1

                    DEPARTMENT OF HEALTH AND HUMAN SERVICES

                          FOOD AND DRUG ADMINISTRATION

                    CENTER FOR DRUG EVALUATION AND RESEARCH

                       DERMATOLOGIC AND OPHTHALMIC DRUGS

                               ADVISORY COMMITTEE

                            Friday, August 27, 2004

                                   8:00 a.m.

                               5630 Fishers Lane

                                   Room 1056

                           Rockville, Maryland 20852 

                                                                     2

                                  PARTICIPANTS

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

             Kimberly Littleton Topper, M.S.

             MEMBERS:

             Paula L. Knudson

             William Gates, M.D.

             CONSULTANTS (VOTING):

             Scott M. Steidl, M.D.

             Jeffrey Lehmer, M.D.

             Vernon Chinchilli, Ph.D.

             CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

          OPHTHALMIC

             DEVICES PANEL MEMBER (VOTING):

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

             PATIENT REPRESENTATIVE (VOTING):

             Elaine King Miller, Ph.D.

             INDUSTRY REPRESENTATIVE (NON-VOTING):

             Peter A. Kresel, M.B.A.

             FDA STAFF:

             Jonca Bull, M.D.

             Wiley A. Chambers, M.D.

             Jennifer D. Harris, M.D. 

                                                                     3

                                C O N T E N T S

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

          Conflict of Interest Statement,

             Kimberly Littleton Topper, M.S.                         5

          Introduction, Wiley Cambers, M.D.                          7

          Eyetech Pharmaceuticals Presentation:

             Introduction, David Guyer, M.D.                        30

             VEGF Overview and Macular Degeneration

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

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

             Pegaptanib Clinical Safety,

               Anthony P. Adamis, M.D.                              79

             Pegaptanib Benefit/Risk Profile,

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

          Committee Discussion                                     114

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

          Committee Discussion                                     153

          Open Public Hearing:

             Daniel D. Garrett, Prevent Blindness America          192

             Ellen Hofstadter                                      196

             Nikolai Stevenson, Association for

               Macular Diseases                                    198

             Carl R. Augusto, American Foundation for

               the Blind                                           201

             Bruce P. Rosenthal, OD, FAAO Lighthouse

               International                                       207

             Bob Liss, OD                                          210

          Committee Discussion                                     211

          Questions                                                217 

                                                                     4

                             P R O C E E D I N G S

                                 Call to Order

                    DR. DUNBAR:  I would like to call the

          Dermatologic and Ophthalmic Drugs Advisory

          Committee meeting to order to review NDA 21-756,

          for Macugen, and I would like the committee members

          to introduce themselves.  I am Jennifer Dunbar,

          from Loma Linda, California, and I would like the

          committee members, starting on my left, to

          introduce themselves.

                    DR. GATES:  I am William Gates, from

          Nashville, Tennessee.

                    DR. LEHMER:  I am Jeffrey Lehmer, from

          Bakersfield, California.

                    DR. PULIDO:  Jose Pulido, Rochester,

          Minnesota.

                    DR. STEIDL:  Scott Steidl.  I am a retina

          specialist from the University of Maryland, in

          Baltimore.

                    MS. KNUDSON:  Paula Knudson, with the

          Texas Health Science Center, in Houston.

                    DR. CHINCHILLI:  Vern Chinchilli, Penn 

                                                                     5

          State Hershey Medical Center.

                    DR. BULL:  Good morning, Jonca Bill,

          Director of the Office of Drug Evaluation V, in the

          Office of New Drugs here, at FDA.

                    DR. CHAMBERS:  Wiley Chambers, Deputy

          Director for the Division of Anti-Inflammatory,

          Analgesic and Ophthalmic Drug Products.

                    DR. HARRIS:  Jennifer Harris, medical

          Officer, same division.

                    MR. KRESEL:  Peter Kresel.  I am the

          industry representative, Irvine, California.

                    MS. TOPPER:  Kimberly Topper, FDA, the

          Executive Secretary for the committee.

                    DR. MILLER:  Elaine King Miller, Amarillo,

          Texas.

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

          read the conflict of interest statement.

                         Conflict of Interest Statement

                    MS. TOPPER:  The following announcement

          addresses the issue of conflict of interest with

          regard to this meeting and is made a part of the

          record to preclude even the appearance of such at 

                                                                     6

          this meeting.  Based on the submitted agenda for

          the meeting and all financial interests reported by

          the committee participants, it has been determined

          that all interests in firms regulated by the Center

          for Drug Evaluation and Research present no

          potential for an appearance of conflict of interest

          at this meeting with the following exceptions:

                    Dr. Jennifer Dunbar has been grated a

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

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

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

          and $50,000.

                    Dr. Jose Pulido has been grated a waiver

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

          of stock in the sponsor.  The stock is valued from

          $5,001 to $25,000.

                    A copy of the waiver statements may be

          obtained by submitting a written request to the

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

          of the Parklawn Building.

                    In the event that the discussions involve

          any other products or firms not already on the 

                                                                     7

          agenda for which an FDA participant has a financial

          interest, the participants are aware of the need to

          exclude themselves from such involvement and their

          exclusion will be noted for the record.

                    We would also like to note that Dr. Peter

          Kresel has been invited to participate as a

          non-voting industry representative.  Dr. Kresel is

          employed by Allergan.

                    With respect to all other participants, we

          ask in the interest of fairness that they address

          any current or previous financial involvement with

          any firm whose products they may wish to comment

          upon.  Thank you.

                    DR. DUNBAR:  Now we will ask Dr. Chambers

          to give an introduction of the issues that we will

          review today.

                                  Introduction

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

          me start with welcoming everybody.  Good morning.

          I want to particularly welcome the advisory

          committee members, and the time that they have

          taken both to review the material and to both 

                                                                     8

          travel and attend today.

                    [Slide]

                    We are here today to discuss Macugen, and

          this is the Dermatology and Ophthalmology Advisory

          Committee meeting.  Those of you who think you

          should be some place else, we would welcome the

          open seats if you want to give them up.

                    My name is Wiley Chambers.  I am the

          Deputy Director for the Division of

          Anti-Inflammatory, Analgesic and Ophthalmologic

          Drug Products, and it is our Division within the

          Office of Drug Evaluation V that will be reviewing

          this application today.

                    [Slide]

                    This application, unlike many others--or

          at least the section that we will be reviewing

          today, unlike many others, is part of the

          continuous marketing application Pilot 1 NDA

          submission which was part of PDUFA 3, which is the

          Prescription Drug User Fee Act that was enacted

          into law in 2002.  This allowed for the

          presubmission of individual modules in different 

                                                                     9

          sections that would then be reviewed, and comments

          given back.  This would not be a final action but

          it would be comments on a particular section, with

          the goal of speeding ultimate approval of

          particular applications by being able to give

          interactive comments early on.  The action on the

          actual NDA will only be taken after all the modules

          are submitted and reviewed.

                    [Slide]

                    Today's discussion is clinical only.  We

          are only dealing with the clinical section. We are

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

          not dealing with the chemistry manufacturing

          section.  So, no one should expect that we will

          take an action on this NDA today, tomorrow or the

          next day because there are other modules which are

          being reviewed in their own time course.

                    The expectation is that we will give

          comments back to the sponsor of the application

          within approximately six months of the time when

          the module was submitted, and so we have scheduled

          this meeting to deal with the clinical issues and 

                                                                    10

          our clinical feedback.  As you will hear later on,

          we have particular questions that are geared toward

          this application, but we are looking primarily to

          see have we missed anything; are there other areas,

          while we are still within the review period, that

          we should be looking at further, or are there

          issues that you think need to be further explored

          before an application would be acted on one way or

          the other?

                    [Slide]

                    I am going to spend some time today going

          through basic clinical trial design issues for

          products for macular degeneration in general.

                    [Slide]

                    The Division gives guidance as trials are

          performed on a way to do a particular trial.  We

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

          clinical trials.  We have tried to give what we

          think is a good way to do trials that will give

          answers that we can then interpret.  We clearly

          recognize that there may be additional ways and

          there may be reasons to have variance from what we 

                                                                    11

          recommend.  But just so that everybody is in the

          same page, I am going to go through what we

          generally recommend to sponsors of trials so you

          know where there are potential differences, which

          you may either agree with or disagree with, but

          more for informational purposes.

                    We ask that trials be parallel on design

          trials; randomized by person as opposed to

          randomized by eye; double-masked, meaning at least

          the investigator and the patient are masked to what

          treatment they are receiving; and to try to

          incorporate dose ranging within the study

          development plan.  That does not mean every trial

          but it means that there be an exploration to dose

          ranging.

                    [Slide]

                    The inclusion criteria for at least wet

          macular degeneration, using that term as broad as

          that is, is that we expect patients to have

          choroidal neovascularization documented by fundus

          photography and/or angiography.  We expect there to

          be specific observable features, including 

                                                                    12

          membranes greater than a particular defined size

          and with particular diagnostic features such as

          leaking on fluorescein, such as leaking on

          indocyanine green or ICG, but define a particular

          population for which we could then label the

          product.

                    [Slide]

                    We try to get the trials in total to be as

          general as possible while still identifying a

          population that the product works for.  Patients

          with concurrent ocular diseases that may be

          associated with choroidal neovascularization we

          think should be excluded to avoid any kind of

          confounding issues.  In this particular case that

          generally means excluding people with presumed

          ocular histoplasmosis and excluding high myopia,

          primarily because these things can also cause

          choroidal neovascularization and we want to try and

          figure out which disease the product is working on.

                    [Slide]

                    We ask for replication.  So, we want

          safety and efficacy, supported by at least two 

                                                                    13

          independent trials of at least two years duration.

          We are looking for robustness in the findings.  We

          want independent trials, and to that extent we mean

          geographically separate so that we know the product

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

          just work in Boston or one particular city where

          the water supply is unique.  These trials conducted

          to date were each multicenter trials and so,

          obviously, clearly meet that criteria.

                    Actually, before I go on let me say one

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

          trials to go on for two years and we have had

          discussions at this advisory committee before about

          how long trials should go on for.  We have

          recognized that endpoints may be acceptable at a

          one-year time point but we have asked that trials

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

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

          trial will continue to go on for two years and we

          will ultimately have that information which we will

          factor into our decision.  But we believe that,

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

                                                                    14

          significant portion in the rest of their lives.

          Consequently, if the product is showing benefit at

          one year we believe we could potentially approve a

          product and label it as working for however long it

          works for, but we think that duration needs to be

          at least one year, but have not been wedded to

          anything more than that.  If you end up disagreeing

          with that, as with anything that I say today,

          please feel free to make those comments to us.

                    [Slide]

                    The clinical trial program we think should

          be able to identify adverse events that occur at

          least at a one percent adverse reaction rate.

          People may argue that one percent is too low, too

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

          have picked.  That means you need at least 300

          patients studied fully through that to be able to

          determine that.  We generally recommend at least

          500 patients so that we are not dealing with,

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

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

          natural age and normal life span, people are not 

                                                                    15

          going to necessarily survive through the

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

          other reasons.  So, we start out asking for people

          to do trials of 500 patients or more.

                    We like the concentration to be studied

          that is going to be marketed, we like

          concentrations that are above what is going to be

          marketed to be studied to try and exaggerate

          potential adverse events so that we can get a

          handle of potential adverse events that may occur,

          even if they are not going to occur on the final

          product that is approved, so that we have some idea

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

          frequency of dosing to be at least as frequent as

          proposed for marketing.  You will see in the trials

          we discuss today dose-ranging studies that look at

          different concentrations.

                    [Slide]

                    The duration, as I mentioned, should be at

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

          could be as short as 12 months.

                    [Slide] 

                                                                    16

                    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 

                                                                    17

          are able to enroll a large number of patients at

          any one center you probably wouldn't do a

          multicenter trial.  So, again, we welcome

          suggestions on how to get around this.

                    [Slide]

                    Stratification is not necessary.  If there

          is a chance of imbalance in factors that someone

          believes may influence the results, and in this

          case there have been discussions about whether

          occult versus classic potentially would influence

          the results or whether baseline visual acuity would

          potentially influence the results.  We have

          suggested that people stratify so that they have a

          higher chance of having an equal distribution

          between the individual groups--again, not required.

          The hope is that randomization will take care of it

          but stratification frequently helps.

                    [Slide]

                    Control agent--we have asked that at least

          one of the clinical trials that is performed

          demonstrates superiority to a control.  We have not

          defined what that control has to be.  It could be 

                                                                    18

          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. 

                                                                    19

                    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 

                                                                    20

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

          these trials today there are multiple doses, in

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

          recognize that having a sham increases the chance

          of bias influence in the results, although just

          having a sham does not necessarily create bias.

                    [Slide]

                    Dose ranging--we prefer to try and bracket

          the dose that will ultimately be marketed, in other

          words, study doses that are higher and study doses

          that are lower than that which will be ultimately

          marketed so we get a better understanding of the

          drug product.

                    [Slide]

                    Efficacy has been discussed a lot.  We

          have a number of parameters that we readily accept

          as being acceptable.  We have other parameters

          which we think may in the future be acceptable or

          we will be willing to entertain if there is

          validation, and validation does not necessarily

          need to occur in this particular trial.  The thing

          that we readily accept as being important is a 

                                                                    21

          change in visual function.  So, our guidance to

          people when we are having discussions about

          clinical trials is that there be statistical

          significance in clinical relevance in visual

          function at more than one time point.  By visual

          function we mean visual acuity, visual fields or

          color vision.

                    [Slide]

                    The evaluations we expect to be carried

          out include, obviously, best corrected distance

          visual acuity.  By that, we generally mean using a

          chart that has equal number of letters per line and

          equal spacing between lines.  The ETDRS is one type

          of chart that meets that, and based on the

          validation information that was conducted at a four

          meter distance so that is our preferred both

          distance and test but we are willing to recognize

          other equivalent tests of best corrected distance

          visual acuity.

                    We expect best corrected visual acuity to

          be measured at every visit, and we expect those

          visits to occur no less frequently than every three 

                                                                    22

          months.

                    We expect to have dilated seven field

          fundus photography sometime during the trial.  We

          expect to have fluorescein or indocyanine green

          depending on what exactly is being studied during

          the trial, and we have not specified exactly when

          that has to be.  We expect dilated ophthalmoscopy

          to be performed both for evaluation and for safety

          at every visit.  We expect a dilated slit lamp exam

          for the same reason.  We expect to have endothelial

          cell counts, not necessarily in every trial but

          somewhere within the development plan, and have at

          least one study that includes it at the beginning

          and end of the trial, and the same thing standard

          systemic clinical and laboratory evaluations.

                    [Slide]

                    Two meters versus four meters has been a

          source of a lot of controversy.  It is my

          understanding it stems primarily from the

          practicality of being able to have exam rooms that

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

          would have required 20 foot length and his exam 

                                                                    23

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

          current trend now.  People use exam lanes that are

          much shorter.  But the subject has been studied.

          It was the source of a lot of discussion in the

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

          as a standard that was published in Ophthalmology

          in 1996 for exactly the purpose of discussing what

          the best distance is.

                    It does not mean that you can't

          theoretically correct.  You know, two meters, four

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

          charts smaller so you are looking at the same angle

          that gets subtended.  The issue is the variability

          that occurs when measuring at two meters versus

          four meters and the potential for any bias if the

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

          down or lock every patient into an exam seat and

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

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

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

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

          various seats, if you are leaning backward or 

                                                                    24

          leaning forward, just sitting in your same seat can

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

          believe that people are attempting to bias the

          results or attempting to lean, and visual acuity is

          a very common measure in ophthalmology so everybody

          is aware to try to keep people from leaning or keep

          that from influencing what goes on.  But studies

          have been done that show poor reliability at one

          meter versus four meters.  So, the assumption is

          that there is also more variability at two meters

          than there would be at four meters.  The overall

          impact on a particular trial is not known, and the

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

          two meters and four meters, which we do not have

          data to discuss today.

                    We think it is more significant for those

          trials that have a feature that allows there to be

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

          is more of an issue in an equivalence trial than it

          is in a superiority trial.  These trials that we

          are talking of today are superiority trials; they

          are not equivalence trials.  But there are issues. 

                                                                    25

                    [Slide]

                    Our recommended endpoints to date have all

          been, as I mentioned earlier, visual function.  We

          think at some point in the future we will end up

          accepting anatomical changes but we have not yet

          found anatomical changes that correlate directly

          with visual function.  So, currently we readily

          accept doubling of the visual angle, which on the

          ETDRS chart at four meters would be 15 letters or

          more; a halving of the visual angle, in other

          words, showing improvement in vision; a quadrupling

          of the visual angle, which would be 30 letters or

          more.  These are all looking at percentage of

          patients that have this particular finding because

          we think a doubling of the visual angle is a

          clinically significant difference that would not

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

                    [Slide]

                    We have also been willing to accept a

          difference in the group mean.  We do not know

          exactly how much of a difference in group mean

          would be clinically significant so for 

                                                                    26

          consistency's sake we have said we will readily

          accept a mean change of 15 letters.  That does not

          mean that something less than that may not be

          statistically significant.  We are just not ready

          to accept without question anything less than 15

          letters.

                    [Slide]

                    Let me just briefly talk about equivalence

          trials just so you know the full scope of what we

          have talked about with individual sponsors.  We

          believe it is possible to do comparison with an

          active agent which has already demonstrated

          repeated success.  Visudyne is currently approved

          for predominantly classic choroidal

          neovascularization in atrial macular degeneration

          and a couple of other things.  So, for that

          particular indication we would accept an

          equivalence trials if one wanted to conduct it.

          The way we have set up equivalence trials is that

          we have asked that at least 50 percent of the

          established treatment effect be preserved so that

          95 percent confidence intervals be drawn around 

                                                                    27

          those parameters to protect at least 50 percent of

          the treatment effect.  Again, it is not a

          particular issue for this product but it may be an

          issue for other products.

                    The analyses that we ask to be conducted

          always include intent-to-treat with last

          observation carried forward and per-protocol with

          observed values only.  We recognize these as

          differences in the data available for analysis.

