS: I don't know. I will find
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
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
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
every secondary visual angiographic
endpoint that we saw. So, that gives us great
confidence in our endpoint. Slide number Q-2,
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.
We can see some of these differences. It
to mention that a 5 or more difference
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.
DR. DUNBAR: We will begin the agency
presentation by Dr. Jennifer Harris.
DR. HARRIS: Good morning.
I am Dr. Harris and I was the primary
medical reviewer for Macugen.
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
that we are going to pose to the advisory committee
and, of course, you will see them again after
Again, there were two Phase III studies,
1003 which was an international study, and 1004
that was done predominantly in North America.
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
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
data is probably sometime soon I think, this month
or next month. This is not the data you will see
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
The primary efficacy endpoint, again, was
a proportion of patients who lost less than 15
visual acuity from baseline at 54 weeks.
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
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
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.
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
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 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
AMD were represented.
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
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
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.
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
significant with a 75 percent
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.
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
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
those patients in the sham group appeared
to lose vision at a faster rate than those in the
Macugen treatment group.
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.
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.
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
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.
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.
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
were we just really seeing the effect of
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,
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.
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
was an international study and you can
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.
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.
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.
Lastly, we wanted to look at the results
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
What we noted, which was good, is that the
majority of the patients who entered the trial
never had any
confounding or problems with
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.
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
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
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
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
meaningful increase in vision seen in
patients during the first year of using Macugen.
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
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.
In the database we had there were 16 cases
endophthalmitis. What we heard this
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.
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.
The original procedure called for the
patients to get 2-3 drops of 50 percent saline
percent povidone-iodine or they could
receive 1 drop of topical antibiotic.
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.
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
endophthalmitis 3 months after the protocol was
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
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?
all the things that we came up with--
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
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
things like cardiovascular events,
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.
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
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
exclusion criteria, are there
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
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
concerns with using this predictive
concomitantly with PDT?
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
that should be in place for patients on
pegaptanib sodium therapy? Thank you.
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.
PULIDO: The other question I had, and
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
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
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
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
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
that still need to be reviewed, but if
this product otherwise looks fine we would
potentially label it based on the information we
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
mentioned, we do have the answer from
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
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
ADAMIS: It is an area that we are
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
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
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
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
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
organisms that have just not been
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
DR. D'AMICO: Well, it is a new
phenomenon. Certainly, these
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,
speculation, as Dr. D'Amico said, but it is a
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
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
and include it in the briefing document
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
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?
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
DR. DUNBAR: Then we will start with Dr.
Chinchilli in terms of general discussion from the
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
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
three months, we have not thought as being
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
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
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?
LEHMER: I just want to make sure I
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
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.
This shows the definition of the various
populations that we looked at, and it shows that
the all-randomized group were those that received
randomization number. In this case it
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.
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
percent of the data, at least for the 0.3
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
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
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
in the treated group. With the
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
DR. ADAMIS: Yes, I think your
interpretation of the data is correct and,
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
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
looked at in the future--the PDT impact.
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
combination use or anything like that,
but I agree with you that certainly future trials
will be able to address those issues and it is
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
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
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
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
tremendous learning curve for retinal
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
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
antibiotic levels within the eye, and also
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
modifications now to make this safer and
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
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
triamcinolone and the incidence which has
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
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
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
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
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
realize this is an incomplete data set
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
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
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.
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.
DUNBAR: Mr. Kresel?
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
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
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
necessarily about delaying it, but I guess
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
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
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
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
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
these elderly patients. To continue
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
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
adjourned for lunch, to resume at 1:00 p.m.]
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
lodging, or other expenses in
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
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
screening, training, advocating,
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
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
population. It is very important that
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
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.
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
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.
DUNBAR: Thank you. Next I will ask
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
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
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
they have the problem of not recognizing
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
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
taken to try to avert the further
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
general public on how we can improve the
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
yourself--this is what is happening with
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
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
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
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
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.
DR. DUNBAR: Thank you. Now I want to
request that speaker number five come to the
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
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
that over 57 percent of people with retinal disease
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
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
DR. DUNBAR: Thank you. This concludes
members of the public that have registered
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,
different than the investigators. The
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
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?
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.
DUNBAR: I am interested in the
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
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
the sponsor right now is presently
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,
some point in the future, as a
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.
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
mentioned; and proliferative diabetic
retinopathy. Those are presently under
DR. DUNBAR: Are there additional comments
from the committee at this time, especially
pertaining to the public hearing?
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
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.
DUNBAR: Dr. Lehmer?
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.
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
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
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
DR. DUNBAR: Ms. Knudson?
MS. KNUDSON: No, I don't have any
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: 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
and in terms of sufficient data, my
only concern is what we have expressed before,
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
DR. DUNBAR: Dr. Gates?
DR. GATES: I am satisfied with the
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
visual acuity measurements were
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?
LEHMER: I was just going to say I
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
differences, and the issue that there is
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
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.
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
DR. CHAMBERS: The agency, having had the
under an IND, is fully aware of how the
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?
will let the sponsor comment on their
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
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,
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
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
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
and masking should be equal between sides. But we
also have some very important quality control
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.
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.
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
did not see anything. So, we have
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
control issues that the sponsor
addressed and was prepared to address.
DR. DUNBAR: Ms. Knudson?
MS. KNUDSON: I will echo what Dr.
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
able or not able. So, with this
randomization I am very satisfied with the
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
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