          The intent-to-treat last observation carried

          forward is the fullest data set we can obtain.  It

          is everybody that was randomized in the trial and

          it is creating a value for everyone whether real of

          extrapolated.  A per-protocol analysis is the

          minimal data set.  It is only those patients that

          fully met the protocol and only the values that we

          have there.

                    We don't believe that either one of these

          two analyses is the best analysis or is the most

          proper or is the most representative.  We think

          they are extremes and we ask that both be conducted

          and we look for differences between these two 

                                                                    28

          analyses.  If there are no differences between

          these analyses we assume that, regardless of how

          much inclusion/exclusion, your results are pretty

          much the same and you can accept either one.  If

          there are differences we ask for additional

          analyses to try and explore which one is likely to

          be telling a better picture or why it is telling a

          different picture.

                    Other analyses which you would have seen

          in the briefing package include things like

          worst-case analyses where we treat all dropouts in

          the control as being successes and all dropouts in

          the test product as being failures.  This is not a

          correct test.  This is not an accurate test.  We

          are making assumptions in the worst direction to

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

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

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

          potential analysis results could be.

                    [Slide]

                    As a general rule, we ask for alphas to be

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

                                                                    29

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

          power to detect a difference to be 80 percent or

          greater, and we ask that any time anybody looks at

          the data, any kind of look any time during the

          evaluation that there be an adjustment in the

          statistical plan, in other words, correction for

          that alpha for any look that occurs.  All of our

          analyses that you see in any of our data sets will

          include these features.

                    [Slide]

                    The last one I want to talk about is

          pediatrics.  There is an agency initiative to try

          and include, when possible, pediatric patients in

          the drug development of particular products.  So, I

          am covering it for completeness. In this particular

          case, choroidal neovascularization is rarely seen

          in pediatric populations and we have not asked the

          sponsor of this application or any of the

          applications that just deal with choroidal

          neovascularization to include pediatric patients

          because the population we don't think is relevant

          in this particular case.  But as a general rule we 

                                                                    30

          do ask for pediatric patients to be included during

          the development.

                    I am happy to take any questions and,

          again, I thank everybody for your time, and look

          forward to a fruitful discussion.

                    DR. DUNBAR:  Are there any questions at

          this point regarding Dr. Chambers' presentation?

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

          forum for the sponsor, Eyetech Pharmaceuticals and

          I will ask that the sponsor introduce each of their

          speakers within their presentation.

                      Eyetech Pharmaceuticals Presentation

                                  Introduction

                    DR. DYER:  Good morning.

                    [Slide]

                    Today we will discuss the first anti-VEGF

          therapy for the eye and the first treatment to

          target the underlying biology of neovascular

          age-related macular degeneration.  Pegaptanib

          sodium achieved statistical significance for

          clinically meaningful, prespecified primary

          endpoint in replicate trials with strong supportive 

                                                                    31

          data in secondary endpoints.

                    The efficacy was against usual care

          controls, and this pharmacological agent also shows

          a favorable safety profile and provides a treatment

          benefit to many patients for whom no effective

          therapy presently exists.

                    [Slide]

                    My name is David Guyer.  I am from Eyetech

          Pharmaceuticals.  I previously was professor and

          chairman of ophthalmology at the N.Y. School of

          Medicine and a practicing ophthalmologist

          specializing in macular degeneration.

                    Also speaking today will be Dr. Tony

          Adamis, who was an ophthalmologist on the full-time

          faculty at Harvard, and is now with Eyetech.  He

          ran the ocular angiogenesis laboratory as well.

          Our risk/benefit section will be presented by Prof.

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

          Harvard.

                    [Slide]

                    Neovascular age-related macular

          degeneration represents 90 percent of the severe 

                                                                    32

          vision loss from this disease.  Many patients note

          a loss of independence and inability to read, to

          ambulate and to recognize faces of their loved

          ones.  This occurs because when the disease forms

          abnormal blood vessels that leak blood and fluid

          waviness or blurred vision can be seen in the

          central area that sometimes can lead to a scotoma

          or blind area centrally that prevents them from

          seeing straight ahead, and in up to a third of

          patients clinical depression can be noted.

                    [Slide]

                    The devastating effects of this disease

          were well summarized in a book by Henry Grunwald,

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

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

          Losing Sight, Gaining Insight" Mr. Grunwald said,

          "after a lifetime during which reading and writing

          have been as natural and necessary as breathing, I

          now feel the visual equivalent of struggling for

          breath."

                    [Slide]

                    Macular degeneration represents a major 

                                                                    33

          public health problem and urgent unmet medical

          need.  It is the most common cause of irreversible,

          severe blindness in developed countries.

          Ninety-five percent of retinal specialists believe

          that macular degeneration represents an epidemic,

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

          United States alone, and a prevalence of up to 1.6

          million patients with active bleeding.  Limited

          treatments are available and 85 percent of retinal

          specialists are dissatisfied with current treatment

          options.

                    [Slide]

                    Macular degeneration represents a

          progressive disease.  Early on in the disease these

          whitish-yellow spots, called drusen, occur and

          patients can progress to the neovascular form of

          the disease which is where pegaptanib is effective.

          This is an angiogenic disorder and what happens is

          abnormal blood vessels grow behind the retina where

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

          untreated, they lead to disciform scarring where

          fibrovascular tissue destroys and replaces the 

                                                                    34

          normal rods and cones in the retina.  At this

          point, usually moderate to severe visual loss is

          noted.

                    [Slide]

                    Let's discuss the therapeutic options

          available for patients with neovascular macular

          degeneration.  In the 1980s, the Macular

          Photocoagulation Study Group showed the beneficial

          roles of thermal laser photocoagulation.  However,

          very few patients are suitable for this treatment.

          The treatment is most suitable when the abnormal

          blood vessel, as seen here on a fluorescein

          angiogram, is away from the center of the macula,

          in what we call extrafoveal or juxtafoveal

          location, because for patients where the blood

          vessel is dead center or subfoveal the laser scar

          itself can destroy the very tissue we are trying to

          save.  Unfortunately, most patients with

          neovascular macular degeneration have subfoveal

          disease where the blood vessel is dead center.

                    [Slide]

                    In the year 2000, photodynamic therapy, or 

                                                                    35

          PDT, was FDA approved for patients with subfoveal

          predominantly classic angiographic subtype.  Thus,

          for approximately three-quarters of patients with

          neovascular macular degeneration there is no FDA

          approved therapy, although there is off-label use,

          with some limited CMS reimbursement, presently.

                    Today we will discuss the first anti-VEGF

          therapy for the eye, a pharmacological treatment

          that targets the protein VEGF that is responsible

          for the hallmarks of all choroidal

          neovascularization.  Increased levels of VEGF lead

          to neovascularization and increased permeability,

          which lead to the clinical features of all

          choroidal neovascularization, and pegaptanib blocks

          VEGF.

                    [Slide]

                    VEGF is the common denominator for

          neovascular macular degeneration.  Numerous peer

          reviewed papers have shown that for all

          angiographic subtypes, by immunohistochemistry

          staining, VEGF is present in both autopsy and

          surgical specimens. 

                                                                    36

                    [Slide]

                    Pegaptanib sodium is a pegylated modified

          oligonucleotide.  It has a selective vascular

          endothelial growth factor antagonist to isoform

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

          aqueous solution in a single-use, pre-filled

          syringe, which is important for safety reasons.

          The recommended dose is 0.3 mg of intravitreous

          injection administered once every 6 weeks.

                    [Slide]

                    We will show you today that pegaptanib met

          a clinically meaningful primary efficacy endpoint

          with statistical significance in replicate,

          well-controlled clinical trials, with a favorable

          safety profile.

                    [Slide]

                    I will now ask Tony Adamis to discuss a

          VEGF overview and macular degeneration

          pathophysiology.

                     VEGF Overview and Macular Degeneration

                                Pathophysiology

                    DR. ADAMIS:  Thank you, David and good 

                                                                    37

          morning.

                    [Slide]

                    In 1971 Judah Folkman first proposed the

          targeting of a specific angiogenic factor as a way

          to treat disease, and specifically a way to treat

          cancer and ophthalmic disease.

                    [Slide]

                    It was in 2004, with the completion of

          pivotal Phase III trials using Avastin which blocks

          VEGF that this theory was in a definitive fashion

          proven correct.  This drug now was approved this

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

          we entered this era of biological anti-angiogenesis

          therapy.

                    [Slide]

                    The target in that trial and in our trial

          is VEGF, which is an acronym for vascular

          endothelial growth factor.  Prior to that it was

          called vascular permeability factor.  Unlike many

          other growth factor names, these two are very

          appropriate in the sense that they describe the

          central biological functions of this protein.  VEGF 

                                                                    38

          makes vessels very leaky and VEGF makes vessels

          grow.  The leaky aspect of it was discovered in

          1983 by Harold Dvorak and then the

          neovascularization aspect or biology of VEGF was

          discovered by Napoleon Ferrara, who has been a

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

                    Since then, if one conducts a MEDLINE

          search, there have been over 11,000 published peer

          reviewed articles on VEGF.  There is a large body

          of knowledge concerning this growth factor.  I show

          you just one example of that here.  This is the

          protein structure of VEGF.  We now can determine

          very precise structure-functional relationships.

                    [Slide]

                    The disease we are here to discuss, as

          David said, is age-related macular degeneration, a

          very prevalent disease in our society and a very

          complex one scientifically when one begins to study

          it.  We are beginning to unravel the earlier stages

          of the disease, the stages where Bruch's membrane

          is altered and gives you those yellow spots, the

          drusen that David showed you in a clinical 

                                                                    39

          photograph.  We are also starting to understand the

          complex interaction of the different cell layers

          with the vasculature.  But the area or the phase of

          the disease, the late phase of the disease that we

          are studying is the neovascular phase where vessels

          begin to grow up towards the retina.  These vessels

          are abnormal and leaky, and they leak fluid and

          lipid and they damage the photoreceptors which

          sense light, and people lose vision and go blind.

          This process, the angiogenic process, has been very

          well studied.

                    [Slide]

                    As David said, the data indicate that it

          is biologically plausible that blocking VEGF would

          have a beneficial effect in this disease in a broad

          population.  When one looks at surgical specimens

          or autopsy specimens of patients with the disease,

          what is seen is that the common denominator is

          VEGF.  It is present in all angiographic subtypes

          and it is present in all active stages of the

          disease.  So, therefore, the hypothesis that

          blocking VEGF in neovascular MD would have a 

                                                                    40

          broad-base effect has some broad biological

          plausibility.

                    [Slide]

                    But those are not the only data that we

          have.  There is a large body of preclinical

          evidence, roughly 15 years worth, which is

          summarized on one slide here.  Let me just briefly

          walk you through it.  In preclinical models of

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

          retina and in the choroid, if one gives a VEGF

          inhibitor you can prevent the growth of vessels and

          you can prevent the leak that is associated with

          those vessels.  So, VEGF seems to be required for

          those processes.

                    Similarly, if one looks at those normal

          tissues and now introduces VEGF into the system,

          either by injecting the protein or genetically

          over-expressing it, VEGF in and of itself is

          sufficient to produce the neovascularization or

          leak that can occur in these tissues.

                    Then, so that we have some context in

          which to interpret those preclinical data, surgical 

                                                                    41

          specimens and autopsy specimens from humans with

          actual corneal neovascularization, iris

          neovascularization, retinal and choroidal

          neovascularization show that VEGF is expressed at

          high levels in those tissues at the time when the

          vessels are growing and leaking.  So, the totality

          of the data supports this approach of blocking VEGF

          in specifically the disease under study today,

          age-related macular degeneration.

                    [Slide]

                    It gets a little more complicated in the

          sense that VEGF really refers to a family of

          related molecules, and I want to talk about one

          specifically, VEGF 165 which is the target of

          pegaptanib.

                    [Slide]

                    We were faced with the paradox a few years

          ago, as we looked at the accumulated data

          concerning the role of VEGF in disease and in the

          normal state.  What we found was that VEGF is

          required for the normal formation development of

          vessels during development throughout the body.  I 

                                                                    42

          am just showing you here two examples.  These are

          the vessels of the normal colon and these,

          obviously, are the normal vessels of the retina.

                    [Slide]

                    In the same molecule, VEGF was shown in a

          number of definitive studies and laboratories

          around the world that VEGF is required for the

          abnormal vessels that can grow in the colon, and

          this is colon carcinoma, and here is a case of

          age-related macular degeneration.  So, how is it

          that the same protein can cause these vastly

          different phenotypes, these different types of

          vessels?  One set of vessels are normal and they

          don't leak and they behave appropriately; another

          set looked very different and they behave very

          differently.

                    [Slide]

                    Perhaps, we thought, some of that

          complexity is encoded in these different isoforms.

          Let me just explain what those are.  There is one

          VEGF gene but that gene encodes multiple

          transcripts or mRNAs for VEGF that have different 

                                                                    43

          sizes that translate into different proteins.  So,

          one of those major proteins or isoforms is VEGF

          165, which just simply means that it is composed of

          165 amino acids.  Another major isoform, especially

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

          could it be that differential expression or

          synthesis of these isoforms underlies the

          complexity that we see in the vessels in the normal

          and the diseased state?

                    [Slide]

                    So, in an experiment we conducted and

          published last year, we studied the retinal

          vessels.  We studied the normal retinal vessels

          that are developing as the retina forms and we

          studied abnormal retinal vessels in a model of

          retinopathy prematurity.  This is a model where

          vessels grow towards the vitreous and leak and are

          distinctly abnormal.

                    What we saw was that when normal vessels

          are developing the isoform expression of the two

          major isoforms, 120 and 164 which are the rodent

          counterparts to human 121 and 165, is roughly equal 

                                                                    44

          during development.  But rather strikingly, during

          disease when disease vessels are growing there is a

          shift to almost exclusive expression of the 164

          isoform.  So, it was an interesting association

          that we saw of 164 with diseased vessels.

                    [Slide]

                    But to really get at the causality of 164

          in the production of diseased vessels we conducted

          the following experiment.  In a model of abnormal

          vessel growth we gave pegaptanib which blocks just

          164 and compared it to a non-selective VEGF

          inhibitor which blocks all the isoforms.  We saw

          that bpth were equally effective in preventing

          abnormal vessel growth.  Here is the control with

          the abnormal vessels, and both are pretty good at

          inhibiting that.

                    We also looked in a model of normal

          retinal vessel development and, again, gave

          pegaptanib and what we saw was essentially zero

          inhibition of normal vessels.  We did not affect

          normal vessels.  Whereas, the non-selective VEGF

          inhibitor had a deleterious effect on these normal 

                                                                    45

          vessels in the retina.  So, the conclusion we made

          was that VEGF 164 may be preferentially associated

          with disease and targeting it gives you a much more

          selective inhibition in that you are much less

          likely to affect normal vessels in the developing

          animal.  But I will tell you that there has

          subsequently been independent support of this,

          specifically from UCSF, where this is also perhaps

          true in the adult animal.

                    [Slide]

                    To be certain of our conclusion because we

          used a reagent here, pegaptanib in particular, we

          wanted to make sure this conclusion was robust.

          So, we created animals genetically that where we

          deleted specifically the 164 isoform and these

          animals were able to make all the other types of

          VEGFs.  What we see here is that these animals have

          completely normal retinas and normal retinal

          vessels and they are no different than animals that

          make all VEGF isoforms.  In fact, these animals

          grow up to a normal age.  They can reproduce.

          There are no abnormalities we can detect, even 

                                                                    46

          though they cannot make any VEGF 164.

                    [Slide]

                    So, how was a drug made that specifically

          blocked VEGF 164?  Well, pegaptanib is an

          oligonucleotide aptamer.  It specifically is 28

          nucleotide in life.  Aptamers are molecules that

          will fold in a very specific fashion.  They have a

          three-dimensional conformation such that they will

          bind to the target protein of interest--in this

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

          in the case of pegaptanib with a very high

          affinity.  This binding occurs extracellularly.

          The drug does not enter the cell.  It is all

          happening outside the cell, which is where VEGF is

          residing.  These features make it act very much

          like an antibody but there are some important

          distinctions, aside from it not being an antibody;

          it is an oligonucleotide.

                    This class of molecules, in the published

          literature and it has been our experience as well,

          are quite non-immunogenic.  In our preclinical and

          in our clinical examination of pegaptanib we have 

                                                                    47

          not seen a single instance when an antibody is

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

          remarkable target specificity and this simply

          attests to that.

                    [Slide]

                    This shows that pegaptanib is very

          efficiently binding to human VEGF 165 and murine or

          mouse VEGF 164, but there is no significant, or

          essentially no binding to VEGF 121 or related

          family member of placental growth factor.

                    [Slide]

                    So, what we would expect when pegaptanib

          is administered to the eye is that you would have

          selective VEGF inhibition of 165 which was

          associated with pathology and in our animal model

          spares the normal vasculature, and we would have

          two very important biological responses as a

          function of that blockade: vessel growth would be

          inhibited, as would permeability, and the thinking

          was this would translate to a better visual

          outcome.

                    [Slide] 

                                                                    48

                    The last thing I would like to talk about

          is how we chose our dose.  This drug is

          administered to the eye nine times a year, and

          there are three doses that we chose.

                    [Slide]

                    Let me show you the data that we had in

          hand when we were planning these trials.  We knew

          from our pharmacokinetic experiments that when

          pegaptanib is given to the eye via intravitreous

          injection it slowly exits the eye and it can be

          measured in the plasma.  Actually, the plasma

          levels mirror the levels that one sees in the

          vitreous.  So, by sampling the blood you can infer

          what is happening in the eye.

                    The other important thing that we learned

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

          in this rabbit model, you have thousand-fold less

          concentration in the plasma than you do in the eye.

          In a more relevant primate model we saw that this

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

          the plasma than it was in the eye.

                    [Slide] 

                                                                    49

                    We learned from those studies that the

          half-life in the primate vitreous is approximately

          four days.  We also had data that we had collected

          in tumor models and in a model of retinopathy

          prematurity that when you give pegaptanib

          intravenously the amount of pegaptanib that is

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

                    We also had another inhibitory

          concentration that we had determined in vitro in

          tissue culture in various assays of calcium

          mobilization and endothelial cell proliferation.

          The relevant concentration in tissue culture of

          pegaptanib that was required to inhibit VEGF was

          significantly lower.  It was 0.01 mcg/mL or 10

          ng/mL.

                    When we started out it was not entirely

          clear which of these inhibitory concentrations

          would be most relevant when you are injecting the

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

          is the most relevant inhibitory concentration, then

          a 3 mg dose, given every 6 weeks would sufficient

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

                                                                    50

          the other hand, this was the relevant

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

          0.3 mg dose would actually all three be sufficient

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

          perhaps that may translate to a plateau of the dose

          response.

                    [Slide]

                    To summarize what I have just discussed,

          VEGF appears to be an important control point for

          neovascularization and vascular permeability, the

          pathologies that lead to vision loss in age-related

          macular degeneration.  Pegaptanib specifically

          targets the VEGF isoform VEGF 165, which we believe

          is operative in disease.  I have shown you data

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

          choroidal neovascularization, diabetic retinopathy

          and other conditions.  And, pegaptanib dosing is

          based on pharmacokinetic data which were collected

          prior to the conduct of this study.

                    [Slide]

                    At this point, Dr. David Guyer will return

          and David will talk to you about our clinical 

                                                                    51

          efficacy data from the pivotal trials.

                          Pegaptanib Clinical Efficacy

                    [Slide]

                    DR. GUYER:  In this section we will show

          you that pegaptanib met a clinically meaningful

          primary efficacy endpoint with statistical

          significance in independent, well-controlled,

          replicate trials, with a favorable safety profile.

                    [Slide]

                    The macular degeneration program consisted

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

          treatments at 117 sites in 21 countries.  The dose

          ranges that were studied ranged from 0.25 mg to 3

          mg per eye.

                    [Slide]

                    These are the six trials.  EOP1003 and

          1004 are pivotal trials, sham-controlled,

          double-masked, randomized trials.  There were 622

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

          in trial 1004 in North America.  The other four,

          smaller trials were pharmacokinetic trials and

          open-label single or multiple dosing trials with, 

                                                                    52

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

                    [Slide]

                    The Phase I/II program showed that

          pegaptanib appeared safe in all tested doses and

          regimens with no dose-limiting toxicities.  There

          were no unexpected retinal or choroidal

          abnormalities noted by angiography as read by an

          independent reading center.  As Tony mentioned,

          these trials established the dosing regimen based

          on pharmacokinetics.

                    [Slide]

                    The study objective of the pivotal trials

          was to establish a safe and efficacious dose of

          intravitreous pegaptanib sodium in patients with

          subfoveal choroidal neovascularization secondary to

          age-related disease.

                    [Slide]

                    The development of these pivotal studies

          was done in conjunction with our expert advisory

          panel, whose names are listed on this slide.

                    [Slide]

                    The study design was two randomization, 

                                                                    53

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

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

          treatment regimen was every 6 weeks and the

          prespecified time point for the primary endpoint

          was 54 weeks.  PDT, photodynamic therapy, was

          permitted per the FDA-approved label at the masked

          investigator's discretion.  Since shams could have

          PDT, this represented a usual care control group.

                    [Slide]

                    Independent monitoring was done both by an

          independent reading center that confirmed the

          eligibility prior to randomization, and an

          independent data safety monitoring committee, or

          IDMC.

                    [Slide]

                    These were the members of the IDMC.  It

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

          today.

                    [Slide]

                    Because of the biology of neovascular

          macular degeneration and the mechanism of action of

          pegaptanib, we designed a trial with a very wide 

                                                                    54

          range of inclusion criteria which included a broad

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

          broad angiographic criteria including all subfoveal

          angiographic subtypes; lesion sizes up to and

          including 12 total disc areas in size; greater than

          or equal to 50 percent of the total lesion size

          needed to be active choroidal neovascularization;

          and for minimally classic and occult disease

          subretinal hemorrhage and/or lipid and/or recent

          change in vision was necessary for inclusion.

                    [Slide]

                    Ocular exclusion criteria included

          previous subfoveal thermal laser therapy, and to

          avoid older chronic cases any subfoveal scarring or

          atrophy or greater than or equal to 25 percent of

          the lesion being scarred or atrophic.  Causes of

          choroidal neovascularization other than age-related

          diseases were excluded, and if a patient had recent

          intraocular surgery or was thought to perhaps need

          cataract surgery in the near future, they also were

          excluded.  Finally, no more than one prior PDT

          treatment was allowed. 

                                                                    55

                    [Slide]

                    The general exclusion criteria included a

          history or evidence of severe cardiac disease such

          as myocardial infarction within the last 6 months,

          ventricular tachyrhythmia or unstable angina;

          evidence of peripheral vascular disease; or

          clinically significant hepatic or renal

          dysfunction; or a stroke within the last 12 months.

          Our population, however, was very characteristic of

          your typical elderly population in that 50 percent

          of the patients had systemic hypertension; 25

          percent were on statins; and 20 percent had

          cardiovascular disease.

                    [Slide]

                    Stratification at randomization included

          study center, a history of prior PDT use and

          angiographic subtype.

                    [Slide]

                    Our primary efficacy endpoint, which was

          prespecified, was the percent of patients losing

          less than 15 letters from baseline to week 54, the

          same endpoint that was used for marketing approval 

                                                                    56

          of Visudyne.

                    This is an ETDRS chart where 5 letters

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

          change represents a doubling of the visual angle

          which is a clinically meaningful change to an

          individual patient.

                    [Slide]

                    Our primary endpoint used in

          intent-to-treat, or ITT, population included

          patients receiving at least one treatment and a

          baseline visual acuity measurement.  The last

          observation carried forward, or LOCF, was used to

          impute missing data.  We will also discuss

          supportive visual and angiographic endpoints, as

          well as exploratory or subgroup analyses.

                    [Slide]

                    This table shows the various study visits.

          Of note, a telephone safety check was done 3 days

          after treatment.  Tonometry or measurement of

          intraocular pressure was done both before treatment

          and 30 minutes after, and fundus photography and

          fluorescein angiography was done at baseline and 

                                                                    57

          weeks 30 and 54.

                    [Slide]

                    In order to preserve the integrity of the

          masking there were two physicians involved in the

          trial.  One physician administered the study

          treatment and the second physician was involved in

          any patient assessments or decisions.  Patients

          were also masked in that the sham procedure was

          identical to the active drug procedure except for

          the actual penetration into the vitreous.  This

          meant that they had application of a lid speculum,

          instillation of topical medications,

          subconjunctival anesthetic, and pressure against

          the globe using a needle-less syringe.

                    The visual acuity examiners were also

          masked to both he treatment arm and also to

          previous vision assessments, and the reading center

          was not aware of the patient's treatment arm.

                    [Slide]

                    This slide represents the patient baseline

          characteristics for both trials 1004 and 1003.

          What we can see in each trial is that the active 

                                                                    58

          doses and the sham are well balanced with respect

          to sex, age, initial visual acuity, angiographic

          subtype, prior use of PDT and lesion size.  The

          only difference between the two trials was that

          there was slightly more prior PDT use in trial

          1004.  That was the North American trial, and that

          was because Visudyne was approved and reimbursed

          earlier in the United States than in Europe.  Out

          of 9 possible injections, on average all patients,

          treated and sham, received 8.5 of the 9 injections,

          and overall there was about a 10 percent rate of

          discontinuation in the trial.

                    [Slide]

                    We prespecified to use a Hochberg

          procedure to account for the multiple doses in this

          pivotal trial.  As per agreement with the FDA, it

          was decided to unmask study 1004 first--that was

          the trial that was recruited first, thus, the

          results were available earlier--in order to

          determine which doses to formally analyze in the

          study trial study, 1003.

                    [Slide] 

                                                                    59

                    So, we proceeded to unmask the first

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

          67 percent of patients lost less than 15 letters

          compared to 52 percent of sham.  This hit our

          Hochberg adjusted p value at 0.0031.  Note that the

          1 mg dose had a similar response rate, about 66

          percent.  The p value was 0.0273.  The 3 mg

          response rate was higher than the shams at 61

          percent, however, it did not hit the necessary p

          value.

                    [Slide]

                    For this reason, prior to unmasking the

          second trial, it was prespecified to the FDA that

          only the 0.3 mg and 1 mg doses would be formally

          analyzed in the second trial.  Then we proceeded to

          unmask the second trial, study 1003.

                    [Slide]

                    This study showed replication of the

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

          percent of the patients in the 0.3 mg dose,

          compared to 59 percent of sham, lost less than 15

          letters, again hitting our Hochberg adjusted p 

                                                                    60

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

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

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

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

          nominal p value because we decided, as we

          mentioned, not to formally analyze it.

                    [Slide]

                    So, we can look at the combined data and

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

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

          lost less than 15 letters compared to 55 percent of

          the shams, and for all of these active treatment

          groups we had low nominal p values.

                    It is important to emphasize that for the

          0.3 mg group we were able to show independent

          replication in two trials of a statistically

          significant effect in a prespecified clinically

          significant primary endpoint.

                    [Slide]

                    I would like to turn now to some

          supportive visual angiographic analyses.  There are

          a variety of ways of looking at various visual 

                                                                    61

          outcomes that are standard for reassurance that the

          treatment effect for showing the primary endpoint

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

          were in favor of pegaptanib which gives us

          confidence in this treatment effect.  Because the

          independent trials had the same protocol and

          demographics, and because we prespecified it in our

          statistical plan, we will present these as pooled

          data.

                    [Slide]

                    This graph shows the percent responders

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

          show that the active treatment group had a

          treatment effect over sham not only at our primary

          endpoint at 54 weeks, but at every studied time

          point the active treatment group did better than

          the sham.

                    [Slide]

                    This is a graph of mean change in visual

          acuity.  Again, the active treatment group is here,

          the sham or usual care group showing a progressive

          decrease in vision, and the difference at 54 weeks 

                                                                    62

          was approximately 50 percent in favor of the active

          treatment group.

                    [Slide]

                    This treatment effect was early and

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

          first visit after the first injection the

          pegaptanib groups had already distinguished

          themselves from the controls and, as we can see

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

          with the low nominal p value.  This sustained

          itself throughout the 54-week course of treatment.

                    [Slide]

                    Sham eyes were twice as likely to suffer

          severe vision loss than actively treated patients,

          as shown in this graph of percent of patients with

          severe vision loss.  We can see the sham controls

          with severe vision loss compared to the

          active-treated groups.

                    [Slide]

                    At week 54, again, there was a low nominal

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

          sham, with progression to severe vision loss which 

                                                                    63

          is 30 letters or 6 lines.

                    [Slide]

                    This also was seen for legal blindness in

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

          see that more sham eyes progressed to 20/200 vision

          or worse compared to actively-treated groups.

                    [Slide]

                    Patients on pegaptanib were also more

          likely to maintain and/or gain visual acuity.  This

          graph shows the prespecified endpoints of

          maintaining or gaining vision that is greater than

          or equal to zero lines gained, as well as greater

          than or equal to 3 lines gained.  These other two

          endpoints were not prespecified but we can see

          again in all cases a treatment effect for

          maintaining or gaining vision compared to sham.

                    [Slide]

                    The next few slides will show the

          distribution of visual acuity change at baseline

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

          0.3 mg group.  This was the range of visual

          acuities at baseline.  Yellow is the 0.3 mg group 

                                                                    64

          and blue is the sham.

                    [Slide]

                    After 54 weeks in the trial we can see

          that more patients in the 0.3 mg treated group than

          sham had good visual acuities and more patients

          with sham than treated patients had poorer visual

          acuity.  So, the shift in distribution was in favor

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

          less than 0.0001.

                    [Slide]

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

          the 1 mg group.  This is the baseline visual acuity

          distribution and at 54 weeks again we can see more

          1 mg treated patients than sham having relatively

          good visual acuities and more shams than treated

          eyes having poorer vision.  Again, this shift in

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

          value of less than 0.0001.

                    [Slide]

                    Finally, we can see that for the 3 mg

          group also.  Here is the baseline distribution and

          at 54 weeks again more 3 mg patients had better 

                                                                    65

          visual acuities than shams, and more shams had

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

          treated patients.

                    [Slide]

                    This is a graph of the cumulative

          distribution function of vision.  What it shows on

          the bottom is the change in visual acuity up to

          week 54 and the cumulative proportion on this axis.

          This shows the robustness of the data as it uses

          all of the data points for 54 weeks.

                    What we can see first is this S-shaped

          curve.  This is the blue sham patients.  You can

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

          15 letters which was our primary endpoint, moderate

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

          talked about, represents severe vision loss, and we

          can see the zero or higher time point which

          represented maintaining vision.  What we can see is

          that, whether we are talking about preventing

          vision, maintaining vision or gaining vision, there

          has been a shift in distribution, a shift in the

          distribution of the sham patients in all active 

                                                                    66

          treatment arms to the right, suggesting benefit in

          all areas.  The area between the lines which

          represents this improvement was highly

          statistically significant for all three doses, for

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

          0.0001 again; and the 3 mg dose 0.0017.

                    [Slide]

                    I would like to now turn to the

          exploratory or subgroup analyses.

                    [Slide]

                    It is important to emphasize that this

          study was powered to test for statistical

          significance in the overall study population, that

          is, to test for the primary hypothesis or primary

          endpoint of all subjects.  Nevertheless, it is

          important to explore various baseline

          characteristics such as lesion composition, lesion

          size, baseline vision, age, sex and pigmentation of

          the iris.

                    [Slide]

                    Despite a reduced ability to draw

          statistical conclusions because of decreased sample 

                                                                    67

          size, in some cases as small as 18 patients,

          multiple subgroup analyses which can both lead to

          false positives and negatives--despite this no one

          subgroup drove the overall effect, as we will show

          you.

                    [Slide]

                    We will first look at the 0.3 mg and 1 mg

          doses as was described in the FDA briefing book.

          We have also analyzed and prepared the 3 mg dose

          and if people are interested later we can show you

          that.  We will present this using pooled data

          because it was prespecified and we will show the

          individual trials after.

                    [Slide]

                    Here we can see for the pooled data at the

          0.3 mg dose that in all cases of all patient

          characteristics the 0.3 mg active treated group did

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

          consistent with the biology of this disease and the

          mechanism of action of pegaptanib, for all

          angiographic subtypes, predominantly classic,

          minimally classic and occult, as seen here; also, 

                                                                    68

          initial baseline visual acuity, size of the lesion,

          race and pigmentation of the iris.

                    [Slide]

                    Here we can see for severe visual

          loss--the first graph was moderate visual loss or

          primary endpoint, but we can see that the

          conclusions we made are supported by severe visual

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

          The blue are the sham so all had more severe vision

          loss than actively treated 0.3 mg group for all

          patient characteristics.  So, this supports our

          primary analysis.

                    [Slide]

                    Turning to the 1 mg group, we can see the

          same thing, that in all patient characteristics the

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

          that this information is supported by severe vision

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

          the actively treated 1 mg dose.

                    [Slide]

                    Let's now turn to the individual trials.

          Individual trials which are under-powered 

                                                                    69

          inherently have more variability.  Nevertheless, we

          can make the same conclusion, that no one subgroup

          drove the overall efficacy.  Again, for trial 1004

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

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

          we can see support for using severe visual loss as

          another important clinical endpoint.

                    [Slide]

                    For trial 1003, with the 0.3 mg dose we

          can see the same thing.

                    [Slide]

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

          trial 1004, that in all cases the treated groups

          did better than the controls and this was supported

          by the severe vision loss in 1004 again.

                    [Slide]

                    And, in trial 1003, again, for moderate

          vision loss treated patients did better than the

          blue shams and support with severe vision loss

          where shams did worse than actively treated

          patients for progression to severe vision loss.

                    [Slide] 

                                                                    70

                    In order to be sure there were no

          important subgroup relationships, we also performed

          a multiple logistic regression to identify any

          potential factors either influencing the outcome or

          modifying the treatment effect.  Subgroups and

          interactions of subgroups with treatment were

          investigated.

                    [Slide]

                    These are some of the subgroups that we

          evaluated, age, angiographic subtype, use of PDT,

          sex, race, lesion size, status of

          smoker/non-smoker, subretinal hemorrhage, the

          fellow eye vision loss and lipid.

                    [Slide]

                    We found for the 0.3 mg dose that no

          factors were identified as significant treatment

          effect modifiers for 0.3 versus sham, and no

          factors except treatment with pegaptanib were

          identified as significantly influencing the

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

          of treatment.

                    [Slide] 

                                                                    71

                    For the 1 mg group we again found that no

          factors were identified as significant treatment

          effect modifiers versus sham, and for pegaptanib at

          1 mg there was a relationship between treatment

          with pegaptanib, again at 0.0001, and age which

          favored patients with less than 75 years of age.

          This is not to say that older patients did not do

          better.  It just said that there was a favor for

          younger patients even both appear to respond.

                    [Slide]

                    What can we conclude from these

          exploratory or subgroup analyses?  First, we have

          shown that the treatment benefit appears

          well-distributed among a broad patient population.

          Second, the efficacy is not consistently

          concentrated in or absent from any particular

          patient subgroup.  No one subgroup drove the

          overall efficacy.

                    [Slide]

                    The 0.3 mg dose represents the lowest

          studied efficacious dose and it met its primary

          efficacy endpoint with statistical significance in 

                                                                    72

          independent replicate trials, as we have shown you.

          The efficacy was substantiated in every clinically

          meaningful endpoint tested.  We have seen the

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

          show no additional benefits over 0.3 mg.  Tony will

          shortly show you that there was no safety

          difference between 0.3 mg and 1 mg as well.

          However, theoretically we all know that a lowest

          dose yields the lowest systemic concentration.  So,

          the sponsor advisory board and independent data

          monitoring committee endorsed the 0.3 mg dose as a

          dose that should be selected.

                    [Slide]

                    I would like to turn now to angiographic

          findings.  We have mentioned to you that we believe

          there are two mechanisms of action for pegaptanib,

          anti-angiogenesis and anti-permeability.  As I will

          now show you, we have anatomical confirmation for

          both mechanisms of action that support the visual

          findings we have shown you today.

                    Let's first look at the anti-angiogenesis.

          Here is a patient in the trial with predominantly 

                                                                    73

          classic neovascularization that showed virtually

          complete regression.  The white large area is the

          neovascularization.  You can see it has almost

          completely regressed after 54 weeks of treatment.

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

          group.

                    [Slide]

                    What we can see is that there was a

          decrease in the lesion size that had a low nominal

          p value in favor of active treatment for the 0.3

          and the 1 mg dose.  So, we have anatomical

          confirmation or support for anti-angiogenesis as a

          mechanism of action that supports the visual

          findings.

                    [Slide]

                    The second mechanism of action that we

          described was anti-permeability.  Here is another

          patient in the trial that had significant cystoid

          macular edema with neovascular disease.  We can see

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

          a lot of permeability.  After 54 weeks of treatment

          we can see a great decrease in the permeability. 

                                                                    74

                    [Slide]

                    Again, we can show that leak size over

          time was less for treated groups than for shams.

          The p values here are noted.

                    [Slide]

                    In addition, we can look at the change in

          leakage to week 54 as a sign of anti-permeability

          action, and we can see that very similar to visual

          distribution curves I showed you earlier, we can

          see again that there was less leakage noted more

          often in actively treated 0.3 mg patients than in

          sham, and more leakage noted in shams than in

          actively treated eyes.  This change in distribution

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

          have anatomical confirmation for anti-permeability

          as an important mechanism of action that supports

          the visual findings.

                    [Slide]

                    I would like to now turn to photodynamic

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

          have a historical perspective of the use of PDT in

          this trial so you can understand some of the 

                                                                    75

          challenges we faced when we were designing this

          trial.

                    At the time of starting the trial PDT was

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

          certainly ethical considerations that required that

          PDT be permitted in patients with predominantly

          classic disease.  However, the PDT usage pattern

          was not yet known.

                    [Slide]

                    So, what we decided to do was to create

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

          What that meant was that patients had to have

          predominantly classic disease and the masked

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

          masked physician determined if the patient was

          eligible for PDT per the FDA label and then whether

          that PDT was recommended for that individual

          patient.  If so, the treatment was administered per

          the FDA label.

                    Now, to ensure that these strict rules

          were being followed, we had a reading center review

          the usage pattern and we found that 92 percent of 

                                                                    76

          the time the reading center agreed with the

          appropriate use of PDT in this trial.

                    [Slide]

                    PDT use could occur three ways: prior to

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

          actually, any combination of the three.  It is

          important to emphasize that overall the use of PDT

          was extremely low.  Three-quarters of patients were

          never exposed to PDT in the study eye at any time

          in the time trial.

                    [Slide]

                    Let's examine each one of these three

          scenarios in detail.  First let's talk about prior

          PDT which was stratified and was balanced at

          randomization.  Also, notice the small numbers

          again, emphasizing very little PDT use in the

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

          was stratified and balanced.

                    [Slide]

                    Baseline PDT is the second scenario, and

          the baseline PDT use was again very similar among

          the groups.  We can see here that for the active 

                                                                    77

          treated groups 10-13 percent of patients had PDT at

          baseline compared to 14 percent for shams and,

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

          patients per subgroup.

                    [Slide]

                    Finally, let's talk about post-baseline

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

          meaningful analysis of potential post-baseline PDT

          effects on efficacy is limited to the inherent bias

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

          the patients were never randomized to post-baseline

          PDT use.  In order to really assess the baseline

          PDT use we would have had to design a trial

          randomizing patients to PDT and baseline.  That

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

          called the channeling bias, a patient with a poor

          response might be the patient that would be

          preferentially channeled to get PDT.  What this

          really means is that post-baseline PDT is an

          outcome variable.  So, for this reason, we must

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

          will show you now. 

                                                                    78

                    [Slide]

                    We need to ask was there increased PDT use

          in pegaptanib patients relative to sham that could

          suggest that some of the pegaptanib efficacy was

          derived from PDT?

                    [Slide]

                    The answer to this question was no.  As we

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

          PDT in active treated patients compared to sham.

                    [Slide]

                    The second important question about

          post-baseline PDT use is was there an increase in

          the average number of PDT treatments in pegaptanib

          patients relative to sham?

                    [Slide]

                    Again the answer is no.  As we can see

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

          active treatment eyes compared to sham.

                    [Slide]

                    The third important question, which will

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

          was there evidence of any adverse events with the 

                                                                    79

          co-administration of photodynamic therapy and

          pegaptanib that could lead to a drug-to-drug

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

          just a few minutes.

                    [Slide]

                    In summary, pegaptanib met a clinically

          meaningful primary efficacy endpoint with

          statistical significance in replicate, independent,

          well-controlled clinical trials.

                    [Slide]

                    I will now ask Tony to come up and discuss

          our clinical safety database.

                           Pegaptanib Clinical Safety

                    [Slide]

                    DR. ADAMIS:  This is the entire safety

          database.  This includes the patients from the

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

          that the total clinical experience to date includes

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

          which 7,500 are intravitreous injections that we

          can monitor for the safety.  There is a slight

          imbalance that you will see in that there are more 

                                                                    80

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

          is because that was the dose that was used

          throughout most of the Phase I/II program.  In

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

          those earlier programs as well.

                    [Slide]

                    The overall safety is shown here.  As

          regards any adverse events, you can see it is

          balanced between all treatment arms and sham.

          There is an imbalance in the serious adverse

          events.  These are largely injection related, and

          we will talk about those in depth in a moment.

                    The discontinuations, you will note, due

          to adverse events are low.  They are one percent in

          both the treated and the sham arms.  Similarly, the

          death rate is balanced to two percent.

                    [Slide]

                    Looking at the death rate just a little

          more closely, we can see that there is no evidence

          here of a dose response.

                    [Slide]

                    Let's look at the most frequent non-ocular 

                                                                    81

          serious adverse events.  This is a busy slide but

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

          good balance between the treated and the sham arms

          and, secondly, there is no clustering within a

          system organ class.  This is rather diffuse.  These

          conditions are age appropriate.  The mean age of

          this population is 77 years old that we studied.

          These people had a number of concomitant illnesses.

          Fifty percent of them had hypertension; 25 percent

          were on statins; 20 percent had cardiac disease.

          So, we believe it is representative of the

          population.

                    [Slide]

                    We looked particularly for VEGF

          inhibition-related adverse events as these have

          been reported with other non-selective inhibitors

          given intravenously at higher doses.  We were happy

          to see that there were no signals here.  The most

          sensitive signal, the one that has been picked up

          with other non-selective inhibitors in smaller

          trials than ours, less powered but nevertheless it

          was evident, was hypertension.  You can see here 

                                                                    82

          that the rate of adverse events is 10 percent both

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

          there for that very sensitive signal of VEGF

          inhibition.  Thromboembolic adverse events are

          similarly balanced, as are ischemic coronary artery

          disorders, heart failure and serious hemorrhagic

          adverse events.

                    [Slide]

                    Why is it that we did not see any of these

          VEGF inhibition-related phenomena?  There is a

          number of reasons.  Some of these are theoretical,

          some are real but in aggregate they provide I think

          an argument.  Pegaptanib is, as I said, selective

          for VEGF 165 so the other major isoform 121 is

          never blocked.  So, all VEGF is never blocked with

          pegaptanib, even if you gave it at very large

          concentrations.  It just does not bind to VEGF 121.

                    Secondly, the concentrations that we see

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

          magnitude less in the plasma and those

          concentrations are below the inhibitory

          concentration that our models have told us both for 

                                                                    83

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

          believe that these are levels that are below the

          ability of pegaptanib to affect VEGF levels in any

          sort of substantive way.

                    Third, as I just said, there was an

          absence of sensitive VEGF inhibition signals, the

          most sensitive being hypertension which I showed

          you but also in our 1006 trial, where we looked

          carefully at proteinuria, again there is no

          evidence that this drug is inducing proteinuria in

          either our clinical population or in our

          preclinical models.

                    Then, the report recently of

          thromboembolic adverse events occurring in cancer

          patients on chemotherapy and receiving Avastin--we

          think there are a couple of very different things

          about our population and that population that was

          studied.  Number one, cancer in and of itself

          predisposes patients to thromboembolic phenomena.

          They have indwelling catheters; they are bedridden;

          and the cancer itself alters the clotting system.

          Secondly, some chemotherapy has been shown to be 

                                                                    84

          vascular toxic, to be prothrombotic.  There is a

          published literature on that.

                    So, add these two hits to the vasculature

          and then block all VEGF to prevent the endothelium

          from healing itself, one can have a theoretical

          basis for understanding now why thromboembolic

          phenomena may be more prevalent in a population

          with cancer and chemotherapy.  That is not age

          related macular degeneration.  This is a very

          different population that is not, by and large, on

          chemotherapy and do not have cancers.

                    [Slide]

                    Let's look at the ocular adverse events.

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

          these events in a little more detail.  They are

          listed here, those that occurred greater than or

          equal to 10 percent of patients on either

          pegaptanib or sham.  You can see that there is a

          slight imbalance in eye disorders, and we will talk

          about these, and you see a number of various

          adverse events listed here.

                    [Slide] 

                                                                    85

                    Let's talk about them in more detail,

          number one that was listed on the previous slide

          being eye pain.  These patients receive nine

          intravitreous injections over the course of a year.

          It is rather remarkable actually that two-thirds of

          them never reported a single instance of pain.  Of

          those patients, approximately the one third that

          did report pain, it was mild or moderate in

          character in 99 percent of them, and only one

          patient exited this trial describing an adverse

          event of pain.

                    The other important thing to note here is

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

          was significantly higher than what is seen in the

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

          that these patients experienced--one conclusion you

          can draw is that it may be due to the preparative

          procedure prior to the injection of the drug.  As

          you recall, these patients have a speculum placed

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

          have a subconjunctival anesthetic injection.  These

          things may have contributed to the lion share of 

                                                                    86

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

          obviously, there is a difference here.  The

          remainder of it here can well be ascribed to the

          actual intravitreous injection itself.

                    Of those patients who reported pain, it

          was in a minority of their injections, two in both

          the treated and the sham arms, and the median time

          to resolution was two to three days which is the

          time of the follow-up phone call.

                    [Slide]

                    With regard to vitreous floaters, there

          was more than an imbalance here.  It was 33 percent

          in the treated arms versus 8 percent in the sham.

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

          between the sham eye and the fellow eye so some of

          this may be due to the preparative procedure but a

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

          likely due to the act of giving an intravitreous

          injection itself.  When giving a 90 mcL volume

          injection into the eye, in the average human a

          volume of 4 mL, you are displacing the vitreous and

          it is perhaps not surprising that as a function of 

                                                                    87

          that you are going to induce floater.  These

          floaters never were severe.  All of them were

          characterized as mild to moderate.  No patient left

          the trial because of floaters.  It was in a

          minority of injections, 1 to 2 injections, that

          these were reported, if they ever were reported,

          and the median time to resolution was 3 days in the

          treated arms versus 7 days in the sham arms.

                    [Slide]

                    We looked at cataract very carefully.  We

          specifically looked at cataract in only the aphakic

          eyes.  One-third of these patients approximately

          were pseudophakic.  What we saw was that across all

          treatment arms there was a slight imbalance, with

          30 percent of the eyes having an adverse event of

          cataract versus 26 in the sham arm.  This slight

          imbalance may be partially explained by the fact

          that the phakic fellow eye also had a slight

          imbalance, 17 percent in the treated versus 15

          percent in the sham arms.

                    But we looked at this a little more in

          depth.  The type of cataract that one would expect 

                                                                    88

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

          has been amply described in the literature, is

          posterior subcapsular cataract.  So, when we looked

          for that specific type of cataract grading, you can

          see there is zero difference.  It is 11 percent in

          both the treated and the sham arms.

                    [Slide]

                    Nuclear cataract was similarly well

          balanced.  In fact, if you remove the eyes that

          were vitrectomized, which we will talk about in a

          minute, vitrectomy can cause a nuclear sclerotic

          cataract to accelerate.  This is 18 percent in both

          arms and there is, indeed, a slight imbalance in

          cortical of 18 versus 15 percent.

                    One piece of objective data we have is

          that the vast majority of these patients came in at

          baseline with cataract and only 3 patients

          underwent elective cataract surgery over the 54

          weeks of the trial in the treatment arms.

                    [Slide]

                    Anterior chamber inflammation was another

          adverse event.  You can see here that there is an 

                                                                    89

          imbalance slightly with 14 percent occurring in

          study eyes versus 6 percent in the sham eyes, and

          there were zero reports in the fellow eyes.  None

          of these cases of anterior chamber inflammation

          were characterized as severe.  All of them were

          mild to moderate and we believe they were largely

          due to the active intravitreous injection and not

          to the drug itself.  The reports of inflammation

          were all moderate and self-limiting and did not

          increase during the course of the trial.  In fact,

          there was a slight trend to decrease, arguing that

          there wasn't a sensitization to the molecule here,

          in fact, supporting that this was due to the

          injection itself.  The median time to resolution

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

          of inflammation.

                    [Slide]

                    We looked at interaction potentially with

          PDT and specifically at ocular adverse events.  You

          can see here that the majority of patients did not

          have the combination of PDT and pegaptanib, but of

          those who did we looked very carefully at the event 

                                                                    90

          rates and the important thing to consider here is

          the event rate difference in the sham arms

          plus/minus PDT, and does that difference change in

          any sort of meaningful fashion when the PDT is

          given together with pegaptanib.  The answer is that

          from these data there doesn't appear to be a

          difference in those two measures.  The same is true

          with vitreous floaters.  There is a slight

          difference here and there is really no difference

          here in the treatment arms.

                    [Slide]

                    But let's look at it another way.  This

          assessment is looking to see if there was a report

          of an adverse event at any time during the 54

          weeks. For instance, if the patient had PDT at

          baseline but had an adverse event at 54 weeks it

          would be captured and presented in these data.  We

          thought we would try to look at this a little more

          carefully and see if there was a better temporal

          relationship.  So, now we are looking at data of

          patients who had PDT plus/minus 2 weeks around an

          injection of pegaptanib.  These events may more 

                                                                    91

          likely signify some sort of interaction and, again,

          there are no alarming signals here.

                    When one looks at eye pain there is very

          little difference here and there is very little

          difference here between the sham and the treatment

          arms.  The same is true for corneal epithelium

          disorders.  For these two specific adverse events

          one can postulate a mechanism as to why that is.

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

          the injection which can affect the epithelium and

          perhaps cause pain.  On top of that is a near

          temporal relationship the placement of a contact

          lens for doing the PDT, and one could understand

          why there might be a slight increase here.  Again,

          no patients dropped out because of any adverse

          events related to a combination of PDT and the use

          of pegaptanib.

                    [Slide]

                    Now let's concentrate a bit on ocular

          serious adverse events.  The three most common we

          are going to discuss in detail here are

          endophthalmitis, retinal detachment and traumatic 

                                                                    92

          cataract.  The ones below occurred at a very low

          event rate.  When the narratives in the cases were

          looked at in depth there really did not appear to

          be an association with the use of pegaptanib so we

          will not discuss them further here unless you wish

          to discuss it later in the question and answer

          session.

                    Endophthalmitis occurred in 12 patients

          over 54 weeks.  That translates to a relative risk

          of 1.3 percent of patients developing

          endophthalmitis over the course of one year of

          therapy.  So that we could compare our rate to the

          published literature this was converted to a per

          injection rate of 0.16 percent.  What we learned is

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

          within the published norm and reported norm in

          cases of endophthalmitis in patients receiving

          intravitreous injected therapeutics.

                    As important as the rate is what happened

          to these patients, what was the outcome.  One

          patient lost severe vision in this trial as a

          function of their endophthalmitis, 1/12, which 

                                                                    93

          translated to a rate of 0.1 percent over the course

          of the year.  Seventy-five percent of the patients

          who developed endophthalmitis elected to stay in

          the trial.

                    Traumatic cataract--you can see there were

          five cases of it and there were five cases of

          retinal detachment, of which three were

          rhegmatogenous in nature.

                    [Slide]

                    I show you here the specific details of

          all 12 cases of endophthalmitis.  What you can see

          here are the starting visions, the visions prior to

          the event, and the change in vision from just prior

          to the event which probably most accurately

          captures the visual loss related to the

          endophthalmitis itself.  What you can see is the

          one patient who lost 11 lines as severe vision

          loss.

                    Let me just tell you anecdotally what

          happened.  It was a protocol violation.  It turns

          out this patient had an active lachrymal sac

          infection prior to the development of the 

                                                                    94

          endophthalmitis and the injection of the mediation,

          and had an active lachrymal sac infection after the

          event of endophthalmitis.  The patient should never

          have been enrolled because that was an exclusion

          criterion.

                    The other patients, as you can see, were

          treated aggressively and their visual outcomes tend

          to be perhaps a bit better than what you would

          expect for a case of endophthalmitis.  In fact,

          there are some patients here who gained one or two

          lines of vision.

                    [Slide]

                    How were these patients diagnosed, and

          were we able to identify the endophthalmitis

          relatively early?  This slide shows you exactly

          what happened.  Three patients were identified in

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

          injection.  Eleven patients presented to their

          physician's office with complaints, and this

          happened between days two and five.  Two patients

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

          The endophthalmitis cases I am describing here are 

                                                                    95

          the 12 in the first year and the ones that have

          occurred subsequent to that which I am going to

          talk about.

                    [Slide]

                    We have been following the endophthalmitis

          issue very carefully and I would like to provide

          you with an update on where we are beyond the

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

          year 0.16 percent of injections, or 1.3 percent of

          patients, developed endophthalmitis.  In the

          second, and now some patients have entered the

          third year of this trial, there have been five

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

          there has been one case in our Phase II diabetic

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

          now, it is 18 cases of endophthalmitis with a

          denominator of over 14,500 injections, and the rate

          now is reduced somewhat to 0.12 percent per

          injection.

                    In the first half of this trial when we

          saw the case reports of endophthalmitis we convened

          an expert panel of ophthalmologists and retinal 

                                                                    96

          specialists who work in the endophthalmitis area

          and we decided that we needed to heighten the

          awareness of the need for strict adherence to an

          aseptic protocol when one is giving an

          intravitreous injection.  In fact, there was a

          letter sent to IRBs and a formal protocol

          modification mandating the use of a sterile drape,

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

          we did these things and we analyzed what the

          potential effect could be, what we saw was that

          prior to that protocol modification being adopted

          at all sites between August of 2001 and May of 2003

          the rate was 0.18 percent, and after that protocol

          modification the rate has now fallen to 0.03

          percent.

                    Can we ascribe the decrease in the rate to

          the change in the protocol?  Not necessarily.

          There was more than one variable that was changing

          here.  At the same time that we instituted this

          protocol modification and heightened awareness

          about the aseptic technique there was a dramatic

          uptake in the number of intravitreous injections 

                                                                    97

          being given for off-label use in diabetic macular

          edema with steroids, triamcinolone in particular.

          So, the knowledge base and the experience of retina

          physicians increased rather dramatically at the

          same time that we saw a drop in our rates.

                    [Slide]

                    The visual outcome for the cataract cases

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

          7 lines of vision, it was ascribed to progression

          of macular degeneration.  All of these patients, in

          fact, had successful cataract surgery.

                    [Slide]

                    The visual outcome of the retinal

          detachment cases is shown here.  All of these were

          successfully repaired and you can see the cases of

          rhegmatogenous detachment which most likely were

          injection related.  The visual outcomes were quite

          good.

                    [Slide]

                    Intraocular pressure was examined.  As I

          said earlier, it is not surprising if one injects

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

                                                                    98

          transient rise in pressure.  In fact, in

          ophthalmology it is common with almost all

          procedures that pressure spikes tend to occur.

          Well, they occurred here and the transient rise in

          mean intraocular pressure at the first prespecified

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

          treatment arms.

                    It is important to note that the mean

          intraocular pressure returned to pre-injection

          levels one week following the injection, which was

          the next visit, and that 90 percent of patients,

          approximately 90 percent of patients, never had a

          spike above the prespecified threshold of 35 mm and

          any patient who did have a spike was not allowed to

          leave the physician's office till the pressure was

          below 30 mm.

                    Very importantly, there was no evidence of

          a persistent increase in intraocular pressure over

          one year.  The drug did not seem to alter the

          outflow of the eye in any way.  In those patients

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

          spike was it because somehow the drug was altering 

                                                                    99

          the outflow mechanisms, and if that was the case

          you would expect to see an increased incidence

          during the course of the trial as it progressed.

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

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

          fact, may have been dropping slightly.

                    [Slide]

                    This slide simply shows the mean

          intraocular pressure values over time for all three

          treatment arms and sham, again giving us some

          confidence that the drug is not inducing a rise in

          chronic IOP.

                    [Slide]

                    We have a safety update for you regarding

          angiography.  Colored photographs and angiograms

          were looked at in the independent reading center at

          the University of Wisconsin.  We have looked at up

          to 97 percent now of our month 18 angiograms and 92

          percent of our two-year angiograms to get a sense

          of is there any evidence of cumulative toxicity.

          The results are that there is no evidence

          whatsoever of alterations in the normal retinal or 

                                                                   100

          choroidal vasculature as a function of the drug

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

          that deviated from the natural history of

          age-related macular degeneration and no alterations

          in the normal vessels.

                    [Slide]

                    The safety update, which was just

          concluded in the past week by the independent data

          monitoring committee, has reviewed 100 percent of

          the patients through month 18 of this trial and 97

          percent through month 24, and there have been no

          deviations from sort of the pattern of adverse

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

          the trial.  There have been no new safety concerns

          except perhaps for a slight increase in the number

          of retinal detachments.  There were 6 that were

          reported in the second year of this trial.

                    [Slide]

                    To summarize the non-ocular safety, there

          was a very low discontinuation rate due to adverse

          events.  It was one percent and it was balanced in

          the treated and the sham arms.  Non-ocular serious 

                                                                   101

          adverse events appeared to be similar in rate and

          character between pegaptanib and sham, and the

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

          population was similar between pegaptanib and sham.

                    [Slide]

                    As regards ocular safety, I think what we

          can conclude is that the majority of the ocular

          adverse events were judged to be procedure related.

          They were transient and mild in character and

          largely self-limiting.  There was a low

          discontinuation rate due to ocular adverse events

          and the serious adverse events were infrequent.

          They were rarely associated with severe vision loss

          and were mostly procedure related.  Finally, there

          were mild transient and predictable, manageable

          increases in intraocular pressure but no evidence

          of a long-term rise in intraocular pressure.

                    [Slide]

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

          practicing retinal specialist at the Massachusetts

          Eye and Ear Infirmary, will come and discuss the

          risk/benefit profile for pegaptanib. 

                                                                   102

                        Pegaptanib Benefit/Risk Profile

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

          Dunbar, members of the advisory committee, ladies

          and gentlemen, with your permission I would like to

          introduce myself a little more fully and my

          perspectives so that you can have the clearest

          context in which to place my remarks.

                    [Slide]

                    With regard to this study, while it was in

          progress I was invited to be a member of the safety

          committee and later became its chair.  At the

          conclusion of the study I was asked to be a member

          of the scientific advisory board.  I perform a

          virtually identical role for the Alcon Corporation,

          chairing their safety committee in the evaluation

          of their anecortave product.  I also advise them on

          surgical themes and instrumentation as well.

          Finally, I am a consultant to the Iridex

          Corporation serving as a member on the safety

          committee for the transpupillary thermotherapy

          trials and their PTAMD or laser for drusen trial.

          I hold no equity in any of these companies nor any 

                                                                   103

          of their competitors.

                    [Slide]

                    I would like to also share four

          perspectives that will inevitably influence my

          remarks and may be helpful to you also in your

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

          the pegaptanib safety committee.  Secondly, I have

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

          interest in endophthalmitis and the effects of

          administration of intravitreal medications.  I am,

          as introduced, an academic in the field of retinal

          diseases and therapy.  But perhaps most importantly

          and most germane is that I have a very active

          retinal practice at the Massachusetts Eye and Ear

          Infirmary and care for many patients with macular

          degeneration.

                    [Slide]

                    As has been said, neovascular AMD is quite

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

          visual acuity driving privileges frequently become

          impossible for a patient.  At 20/80 or worse

          difficulty is even present in trying to read large 

                                                                   104

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

          level of definition of legal blindness at which it

          is difficult to recognize faces and independent

          function is threatened.

                    [Slide]

                    How extant is this problem in the world

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

          comprehensive studies recently reported by the Eye

          Diseases Prevalence Research Group, they looked at

          studies in the United States, Western Europe and

          Australia over an 11-year period.

                    [Slide]

                    Based on their analysis, it is the leading

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

          40 years or older.  You see that slightly over half

          are due to age-related macular degeneration.

                    [Slide]

                    They then applied their model to the U.S.

          Census data for both 2000 and projected to the

          future.  In a morning filled with numbers, I will

          spare you all the numbers here, but using a

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

                                                                   105

          worse as visually impaired, there are 3.3 million

          Americans with visual impairment today.  In the

          future there will be approximately 5.5 million

          American with visual impairment at some level,

          again slightly over half, due to age-related

          macular degeneration.  So, it is clearly a problem.

                    [Slide]

                    As such, it merits our highest attention

          as physicians, researchers, etc. to try to find

          treatments and even cures.  This slide is color

          coded and it lists the candidate therapies for

          neovascular subfoveal age-related macular

          degeneration.  Therapies which have demonstrated

          effectiveness in replicate clinical trials are

          shown in yellow.  We have laser photocoagulation,

          photodynamic therapy with Visudyne and the data you

          have just heard on pegaptanib.  The great majority

          of interventions are listed in white, which

          indicates ongoing study with various degrees of

          promise, and it includes surgical options, as you

          see here and a variety of other laser treatments,

          as well as other pharmaceuticals, many of which are 

                                                                   106

          nearing the end of their clinical trials.  There

          are also some abandoned therapies that were

          ineffective and combination strategies, as you see

          in the lower right, are becoming of increasing

          interest.

                    [Slide]

                    Looking at the established therapies,

          there are two.  One is photocoagulation with

          thermal laser which has been effective in

          extrafoveal, juxtafoveal and subfoveal lesions.

          However, in subfoveal lesions this therapy has been

          abandoned due to the immediate destruction of

          central vision following treatment and is no longer

          in clinical use. Photodynamic therapy with Visudyne

          is approved for subfoveal predominantly classic

          lesions.

                    [Slide]

                    In addition, evolving clinical practice,

          in a hope to provide improved care for patients

          with macular degeneration, has led to a new

          accommodation therapy which has become widespread.

          That is the combination of a PDT treatment with 

                                                                   107

          Visudyne in association with an intravitreous

          induction of triamcinolone in the peri-PDT period.

          This treatment has had some very promising early

          pilot results but the literature is quite minimal

          at present.  Nevertheless, it has become a common

          treatment in clinical practice.

                    [Slide]

                    Intravitreous injections are quite common

          in my world as a retinal specialist.  They were

          employed and were actually the pathway to great

          success in the therapy of endophthalmitis, and are

          still continued widely in use for that indication.

          We also utilize intravitreal injection as a

          treatment of retinal detachment, as well as

          administering agents for CMV retinitis.  However,

          there has been great expanded use recently in

          office practice of intravitreal injections as

          regards the use of triamcinolone acetodine for

          diabetic macular edema, retinal vein occlusions,

          uveitis, as I have just mentioned, in association

          with photodynamic therapy.

                    [Slide] 

                                                                   108

                    Pegaptanib represents the potential for a

          new approach, a pharmacotherapy, and what are the

          advantages of pharmacotherapy?  They are both

          general and specific.  In general, pharmacotherapy

          offers the prospect of treatment at a molecular

          level with improved targeting of the disease

          process and, more importantly, limitation of the

          collateral damage that invariably occurs with

          larger scale interventions such as surgery or

          laser.

                    Pegaptanib quite specifically is based on

          very extensive basic science into the most widely

          accepted, central disease processes in AMD, namely

          neovascularization and leakage, with consistency

          across multiple experimental models and studies.

                    [Slide]

                    As a member of the safety committee, we

          looked for three specific areas in great detail.

          One, were there any potential systemic side effects

          from receiving an anti-VEGF medication?  Secondly,

          were there intraocular drug-related side effects

          from this VEGF medication?  Thirdly, were there any 

                                                                   109

          mechanical side effects or complications from the

          intravitreal injection procedure itself?

                    [Slide]

                    We did find serious ocular adverse events

          related to the injection procedure.  As you have

          heard, there were 12 cases of endophthalmitis.

          This incidence rate is quite comparable to that in

          published series for intravitreal injection with

          the other forms of intravitreal injection therapy

          that I have mentioned previously.  One of these

          patients had severe visual loss.  Nine of the

          patients continued in the study and elected to

          continue receiving study medication.  Finally,

          after protocol modifications, the incidence is

          clearly trending downward.

                    There were five cases of retinal

          detachment, which were repaired and some were

          related to the underlying macular degeneration

          itself.  Traumatic cataract was seen in five cases

          and all were surgically repaired without sequelae.

                    [Slide]

                    So, in these 22 serious ocular events, we 

                                                                   110

          considered them in the context of 7,545

          intravitreous injections performed in 1,190

          patients by 117 centers worldwide, and many of

          those centers had more than one injector.  We felt

          that this denominator indicated substantial safety

          for this procedure.

                    We also found no evidence of systemic side

          effects, no evidence of ocular drug-related side

          effects, and the majority of other adverse events

          were mild and transient within the eye.  The

          serious ocular adverse events were infrequent and

          manageable.  So, we concluded that there was a very

          favorable safety profile that, in addition, may be

          further improved by education and additional

          training.

                    [Slide]

                    If we look at severe vision loss, again to

          understand the context of these adverse events, if

          a patient presented to the trial and received sham,

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

          per year of suffering severe visual loss.  When

          they were enrolled in the pegaptanib group that 

                                                                   111

          risk was reduced to 9.5 percent per year.

                    [Slide]

                    In the endophthalmitis, retinal detachment

          and cataract serious ocular events that we saw, the

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

          of vision, was 0.1 percent, indicating substantial

          order of magnitude less risk from endophthalmitis

          than from the real problem here which is the

          macular degeneration itself.

                    [Slide]

                    Regarding efficacy, you have heard a

          detailed presentation and I will just summarize.

          There was significant reduction in moderate and

          severe vision loss compared with sham.  There was

          promotion of vision stability and gain in a

          proportion of patients.  There was efficacy with

          broad-based entry criteria including a range of

          subfoveal neovascular AMD lesions.  And, the

          benefit of intravitreous pegaptanib therapy was

          early and sustained.

                    [Slide]

                    As we have seen, in this slide baseline 

                                                                   112

          visual acuity is on the left.  Sham is indicated in

          purple and pegaptanib in grey.  At 54 weeks there

          is a definite shift in the 0.3 pegaptanib group to

          preservation of better vision on the left of this

          chart compared to the visual acuities observed with

          sham.

                    [Slide]

                    I am not a biostatistician but I will try,

          for myself and for all of us, to place these

          results in some kind of a wider context.  What

          could this mean?  No one knows exactly how many new

          subfoveal neovascular lesions occur a year, but

          120,000 per year of new treatment-eligible patients

          is probably a reasonable estimate.  If those

          patients were to behave similar to the gathered

          group enrolled in this trial, we could make some

          statements, and here they are:

                    Pegaptanib potentially prevents severe

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

          vision, in 15,000 additional patients per year in

          the United States compared with usual care, based

          on a 57 percent reduction in the rate of severe 

                                                                   113

          vision loss with pegaptanib.

                    [Slide]

                    Secondly, reaching a level of 20/200 or

          worse within the treated eye, we could call that

          blindness in the treated eye.  Pegaptanib

          potentially prevents treated-eye blindness in an

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

          again compared with usual care, based on a 38

          percent reduction in the rate of treated-eye

          blindness with pegaptanib.

                    [Slide]

                    In conclusion, from the perspectives

          available to me and now available to you, I have

          concluded that pegaptanib will have a significant

          impact on AMD in regard to both individual patients

          with AMD lesions that would become amenable to

          treatment and, secondly, in its effects on visual

          function and its preservation in the aging U.S.

          population.

                    The positive results in this trial

          indicate the beginning, and not the limit, of

          pharmacotherapy for AMD.  I agree with the 

                                                                   114

          sponsor's recommendations that the benefits of

          pegaptanib therapy for AMD strongly outweigh the

          risks.  Thank you.

                              Committee Discussion

                    DR. DUNBAR:  Thank you to the sponsor and

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

          would like to open the floor for discussion and

          questions for the sponsor from the committee

          members, and ask that you will speak your name into

          the microphone as you ask each question.  Are there

          any questions from the committee members?  Dr.

          Chinchilli?

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

          about the disease and the patients that were

          recruited for the two trials so, please, bear with

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

          roughly what proportion of patients that were in

          the trials had that situation?

                    DR. GUYER:  In general, for neovascular

          age-related macular degeneration usually one eye

          becomes active at a time.  If the patient lives

          long enough, they often will get it in the second 

                                                                   115

          eye.  In this particular trial the investigator

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

          there would be active disease that was eligible for

          the trial, the doctor would make that decision.  If

          we look at slide D-82--

                    [Slide]

                    --here we can see some of the baseline

          characteristics.  In two-thirds of the patients

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

          patient was treated in both eyes at the same time.

          But in the lifetime of a patient there could be

          some overlapping times where they have an active

          lesion and the second one becomes active.  Some

          patients are fortunate enough not to get it in

          their second eye but, unfortunately, if they live

          long enough many will.

                    DR. CHINCHILLI:  Thank you.

                    DR. DUNBAR:  Dr. Pulido?

                    DR. PULIDO:  A superb presentation; very

          interesting results.  Just two questions.  Number

          one, glaucoma was not an exclusion criterion in the

          study.  So, some of the patients had glaucoma and 

                                                                   116

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

          chronic injections on the small subgroup of

          patients that had glaucoma?

                    DR. GUYER:  I will let Tony answer that.

                    DR. ADAMIS:  We were interested in that

          question as well.  Slide OS-31.

                    [Slide]

                    We looked specifically at patients with a

          history of ocular hypertension and/or glaucoma, and

          then followed their pressures throughout the entire

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

          in their intraocular pressure as a function of

          treatment.

                    DR. PULIDO:  The other question probably

          is to you as well.  There are some recent

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

          delivery with retrograde transported Lentivector

          prolongs survival in a mouse ALS model.  Here is

          another one: mural protection of ischemic brain by

          VEGF is critically dependent on proper dosage.

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

          assumption that VEGF and VEGF 165 is specifically a 

                                                                   117

          cytokine for angiogenesis, but there is more data

          to show that there is an independent effect

          directly on neural tissue, separate from its

          angiogenic effect.  ERG was not a part of this

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

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

                    So, considering the neuroprotective

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

          angiogenesis is important, critical to take care of

          this significant problem in patients.  But my

          concern is the long-term chronic dosaging

          considering that there is an independent effect of

          VEGF as a neuroprotective agent.

                    DR. ADAMIS:  As always happens in science,

          what seems very straightforward becomes more

          complex, and what you quote is absolutely correct.

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

          But what has been learned in about the last five

          years is that neural cells have VEGF receptors and

          VEGF may be neuroprotective for certain tissues.

          Certainly, in the ALS model that is the most

          convincing story to date.  Whether the effect is 

                                                                   118

          direct or not is still being debated in the

          scientific world, but it may well be direct because

          of the VEGF receptor on the neural cells.

                    We were interested in this as well.  Even

          before we got into the scientific question as part

          of our preclinical safety testing, there was a

          9-month dog study where the dogs received 3 mg

          injections every 2 weeks bilaterally.  Then they

          had ERGs done and there were no abnormalities seen

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

          but, more importantly, recently we examined this

          issue and looked specifically at the isoform story.

          We presented a paper at ARVO last spring where we

          showed that in a model of retinal ischemia if one

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

          you can in fact induce some neural apoptosis.  But

          when we gave pegaptanib in the exact same setting

          there was no induced apoptosis.  So, again getting

          at this thesis, the important thing with pegaptanib

          I think is that you are sparing some VEGF to allow

          it to have its physiological or perhaps these

          rescue functions that can occur in the eye.  So, 

                                                                   119

          that gave us an additional measure of comfort that

          we are not going to have neural toxicity.

                    DR. PULIDO:  But the question still arises

          have you done long-term ERG studies on these

          patients?

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

          not done those in these patients.

                    DR. DUNBAR:  Mr. Kresel?

                    MR. KRESEL:  My disclaimer is that I am

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

          even an appropriate way to ask this but I am going

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

          at endophthalmitis which, you know, obviously is

          one of the things that people have concern about,

          and referred to a decrease in patients that was

          only five cases in years two and three.  My

          question is how many patients continued therapy

          that far?  So, did the number of patients decrease

          and, therefore, the percent not go down?  Because

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

          did go down.

                    DR. ADAMIS:  It is a fair question.  The 

                                                                   120

          number of patients was decreased in the second

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

          injection basis.  That accounts for any loss of

          patients and those were the rates that I presented

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

          Slide 129.

                    [Slide]

                    Just to show you the data, you can see

          that prior to the amendment on a per injection

          basis it was 0.18 percent, and then post the

          amendment it was 0.03 percent but with that

          additional confounding variable of a lot of

          off-label steroid injections going on.

                    DR. DUNBAR:  Dr. Gates?

                    DR. GATES:  In the context of the cases of

          endophthalmitis, could you expand on the initial

          injection technique versus some of the changes that

          you made secondarily?  Because draping oftentimes

          means different things to different people.

                    DR. ADAMIS:  Correct.  The details of the

          injection procedure are on a slide but let me see

          if I can recite them from memory for you, the 

                                                                   121

          changes.  There was a requirement for the

          installation of an antibiotic drop or dilated

          povidone-iodine prior to the amendment.  Then,

          after the amendment the drape that was specified is

          a clear plastic one that adheres around the lids

          and the lashes, and then the placement of the

          speculum, and then also asking for a

          povidone-iodine flush to be done, and then patients

          received postoperative antibiotics.  So, what we

          tried to instill there was a sense of uniformity in

          the procedure.  There was more latitude prior to

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

          memory, that were instituted.

                    DR. DUNBAR:  We have more than one-year

          data, but would you anticipate that the patients

          will continue every six-week intravitreal

          injections for the rest of their lives?

                    DR. ADAMIS:  That is an important

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

          second year of the design.  We want to know,

          obviously, about the safety in the second year and

          then an important question was do people need to be 

                                                                   122

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

          is one of randomized discontinuation to try to get

          to an answer as regards that very important

          question, do people need another nine injections?

                    DR. DUNBAR:  Dr. Lehmer?

                    DR. LEHMER:  I noticed in the data that

          most of the p values were significant, at least in

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

          mg doses, and for the higher dose there was less

          incidence, at least in the tables and graphs, of

          statistically significant levels.  Are there any

          conclusions you have drawn about that?  Is more not

          better, etc.?

                    DR. GUYER:  It is a great question and

          obviously one we spent a great deal of time

          analyzing.  There really is no definite answer to

          why the 3 mg, as you mentioned, perhaps appeared

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

                    [Slide]

                    There is one possible explanation that we

          have looked at.  This shows the mean change in

          vision over time for each individual trial.  On the 

                                                                   123

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

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

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

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

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

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

          to do quite as well as the other two active

          treatments--still doing better than the sham.  In

          1003 you can see that actually all three doses

          seemed to do equivalently.

                    So, one possibility is, you know, six

          different events, three doses, two trials, one out

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

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

          mentioned, all of these clinical parameters,

          secondary parameters, etc., are all dependent on

          the other.  That is one explanation.

                    The thing that we do know, however, is

          that the 0.3 mg dose, which represents the lowest

          efficacious studied dose, clearly hit the primary

          endpoint in replicate trials and showed consistent

          behavior throughout the trials.  Because of safety 

                                                                   124

          issues, theoretical safety issues, we believe that

          the 0.3 mg dose has met the requirements to be an

          effective treatment here.

                    DR. DUNBAR:  Dr. Miller?

                    DR. MILLER:  Thank you.  In terms of the

          number of patients that have been in the trials,

          are you comfortable or is the model sufficient

          enough to tell us that there are no adverse risks

          related to the population?  For example, with Vioxx

          we now know that after a period of time there are

          now people that are coming up with cancer, that it

          is causing cancer in some of them.  Have you given

          it to enough patients so that you would know if

          there were rare cases where other problems would be

          caused?

                    DR. ADAMIS:  The population studied was

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

          ophthalmology trial.  But for very rare events, and

          this is a problem faced with all clinical trials,

          that show up in patients on the order of one in

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

          in these types of trials to detect in a very 

                                                                   125

          air-tight manner those signals.

                    That being said, with the power we have,

          and we do have some significant power according to

          the guidelines Dr. Chambers talked about earlier,

          we were happy to see with all three doses that

          there wasn't any evidence of toxicity, either

          systemically or in the eye, related to the drug.

          But we will never know with absolute certainty for

          those very, very rare events.

                    DR. MILLER:  Thank you.

                    DR. GUYER:  Also as Dr. Chambers

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

          higher dose, 10 times higher than the dose that we

          believe is the correct dose, gives us some comfort

          that a dose 10 times higher has been studied in

          many patients.  So, that gives us more comfort than

          in many other trials.

                    DR. MILLER:  Thank you.

                    DR. DUNBAR:  Ms. Knudson?

                    MS. KNUDSON:  I was just curious about the

          necessity for pregnancy tests and two forms of

          birth control when your animal data indicated no 

                                                                   126

          problems and you are dealing with a very elderly

          population.  What was the necessity for this?

                    DR. ADAMIS:  That is the miracle of modern

          medicine.  There are people over age 50 having

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

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

          reason for that.

                    MS. KNUDSON:  Two forms of birth control?

                    DR. ADAMIS:  That is the standard protocol

          in clinical trials.

                    [Laughter]

                    MS. KNUDSON:  Did you pay for them?

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

          out.

                    [Laughter]

                    DR. DUNBAR:  Are there any additional

          questions?  Dr. Steidl?

                    DR. STEIDL:  Thank you for a superb

          presentation.  I think I understand some of the

          rationale behind the 15-letter vision loss, the

          primary endpoint.  I understand the comparison to

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

                                                                   127

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

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

          they agree with me.

                    I guess one of the things that I really

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

          could see, only one paragraph devoted to quality of

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

          may notice more in the treated eye than if the

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

          feelings are, your comfort is with this.  As

          physicians, we often think it is good for the

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

          perspective on this what have you gotten from your

          trial?

                    DR. ADAMIS:  Sure.  First, I would also

          mention that this difference, as we mentioned

          earlier, is against a usual care control and

          actually provides for approximately three-quarters

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

          we think that that is very, very important, in

          addition to the fact that the primary endpoint was

          supported by every secondary visual angiographic 

                                                                   128

          endpoint that we saw.  So, that gives us great

          confidence in our endpoint.  Slide number Q-2,

          please.

                    [Slide]

                    We agree that it is very important to look

          at quality of life measurements, and we did using

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

          validated measure.  It was only measured in one of

          the trials, in trial 1004 which was the North

          America trial.  Because validated foreign language

          versions were not consistently available we did it

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

          significantly under-powered.  We could not pool the

          data.  The results were not statistically

          significant but there were trends that favored

          pegaptanib treatment.  As I said, it was

          under-powered really to detect the small but

          potentially meaningful differences between groups.

          Slide Q-3.

                    [Slide]

                    We can see some of these differences.  It

          is important to mention that a 5 or more difference 

                                                                   129

          in the LS mean is considered potentially to be

          meaningful.  So, anything between 0 and 5 is

          probably not meaningful.  What you can see here are

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

          dose, and this has to do with color vision,

          peripheral vision, distance vision, social

          functioning and role limitations.  So, these strong

          trends, despite a very under-powered sample, give

          us some confidence that the QOL, very much as the

          angiography and the other secondary visual

          endpoints, also supports the primary endpoint, and

          we are getting significant benefit for these

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

          chart, but actually benefit that is important to

          them in the real world to help them get around.

                    DR. DUNBAR:  Thank you very much.  At this

          point we will take a 15-minute break and begin

          again at 10:30.

                    [Brief recess]

                    DR. DUNBAR:  We will begin the agency

          presentation by Dr. Jennifer Harris.

                                FDA Presentation 

                                                                   130

                    DR. HARRIS:  Good morning.

                    [Slide]

                    I am Dr. Harris and I was the primary

          medical reviewer for Macugen.

                    [Slide]

                    I am not going to repeat everything that

          the sponsor has presented to you; I am just going

          to try and bring up the salient points to try and

          give you an idea of how we went through the

          application and what we thought was important to

          present this morning.

                    I will go briefly over the study design;

          the efficacy results for each individual study so

          you can see what replicated itself and what did not

          replicate itself; conclusions about the efficacy; a

          safety overview of the combined study, the pooled

          study overview.  There are a couple of specific

          safety concerns that we want to talk about a little

          bit more and the sponsor discussed a little bit

          this morning but we just wanted to go over those

          again.  Then conclusions about the safety and then

          we are going to briefly go through the questions 

                                                                   131

          that we are going to pose to the advisory committee

          and, of course, you will see them again after

          lunch.

                    [Slide]

                    Again, there were two Phase III studies,

          1003 which was an international study, and 1004

          that was done predominantly in North America.

                    [Slide]

                    Both trials were randomized,

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

          dose-ranging, multicenter trials.  Within the

          trials patients received intravitreous injections

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

          54 weeks.  These trials were actually 2 years in

          duration.  The data that we will be looking at

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

          the 54-week time period these patients were

          re-randomized.

                    [Slide]

                    This is just a little schematic, just to

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

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

                                                                   132

          data is probably sometime soon I think, this month

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

          today.

                    [Slide]

                    Subjects that were enrolled in these

          trials were over the age of 50.  They had subfoveal

          choroidal neovascularization secondary to AMD.  The

          total lesion size was less than 12 disc areas, and

          greater than 50 percent of the lesions had to be

          active CNV.  The best corrected visual acuity had

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

          you have heard, were allowed to have PDT before

          entering into the trial and they were also allowed

          to have PDT during the trial.  Prior to the trial

          they could not have had anymore than one prior

          photodynamic therapy treatment, and the patients

          could not have had any previous subfoveal laser

          treatment.

                    [Slide]

                    The primary efficacy endpoint, again, was

          a proportion of patients who lost less than 15

          lines of visual acuity from baseline at 54 weeks.  

                                                                   133

          Those are considered responders.  Secondary

          efficacy endpoints were the proportion of patients

          gaining greater than 15 letters of vision,

          proportion of patients gaining more than zero

          letters of vision, and a mean change in visual

          acuity.

                    [Slide]

                    Just to give you an idea of the subject

          disposition, there are approximately 612 patients

          in the 1003 study that were randomized to

          treatment.  Approximately 53 percent of these

          patients discontinued.  As you can see, it was

          pretty well distributed.  The treatment groups were

          consistent, with approximately 10 percent or so of

          patients discontinuing in each of the treatment

          groups.

                    [Slide]

                    For the second study, 1004, we see the

          same thing.  The distribution of patients enrolled

          was approximately the same in each treatment group,

          including sham and, again approximately 10 percent

          or so of the patients discontinued therapy. 

                                                                   134

                    [Slide]

                    I am showing you this, not that I think

          that you can probably read it but just to give you

          an idea of who was enrolled and to show you really

          that the groups were well balanced.  They were very

          well balanced between all three active treatment

          arms, including the sham.  The demographics of

          patients that were enrolled in the 1003 trial were

          consistent with patients who actually had the

          disease.

                    I also wanted you to note down at the

          bottom that patients with all subtypes of

          neovascular AMD were enrolled.  There was a

          substantial number of patients with predominantly

          classic and occult lesions that were enrolled in

          the trial.

                    [Slide]

                    The same thing can be seen for study 1004

          where the groups, again, were well balanced, were

          representative of the population in which the

          disease was seen and, again, all three subtypes of

          neovascular AMD were represented. 

                                                                   135

                    [Slide]

                    Now I will go into the efficacy results.

          Before we go to the efficacy results I want to just

          put up this slide to show you how corrections were

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

          trials we did not go into these trials with one

          optimal dose and, therefore, you know if you have

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

          0.05 value and you can determine whether the drug

          works or not.  We went into the Phase III trials

          and we had three different doses so we had to find

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

          use the Hochberg procedure to actually control for

          these multiple comparisons.

                    With the Hochberg procedure, each of the

          treatment groups was compared to sham and if all

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

          were considered to have three active doses.  If

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

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

          values was less than 0.0167, then we had one active

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

                                                                   136

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

          results you may see some 0.05 or even 0.025 and

          that may or may not mean that that was actually

          statistically significant.

                    [Slide]

                    This is the primary efficacy result for

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

          the 0.3 mg dose there was approximately 67 percent

          treatment effect versus 53 percent of the sham

          group.  This was a statistically significant

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

          treatment effect is about 14 percent over sham.

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

          treatment effect versus 53 in sham.  However, this

          did not meet our pre-required p value.

                    [Slide]

                    For study 1003 we have similar results

          and, again, the 0.3 mg group shows approximately a

          73 percent treatment effect versus 60 percent of

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

          also seen that the 1 mg group was also

          statistically significant with a 75 percent 

                                                                   137

          treatment effect versus 60 percent.

                    So, it appears that both the 0.3 mg and

          the 1 mg group have approximately a 15 percent

          treatment effect over sham, with the 0.3 mg

          replicating its results in both trials and the 1 mg

          dose did not replicate these results.

                    [Slide]

                    You have seen this graph before.  This

          shows you what was happening to the patients'

          visual acuity in study 1004 throughout the first

          year of the study.  What we see is that all

          patients continued to lose vision in all treatment

          groups, including sham, throughout the first year

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

          the patients in the sham group lose vision at a

          higher rate than those in the other three active

          treatment groups.

                    [Slide]

                    In study 1003 we see the same thing.  All

          patients continued to lose vision throughout the

          first year of study on active treatment and in

          sham, but those patients in the sham group appeared 

                                                                   138

          to lose vision at a faster rate than those in the

          Macugen treatment group.

                    [Slide]

                    We have a chart similar to the sponsor's

          in that we looked at a subgroup analysis.  The

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

          one particular group that is actually driving the

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

          if we look at all the subgroup analyses that were

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

          lesion size, baseline demographics and male/female,

          what we see is that for each subgroup analysis the

          0.3 mg group shows a higher response rate than the

          sham group in each of the subgroups.

                    [Slide]

                    This was repeated in study 1003 where,

          again, the 0.3 mg group shows a higher response

          rate in all of the subgroup analyses over sham.

                    [Slide]

                    We also wanted to take a look at lesion

          size, basically because of the proposed mechanism

          of action of Macugen, and that is to inhibit 

                                                                   139

          endothelial cell growth.  So, we wanted to see

          whether that was, indeed, happening.  What we

          noticed was that actually the total lesion size for

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

          the total leak size, continues to increase for all

          treatment groups.  Even in patients receiving

          Macugen, lesion size does increase but it does

          appear that it increases to a lesser degree in the

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

          that it does increase in size.

                    [Slide]

                    The same thing was seen in the 1003 study

          where, again, the total lesion size for all

          treatment groups did increase in size, however, for

          the 0.03 mg group it does seem to increase to a

          lesser degree than in the sham group.

                    [Slide]

                    As you have heard, patients who entered

          the trial were allowed to get photodynamic therapy,

          which is an approved therapy for AMD.  So, our

          question became were we really seeing an effect of

          Macugen or were we just really seeing the effect of 

                                                                   140

          patients receiving an already approved therapy?

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

          chart you see here is the number of patients who

          actually got on-study photodynamic therapy

          treatment in study 1004.  We see that approximately

          the same amount of patients actually received

          photodynamic therapy in all treatment groups,

          including sham.

                    Another thing that we did note is that

          while the protocol specified that only patients

          with predominantly classic should have been allowed

          to get photodynamic therapy, there were many people

          who had occult or minimally classic CNV who also

          received photodynamic therapy.

                    [Slide]

                    The same thing was seen in study 1003

          where approximately the same amount of patients

          across the treatment groups received photodynamic

          therapy, with some occult patients and minimally

          classic patients, again, receiving photodynamic

          therapy.  What was also interesting was that the

          1003 study was an international study and you can 

                                                                   141

          see that there were approximately half as many

          patients who received PDT in the international

          study versus the American study.  That could be

          based on practice patterns across the ocean.

                    [Slide]

                    We also wanted to look at not so much what

          percentage of patients got photodynamic therapy but

          were more patients in one group or the other

          receiving more treatments?  As we look at this

          chart for study 1004, we are looking at the total

          number of photodynamic therapy treatments.  We see

          that there is substantially less number of

          treatments that were given in the 0.3 mg group

          versus that given in the sham group.

                    [Slide]

                    For study 1003 the results are similar.

          While there is not that big of a difference between

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

          were less photodynamic therapy treatments given in

          the 0.3 mg treated group.

                    [Slide]

                    Lastly, we wanted to look at the results 

                                                                   142

          and say, well, it looks as though the same

          percentage of patients were receiving photodynamic

          therapy; it looks as though the same number of

          treatments were given.  Well, did that make any

          difference in terms of the responder analysis, the

          primary efficacy endpoint?

                    So, what you are looking at here is the

          responder analysis at month 12 for four different

          groups, the first group being the group that

          received no photodynamic therapy either before the

          trial or during the trial.  The second one are

          those patients who only received pre-study PDT.

          The third is a group that received on-study

          photodynamic therapy only.  The fourth group are

          those patients who received pre-study and on-study

          photodynamic therapy.  The last line here is for

          reference so you remember what the primary efficacy

          results were for all patients that we just looked

          at.

                    What we noted, which was good, is that the

          majority of the patients who entered the trial

          never had any confounding or problems with 

                                                                   143

          photodynamic therapy, and that their results

          actually were pretty consistent with the overall

          results.  In terms of the number of patients who

          received photodynamic therapy either before or

          during the trial, or both before and during the

          trial, those numbers were so small that we really

          can't make any conclusions about whether receiving

          photodynamic therapy before or during the trial has

          any effect on the efficacy results.

                    [Slide]

                    Similar results were seen for study 1003,

          where we looked at the number of patients who

          actually received photodynamic therapy.  They are

          extremely small and no conclusions can be drawn

          from using concomitant PDT therapy.  The results

          for those patients who received no photodynamic

          therapy, again, were consistent with the overall

          efficacy results.

                    [Slide]

                    We were curious, I mean, our primary

          efficacy endpoint is really those patients who lose

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

                                                                   144

          the disease process, that patients will continue to

          lose vision so those patients who lose less than 15

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

          we wanted to know was there any possibility that

          you could actually gain vision if you use this

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

          gained greater than 15 letters of vision.

                    If you look at study 1004, actually there

          is a statistically significant increase in patients

          who actually gained vision in the 0.3 mg group and

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

          results were not replicated in the 1003 study where

          you see no statistically significant gain in

          vision.

                    [Slide]

                    So, in terms of our efficacy conclusions,

          we believe that Macugen 0.3 mg does reduce the risk

          of vision loss in patients with neovascular

          age-related macular degeneration.  But keep in mind

          that there is only approximately a 15 percent

          treatment effect over sham, and that there is no

          clinically meaningful increase in vision seen in 

                                                                   145

          patients during the first year of using Macugen.

                    [Slide]

                    The sponsor has presented all of the

          safety results.  I am not going to go back through

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

          similar events were seen in all treatment groups

          and no dose-dependent adverse events were seen.

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

          act of giving an intraocular injection itself and

          no so much to the drug.  The majority of adverse

          events, things like eye pain, superficial punctate

          keratitis, floaters, iritis are those things that

          we commonly seen with intraocular injections of any

          drug.

                    [Slide]

                    But there are two safety concerns that we

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

          endophthalmitis again and also a little bit about

          systemic VEGF inhibition and what that could mean.

                    [Slide]

                    In the database we had there were 16 cases

          of endophthalmitis.  What we heard this morning is 

                                                                   146

          that actually there are 2 more cases.  I guess

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

          of those 16 cases occurred in the pegaptanib sodium

          treated patients, and none of the cases were in the

          sham treated patients.  All 16 cases occurred

          within one week of injection.

                    [Slide]

                    So, I took a look at what kind of

          organisms were actually coming out of the

          endophthalmitis samples.  We see that of the 16

          cases, the overwhelming majority are those types of

          organisms that are commonly seen around the lid or

          around the ocular area--coagulase negative Staph.,

          Staph. epi.  There were about 6 cases that were

          actually negative on the samples.  So, it stood to

          reason that maybe the problem was with the

          injection procedure and the sponsor did take a look

          at that and made some changes.

                    [Slide]

                    The original procedure called for the

          patients to get 2-3 drops of 50 percent saline

          diluted, 10 percent povidone-iodine or they could 

                                                                   147

          receive 1 drop of topical antibiotic.

                    [Slide]

                    An amendment was made in the protocol

          after I think 12 cases of endophthalmitis, and it

          was changed so that patients would undergo a more

          sterile preparation procedure, similar to most

          intraocular surgeries, and patients would be

          prepped and draped similar to intraocular surgery

          and patients would receive either pre-injection

          topical antibiotics for 3 days prior to injection

          or 5 percent povidone-iodine flush immediately

          prior to injection.

                    [Slide]

                    So, what happened to the endophthalmitis

          cases?  Well, we saw in the database that actually

          13 of the 16 cases occurred before the protocol

          amendment.  Three of those 16 cases occurred within

          3 months after the protocol amendment.  This is

          actually wrong now because I guess there have been

          2 additional cases since that time.  Based on the

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

          of endophthalmitis 3 months after the protocol was 

                                                                   148

          amended.

                    [Slide]

                    I just want to touch a little bit on

          systemic VEGF and what that could or could not mean

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

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

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

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

          circulation, mainly because it plays an active role

          in cardiac angiogenesis.  This is important in

          collateral blood vessel formation in patients with

          myocardial ischemia.  It is also an important

          vasodilator and it helps to maintain coronary

          artery blood flow and helps maintain patency of

          coronary arteries.

                    [Slide]

                    So, what we did is we looked at the whole

          database and we said, well, are there any events

          within the database, the adverse event database,

          that could possibly in any way be related to VEGF

          being inhibited in the systemic circulation?

                    Of all the things that we came up with-- 

                                                                   149

          arrhythmia; atrial fibrillation which could be an

          early indication of myocardial ischemia;

          bradycardia; chest pain; coronary artery disease,

          not just those cases where patients obviously came

          into the study with a known diagnosis but those

          patients who were diagnosed with coronary artery

          disease during the trial; and myocardial

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

          well, is there a problem?  Could we actually have

          these systemic anti-VEGF effects based on the

          intravitreal injections?  What you see here on the

          chart is that actually all the numbers are pretty

          small across all the groups, and there is no real

          indication that the intravitreal injection of

          pegaptanib will have any systemic anti-VEGF

          effects.

                    [Slide]

                    Just for completeness, in terms of the

          death rate, there were approximately 25 patients

          who did die during the study, approximately the

          same in each study, and the majority of causes were

          actually things like cardiovascular events, 

                                                                   150

          malignancies and they were pretty typical of the

          age of the population that we were studying.  So,

          we think those events were really due to the

          population and not actually to the drug.

                    [Slide]

                    In terms of safety, similar events were

          seen in all treatment groups.  The most frequently

          occurring adverse events related to the intraocular

          injection itself and not to the drug.  The risk of

          endophthalmitis appears--and I have to emphasize

          "appears" since there may be more cases that we

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

          and there does not appear to be an apparent

          increase in the risk associated with systemic

          anti-VEGF activity.

                    [Slide]

                    We will just go over the questions

          briefly.  You are going to see the questions again

          this afternoon but just so you can start thinking

          about them.  The questions that we would like to

          have discussion about are, one, based on the

          inclusion and exclusion criteria, are there 

                                                                   151

          patients excluded from the studies that you believe

          need to be studied?

                    Visual acuity measurements were conducted

          using the ETDRS scale at 2 meters.  The validity of

          the ETDRS scale was established based on ratings at

          4 meters.  Are the visual acuity findings

          sufficiently robust to overcome the potential bias

          introduced by visual acuity measurements taken at 2

          meters?

                    [Slide]

                    Has sufficient data been submitted to

          evaluate the efficacy and safety profile of

          pegaptanib sodium for the treatment of the

          neovascular form of AMD?  If not, what additional

          data are needed?

                    Are additional analyses of the current

          data needed to understand the efficacy or safety of

          pegaptanib sodium for the treatment of the

          neovascular form of AMD?

                    Has the concomitant use of PDT therapy

          with pegaptanib been explored sufficiently?  Are

          there concerns with using this predictive 

                                                                   152

          concomitantly with PDT?

                    [Slide]

                    Do the route and/or frequency of

          administration of the drug raise any concerns that

          are not addressed by the studies?

                    Endophthalmitis was observed in

          approximately 2 percent of patients in the studies.

          What is the optimal follow-up needed to minimize

          the impact of potential endophthalmitis cases?

                    Are there any other adverse experiences

          that are of particular concern for this product?

                    VEGF has been shown to be an important

          component in the development of collateral vessels

          in ischemic heart disease.  Inhibition of VEGF in

          the systemic circulation could present a

          theoretical increased risk of symptomatic

          cardiovascular disease in the target population of

          elderly patients with AMD.  Has the adverse event

          profile of the two randomized Phase III trials

          raised any concern over the possible systemic

          effects of this therapy?  Is there additional

          monitoring that should be in place for patients on 

                                                                   153

          pegaptanib sodium therapy?  Thank you.

                              Committee Discussion

                    DR. DUNBAR:  At this point I would like to

          open the floor for questions for either the agency

          or for the company.  Dr. Pulido?

                    DR. PULIDO:  Thank you.  Two questions,

          the first one is you said the treatment effect was

          15 percent.  That is because you took the 67 minus

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

          clinician--shouldn't it be the difference divided

          by 50 to give you 25 percent as the treatment

          effect?  So, the delta of 15 over the baseline

          which is 50?

                    DR. CHAMBERS:  There are obviously lots of

          different ways to look at it.  What we have been

          doing for ease of description is just to describe

          what the percentage difference is between the two

          different modes of therapy, and we thought that

          easiest to be described as just a 15 percent

          difference in the percentage of people who have

          lost 3 lines of vision.

                    DR. PULIDO:  The other question I had, and 

                                                                   154

          maybe it would be better answered by the company,

          when one looks at the serum levels, is that the

          total amount of the drug that is being measured or

          is that the unbound free form that is being

          measured?

                    DR. ADAMIS:  It is the total level.

                    DR. DUNBAR:  Dr. Lehmer?

                    DR. LEHMER:  Are there known levels for

          VEGF or VEGF inhibition that are clinically

          significant from the cardiovascular current

          literature?

                    DR. ADAMIS:  The short answer is no in

          humans.  The longer answer is that the most

          sensitive signal of systemic VEGF inhibition is

          hypertension.  In the Avastin trials they picked it

          up in their colon cancer, the renal study, their

          lung cancer study, and some of those were much

          smaller studies than ours and there was no evidence

          of hypertension as a function of use of pegaptanib

          in our study.  So, I guess whatever that level

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

          well below that. 

                                                                   155

                    DR. DUNBAR:  I have a question for the

          agency about the duration of use of the drug.  I

          would like to know who will decide when to stop

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

          physician?  Is this something that will be

          specified by the agency in relationship to the drug

          approval process?  Would it be included in the

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

          for many years and would be addressed in further

          labeling decisions?

                    DR. CHAMBERS:  The most accurate answer is

          that I think we will not know for a number of

          years.  The answer that everybody would like to

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

          of giving a particular product.  We obviously run

          into the difficulty of not having a therapy that is

          potentially valuable available during the time that

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

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

          repeat that decisions have not been made on this

          particular product and there are lots of other

          parameters that still need to be reviewed, but if 

                                                                   156

          this product otherwise looks fine we would

          potentially label it based on the information we

          have available.

                    As you have heard, the sponsor presented

          that as of their latest data safety monitoring

          committee they have 90-some odd percent of the

          information for the two years.  To the extent that

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

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

          data becomes available we intend to amend the label

          to reflect what we know.

                    DR. BULL:  I have one thing to add to

          that.  There is the opportunity for the committee

          to make recommendations if you are uncomfortable

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

          IV commitments.  I mean, there are a number of

          options that can be systematically required of the

          sponsor to do to look at the long term.

                    DR. GUYER:  I think in answer to your

          question, also clinical judgment of the

          ophthalmologist will decide much of it until, as

          Dr. Chambers mentioned, we do have the answer from 

                                                                   157

          continuation of trials.  If a physician sees a

          patient that is, for example, scarred down and

          realizes there is no further benefit of treatment,

          we would expect that the physician would stop that

          treatment, whenever that is and.  Similarly, if the

          physician sees active bleeding going on they might

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

          the clinical ophthalmologist's hands, at least in

          the beginning.

                    DR. DUNBAR:  That was my concern, that a

          patient with a quiescent, scarred lesion was

          vulnerable, worried about their blindness and might

          subject themselves to very frequent injections for

          a long period of time.  Dr. Lehmer?

                    DR. LEHMER:  We are certainly in the era

          of implantable sustained release drug delivery

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

          determined to need to continue past a year or past

          two years, should a recommendation for conversion

          of this drug to an implantable device become

          necessary?

                    DR. ADAMIS:  It is an area that we are 

                                                                   158

          very interested in, in the laboratory of the

          sponsor.  So, we are working on alternative

          formulations to see if we can get an extended

          release profile in implantables of that sort.  I

          think ultimately that may end up being an

          improvement.

                    DR. DUNBAR:  Ms. Knudson?

                    MS. KNUDSON:  I just don't seem to

          understand why the DSMB permitted the trial to

          continue with the sham arm when at every point it

          appears the sham arm is inferior to every drug dose

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

          it, which continually advances and one should treat

          patients.

                    DR. ADAMIS:  Yes, the data safety and

          monitoring committee, their charge was to monitor

          for safety.  But the point you raise is a very

          important one.  So, in this randomized,

          discontinuation trial design we actually allow

          people who discontinue the drug and lose two lines

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

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

                                                                   159

          on sham for two years.

                    DR. DUNBAR:  I have a question for Dr.

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

          presentation that 6/16 endophthalmitis patients had

          sterile endophthalmitis.  I wonder, with your

          experience with endophthalmitis, if you could tell

          us do you think that these patients had infectious

          endophthalmitis that were culture negative, or do

          you think that that may be more of inflammatory

          response?

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

          for both of those things, that is inflammation

          after injection or specifically infections, we

          found really no evidence of a widespread

          inflammatory effect at all.  In studies of

          endophthalmitis in general, for example after

          cataract or other forms of ocular surgery,

          invariably large studies always find that

          approximately two-thirds will be culture positive

          and one-third are, inexplicably, culture negative.

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

          will be organisms that have just not been 

                                                                   160

          successfully collected by the culture technique.

          Perhaps the specimen was too small;  perhaps the

          laboratory didn't plate it properly, or something

          of that nature.  Some of them may be fastidious

          organisms that are difficult to culture.  But

          clinically I think we treat those cases as presumed

          infectious.  The patients had acute presentations

          and they were invariably managed with TAP and

          antibiotic injection.  So, I think that they mirror

          my clinical experience with endophthalmitis cases,

          except somewhat for their outcomes which were

          surprisingly somewhat better.  They suggested

          somewhat better visual outcomes than we might see

          in clinical cases that, for example, would occur in

          another context, after cataract or something like

          that.  Have I answered your question?

                    DR. DUNBAR:  Thank you.  Dr. Gates?

                    DR. GATES:  Any conclusions as to that?

          Is it a smaller bacterial load perhaps with this

          injection?

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

          phenomenon.  Certainly, these patients were 

                                                                   161

          extremely well followed and they included, you

          know, contact with the patient and education to

          inform patients about side effects, etc.  So, the

          patients were promptly detected, but it could be

          that the load that is introduced in an intravitreal

          injection is lower and, consequently, it has a less

          fulminating presentation, but I don't know.

                    I will raise it because someone will, it

          also may be that there is some interaction between

          a VEGF medication and a profound inflammatory

          infection in an eye.  But that remains completely

          speculative but it is something interesting, as a

          scientific point of view, for further research.

                    DR. ADAMIS:  Just to follow on Dr.

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

          laboratory now that VEGF can be pro-inflammatory,

          and in models of ocular inflammation VEGF levels

          come up and it is associated with the vitritis and

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

          if you block VEGF in that sort of instance you can

          decrease the inflammation as well as the leak.  So,

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

                                                                   162

          plausible hypothesis that it may be having somewhat

          of an anti-inflammatory effect as well and you get

          less standard damage that occurs when neutrophils

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

          theory.

                    DR. DUNBAR:  Dr. Chinchilli?

                    DR. CHINCHILLI:  Yes, I have a question

          for the agency.  In the briefing document you

          showed the results from the worst-case analyses.  I

          notice that in your presentation you really didn't

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

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

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

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

          they are in the briefing document, or am I reading

          too much into that?

                    DR. CHAMBERS:  We do a large number of

          analyses, which are neither shown in the briefing

          document nor shown in the presentation, to try to

          look at the robustness of the findings.  We thought

          it instructive to give what potentially is a bottom

          lower limit and include it in the briefing document 

                                                                   163

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

          magnitude could be of inclusion or exclusion of

          different findings, but since it does not

          necessarily represent an accurate finding we didn't

          think, from a time perspective, that it was worth

          continuing to present in a presentation.

                    DR. CHINCHILLI:  Well, I think it is

          highly inaccurate.  I know you try to look at the

          bounds but I think they are highly inaccurate

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

          get into this now, but I do have some

          recommendations about analyses, endpoints and

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

          that now.

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

          We don't think either of the analyses are

          necessarily the most accurate; we could do

          something in between.

                    DR. DUNBAR:  Is there additional

          discussion for the agency presentation at this

          point in time?

                    [No response] 

                                                                   164

                    Now we have a decision about our agenda

          because we have significantly more time with our

          morning session than we expected.  It is imperative

          that we start the open public hearing as it is

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

          their voice in this matter.  We have two options.

          One is that we can take a longer lunch period and

          then start the agenda for the afternoon as

          previously published.  Or, we can begin to answer

          some of the FDA questions now and start our lunch

          closer to the scheduled time and then have the

          public hearing at 1:00 p.m.

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

          questions now and then we will, of course, begin

          the public hearing at 1:00 p.m.

                    DR. CHAMBERS:  We would like to hear some

          general discussion as opposed to just going through

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

          some of the time this morning, just a general

          discussion of the different topics that are on

          there and then specifically go through questions

          later. 

                                                                   165

                    DR. DUNBAR:  Then we will start with Dr.

          Chinchilli in terms of general discussion from the

          committee.

                    DR. CHINCHILLI:  Well, I mentioned this in

          my previous question and I would like to talk about

          the endpoint that is used and the analysis.  I

          don't quite understand why the analysis was done

          this way, and then looking at the briefing

          documents I see that this is the way the FDA

          recommends the analysis be done.  But there is

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

          would be better to reverse the definition, to look

          at someone who fails, someone who is a treatment

          failure who has 15 or more letter loss and then

          look at the time to occurrence of that event.  This

          way you would better handle the dropouts and the

          censoring that occurs.

                    Now, I realize the subjects in these

          particular studies come into the study every six

          weeks so you don't have a nice continuum for

          determining when this treatment failure takes

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

                                                                   166

          failure time process.  It would just get away from

          looking at these extreme cases, the worst-case

          scenario that the agency likes to look at in terms

          of bounding the results.  It just seems to me that

          that would be a better approach to the analysis,

          that is, to reverse the definition and talk about

          treatment failure and look at time until treatment

          failure occurs, and doing time to event analyses.

          That would be a much more accurate analysis, I

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

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

          there is some reason I am missing that that is not

          a good approach.  And, maybe the company would like

          to comment on that as well.

                    DR. CHAMBERS:  We are certainly open to

          looking at a number of different types of analyses

          and different ways of doing it.  The general

          recording of visual acuities has been every three

          months, not every six weeks.  Consequently, you

          have set fixed time points when you are getting the

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

          at every three months, we have not thought as being 

                                                                   167

          particularly meaningful.

                    Whether you look at it on either side of

          this coin, whether it be the people that improve or

          the people that fail, we have generally thought as

          being relatively similar.  There are certain biases

          that go in as far as the dropouts and which way

          they are treated.  Obviously, if you are assuming

          that somebody is going to drop out and they never

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

          That accounts for some of the reason for doing a

          number of the analyses that we do.

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

          different analyses looking at these things to try

          and look for the robustness of the findings.  In

          this particular case, any way you look at it you

          have very similar results.  So, we did not stress

          how it needed to be presented for this particular

          case.

                    DR. CHINCHILLI:  I agree.  I mean, the

          dropouts in these two trials was between 10-12

          percent so that is not extreme.  But I think you

          are going to have trials where you may see more 

                                                                   168

          dropouts, a higher rate than that, and all these

          cases that you are proposing for analysis all

          involve some form of data imputation.  If you look

          at the treatment failure approach and time to event

          analysis, you know, you account for that censoring

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

          current methods.  You know, I think I am getting

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

          with me the way the outcome is constructed and all

          these analyses are performed that involve some form

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

          it makes a bit of difference with these two

          particular trials here but in general it is not

          really good methodology.

                    DR. CHAMBERS:  We certainly are interested

          in additional comments you have along that,

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

          have some type of bias and some type of assumptions

          in the way it is presented, including the methods

          you are discussing.

                    DR. DUNBAR:  Dr. Lehmer?

                    DR. LEHMER:  I just want to make sure I 

                                                                   169

          understand correctly that, with regard to the

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

          presented, being the most inclusive; the

          per-protocol analysis being the most exclusive.  As

          I understand from the briefing, when the two were

          compared there were no significant differences and,

          therefore, that is why we are using the

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

          as possible to get the safety data.  Is that a

          correct interpretation of why we are using the

          intent-to-treat analysis?

                    DR. ADAMIS:  The safety data population is

          even a little bit larger.  Everybody was randomized

          and received one treatment.  The intent-to-treat

          was the folks who had one baseline vision as well.

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

          Maybe we can just summarize this.

                    [Slide]

                    This shows the definition of the various

          populations that we looked at, and it shows that

          the all-randomized group were those that received

          an actual randomization number.  In this case it 

                                                                   170

          was 1,208 and that represents the largest

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

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

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

          sponsor's definition, that received study drug and

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

          The per-protocol was all of the ITT patients that

          had an observed post-baseline vision and no major

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

          much smaller group because they observed the

          protocol perfectly and also had an observed time

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

          Then you have a week 54 observed which are the

          actual patients who received the study drug and had

          a baseline vision and also a week 54 vision, and

          that is 1,085.

                    [Slide]

                    Just to illustrate further maybe some of

          the differences, E-102 shows again, starting with

          the all-randomized where you start with 100 percent

          of your population, going down to week 54 where you

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

                                                                   171

          mg.

                    [Slide]

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

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

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

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

          medication and baseline visual acuity occurred,

          which is in our briefing book.  Very importantly,

          you can see that they are all the same.  Slide

          E-113.

                    [Slide]

                    We can see that on the left we have the

          ITT population using an LOCF, which is in the

          sponsor's briefing book, and we have the

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

          the FDA briefing book.  Then we have some of the

          extremes, the per-protocol observed and the week 54

          observed.  Then you can see that we have very

          robust data and that the sensitivity analysis and

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

          statistically significant change.  So, any way you

          look at it, either extreme, we see robustness of 

                                                                   172

          the data.

                    DR. DUNBAR:  Dr. Pulido?

                    DR. PULIDO:  Ms. Chairwoman, your question

          had been do we have general comments at this point,

          and I would just like to state that I think the

          data at this point looks very favorable.  I would

          say that my concerns about systemic complications,

          from the data, appear very small.

                    My only concern is the long-term use and

          the fact that there is the second aspect of VEGF

          that only recently we are learning about, and I

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

          ERGs and possibly visual fields in a small group of

          these patients to make sure that there are no

          long-term consequences of long-term use of this

          drug.  Otherwise, I am very impressed.

                    DR. DUNBAR:  Are there any other general

          comments from committee members?  Dr. Steidl?

                    DR. STEIDL:  You can correct my thinking

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

          lesions continued in general to grow, maybe at a

          slower rate, in the treated group.  With the 

                                                                   173

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

          effective vitreous concentrations that are weeks,

          it would seem with that trend that it is quite

          possible that this may be needed for a while beyond

          the study time period.  You know, somebody

          mentioned the 0.16 percent per injection in

          endophthalmitis rate.  If you multiply that times

          nine it gets pretty close to what was seen.  I

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

          then if you start thinking about doubling the time

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

          view, it is getting pretty scary.

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

          point of view, as sterile endophthalmitis because

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

          infectious cases that don't come back positive.  I

          am wondering if that seems like a logical

          assumption, that if this is to carry on we could

          assume that the endophthalmitis rate would grow

          proportionally.

                    DR. ADAMIS:  Yes, I think your

          interpretation of the data is correct and, 

                                                                   174

          obviously, the cumulative risk increases as a

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

          this responsibility seriously, is to make sure that

          the injection procedure, which may be a modifiable

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

          We were fortunate in the second year after the

          amendment to actually see that rate go down and,

          subsequent to the amendment that occurred last May,

          it is down to 0.03 percent per injection.

                    The other aspect of it that is equally

          important is the visual outcome.  That is, if this

          event happens, are these patients being diagnosed

          rapidly and being treated appropriately, and then

          doing everything you can to preserve the vision as

          a function of getting the infection.  I think our

          investigators did a rather superb job in the sense

          that everybody was diagnosed within a week.

          Everybody got intravitreal antibiotics.  Over half

          of them had vitrectomies and you saw the visual

          outcomes.  I will tell you that the visual outcomes

          in the second year with the additional cases are

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

                                                                   175

          data presented today.  But your thesis is correct

          that the more you use the drug, there obviously is

          an incremental risk over time that increases.

                    DR. DUNBAR:  Dr. Pulido?

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

          using intravitreal injections, but the alternative

          is the present forms of treatment or systemic

          medication that also increase the risk.  It is a

          small risk but I would rather take that risk than

          give something that has systemic effects.

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

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

          the context of the potential benefit.  So, the

          reduction in severe vision loss is greater than 50

          percent and the severe vision loss we saw as a

          function of endophthalmitis was 0.1 percent.  On

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

          the benefit outweighs the risk.

                    DR. DUNBAR:  Dr. Lehmer?

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

          data are very impressive.  Along the lines of what

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

                                                                   176

          Obviously, we are not able to really assess that

          based on the numbers, but taking this information

          forward, seeing what are the clinicians going to do

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

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

          with macular degeneration, do we use Macugen?  Do

          we use PDT?  Do we use both?

                    I suppose if patient recruitment were

          going to start now we would see a much larger

          percentage of the European community using PDT

          since it has been approved there and there has been

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

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

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

          impact of PDT.

                    DR. GUYER:  I think that is a very

          important point.  One of the things that was

          important to us when we designed this trial was to

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

          possible.  That is why we allowed photodynamic

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

          lot about combination use or anything like that, 

                                                                   177

          but I agree with you that certainly future trials

          will be able to address those issues and it is

          important.

                    DR. DUNBAR:  Mr. Kresel?

                    MR. KRESEL:  I guess being the pragmatic

          industry representative, I will ask the question

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

          lot of discussion about endophthalmitis and I think

          you gave a really good answer as far as how the

          patients were treated and how they were followed

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

          know, they came back to see the physician at these

          intervals.  So, would you recommend in labeling

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

          tracked and, in fact, appropriately diagnosed and

          treated?

                    DR. ADAMIS:  The optimal follow-up I think

          still remains to be determined.  One of the things

          we have done is we have given grants to specialists

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

          a preferred practice recommendation.  The only

          thing we can say is what we did and what the 

                                                                   178

          results were.  I think it is still an open question

          as to which variables that we changed, and we

          changed multiple and, as I said, the steroid

          injections were taking place at the same time in

          another population--which of those factors is the

          most important still remains to be determined and I

          think a lot more work needs to be done in that

          area.

                    So as regards to what we will recommend,

          it is still being decided.  Until we hear back from

          the experts we obviously will tell people what we

          have been doing and the results that were

          associated with that.

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

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

          the last three or four years there has been a

          tremendous experience in the retinal world with the

          use of off-label intravitreal steroids because

          there is such an unmet medical need not only for

          this disease, macular degeneration, but also for

          diabetic macular edema.  So, I actually think there

          was a tremendous learning curve for retinal 

                                                                   179

          physicians learning the best way to do intravitreal

          injections.  That occurred.  We talked about the

          protocol amendment and we hope that that had some

          effect.  But I think also equally important may be

          that the retinal doctors had a very, very good

          experience of the best way to practice intravitreal

          injection administration.

                    As Tony mentioned, we did sponsor a

          roundtable to try to get the thought leaders

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

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

          the findings from that that could help guide us.

                    DR. D'AMICO:  Yes, under an educational

          grant a roundtable was convened to look at the

          growing use of intravitreal injections in

          ophthalmic practice, and to try to assemble the

          best available information on what we know about

          how to make this procedure as safe as possible.  In

          this roundtable there were experts from the point

          of view of infectious disease, from the point of

          view of vitreal-retinal surgeons, people who deal

          with antibiotic levels within the eye, and also 

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          substantial representatives across industry who

          have pharmaceuticals that are used by intravitreal

          injection.  While all I can tell you is that an

          article is in preparation that will be ultimately

          submitted to peer review literature, we have

          initial plans to submit that article to the journal

          Retina.  It includes things such as the premise of

          using povidone-iodine which emerged as an

          incredibly important central aspect of using a lid

          speculum.  We were finding that, in many casual

          surveys, people would do injections and allow the

          lid margins, etc. to contaminate the needle, and

          probably most importantly, to treat this as a

          sterile intraocular procedure.

                    I was present.  I was asked to be a part

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

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

          document will be very valuable in helping the

          evolution of the understanding of intravitreal

          technique.  So, it will become something that I

          think we can go forward with.  We can look at

          various modifications now to make this safer and 

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          safer.

                    But having participated in both the data

          safety committee and also this panel, I am quite

          convinced that the protocol modifications had a

          very real effect on reducing the incidence of

          endophthalmitis, and I am confident that incidence

          can be kept low and probably be even further

          reduced with appropriate education of both patients

          and physicians, as well as appropriate training.

                    DR. DUNBAR:  Dr. Pulido?

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

          recent article I believe in The American Journal of

          Ophthalmology.  It included people from Baskin

          Palmer, looking at the incidence of endophthalmitis

          following intravitreal triamcinolone injections,

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

          it?

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

          never have been known when these trials were begun,

          but intravitreal injections have become quite

          commonplace in retinal practice now with off-label

          use of triamcinolone and the incidence which has 

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          been reviewed shows that it is substantially

          higher.  Although I believe that that incidence, in

          fairness, is decreasing as physicians treat the

          injection technique with additional seriousness and

          care.  But, actually, a detailed review has been

          made available to this review committee and showed

          that the rate of endophthalmitis following

          intravitreal injection with pegaptanib was well

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

          for intravitreal medication administration across

          the board.

                    DR. DUNBAR:  Ms. Knudson?

                    MS. KNUDSON:  The only thing that confuses

          me a little is that you say that no patients

          receiving the sham treatment had endophthalmitis.

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

          causing it?

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

          not receive the penetration of the eye with the

          needle so that explains why it is that event which,

          presumably, allows bacteria to gain entry into the

          eye. 

                                                                   183

                    DR. DUNBAR:  Recently several of the

          comments reflected not so much concerns about the

          statistical significance of the efficacy of the

          drug but, rather, concerns for the future.

          Previously Dr. Bull mentioned that the committee

          can make Phase IV recommendations for plans for the

          future, for future studies.  What is the mechanism

          for this?  And, perhaps this is an appropriate time

          for the committee to discuss some of these future

          concerns.

                    DR. BULL:  That would fundamentally fall

          under recommendations for additional studies.  If

          these are data deficiencies that you might see as

          impacting marketing of the product, it would argue

          against whether or not you feel the data is

          sufficient at this point in terms of the efficacy

          assessment.  If these are data needs that need to

          be obtained in a systematic way, they can certainly

          not hold up marketing of the product if you feel

          there is sufficient efficacy in terms of what you

          have seen.

                    We realize this is an incomplete data set 

                                                                   184

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

          given the earliness of where we are in this

          submission.  In fact, there are modules in the NDA

          that have not come in and have not been vetted by

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

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

          terms of the re-randomization.  There are a number

          of sort of outstanding assessments here that I

          think certainly have significant implications for

          further work.  But I think things that need to be

          looked at systematically certainly have the

          potential of being addressed in Phase IV.

                    DR. DUNBAR:  Dr. Pulido?

                    DR. PULIDO:  Just for clarification, that

          could be a postmarketing surveillance.  For

          instance, study ERG could be postmarketing,

          following marketing approval surveillance in that

          regard.

                    DR. BULL:  You mean is post-approval?

                    DR. PULIDO:  Yes.

                    DR. BULL:  Potentially but, again, as I

          said there is a huge caveat here that we are still 

                                                                   185

          very early in the review of this application and

          there are a number of other aspects, particularly

          from chemistry manufacturing issues, that will need

          to be addressed and other things that will impact

          the totality of our assessment of the data.

                    DR. DUNBAR:  Dr. Chambers and then Mr.

          Kresel.

                    DR. CHAMBERS:  Let me just clarify, the

          range of different options includes additional

          Phase III trials, additional Phase IV clinical

          trials, as well as postmarketing commitments,

          postmarketing monitoring.  There is going to be a

          certain amount of postmarketing monitoring that

          automatically goes with any new drug product.  But

          what you are describing would probably more

          accurately be done as actual controlled clinical

          trials because you want, obviously, a baseline as

          well as continued follow-up in order to look for

          any potential changes.  That is probably better

          done with a control group and making sure you have

          everybody in your trial.

                    DR. DUNBAR:  Mr. Kresel? 

                                                                   186

                    MR. KRESEL:  I guess my question isn't

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

          rest of the committee because it is not one for me

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

          and I have heard people commenting on how long can

          we use this drug and what are the consequences, I

          guess I would like to hear the committee weigh in

          on how much follow-up post-approval the committee

          thinks is appropriate, for planning purposes.  That

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

          years of data pretty soon.  How much data does the

          rest of the committee think is appropriate to

          continue follow-up?

                    DR. DUNBAR:  Dr. Pulido?

                    DR. PULIDO:  Trying to answer your

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

          don't know whether it is necessary to do a

          randomized, controlled trial for the results of

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

          change whatsoever so that if you take the patients

          that already have been in the trial for a year and

          do ERGs in a small group of them and compare it 

                                                                   187

          even to the fellow eye and there is no difference,

          well, that tells you volumes.  That decreases the

          chances of having to go ahead and do another

          randomized, controlled trial and slow the

          acceptance of this drug into the marketplace.

                    DR. DUNBAR:  Dr. Chambers?

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

          think there is likely to be decreased ERG in

          patients that had macular degeneration compared to

          the other eye?

                    DR. DUNBAR:  Dr. Pulido?

                    DR. PULIDO:  Not necessarily because

          macular degeneration is such a localized area that

          is involved that the ERG overall may not be

          affected.  We know that macular disease does not

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

          concern, again, is, is this affecting a broader

          area of the retina than what we are measuring by

          doing visual acuity measurements?  If that is not

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

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

          talking necessarily about delaying it, but I guess 

                                                                   188

          the question still in my mind is interpretation.

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

          you do see something, is that necessarily the drug

          product or is that the disease going on?  And you

          don't know the answer to that.

                    DR. PULIDO:  Then you would have to do the

          trial you were considering.

                    DR. DUNBAR:  Taking a step back to Mr.

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

          committee members if there is any sense among the

          committee to build a consensus of how long the

          company should study the drug for the future after

          this they finish this planned two-year period.  Not

          so much requesting additional data such as the

          visual field and ERG that Dr. Pulido mentioned, but

          just to continue the clinical trial, is there any

          sense among the committee?  Dr. Lehmer?

                    DR. LEHMER:  In the PDT studies there was

          a physical endpoint of no leakage.  Is there a

          similar endpoint with regard to this study looking

          for that type of endpoint or stabilization of

          vision?  I think we have to have some kind of 

                                                                   189

          clinically meaningful endpoint on which to base the

          answer to that question of how long do we carry the

          study for and, therefore, how long do clinicians

          expect to carry on the treatment.

                    DR. GUYER:  In the photodynamic studies

          there was  continued leakage.  When they decided to

          retreat they would do a fluorescein angiogram to

          determine that.  But over the course of the year,

          similar to what we have seen, there was still

          leakage occurring and that us the disease, and Tony

          can perhaps give us some hypothesis for why.

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

          data will be very, very important in the sense that

          we will learn more about two years of therapy

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

          mentioned earlier, I think what is nice about the

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

          a patient who has significant disease with large,

          scarred, poor vision obviously wouldn't be

          necessarily a good candidate to continue treatment.

          Someone that might not have any leakage, as you

          say, could be used as a clinical endpoint for 

                                                                   190

          perhaps stopping treatment, and people who are

          actively bleeding would continue.

                    But it is important to say that really the

          only recommendation we can make is this clinically

          important finding is based on one year or 54 weeks

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

          more and it would be dangerous to try to speculate

          that less treatment could give the same effects.

          So, we believe that clinical judgment would be

          very, very important in determining long-term

          treatment.

                    DR. DUNBAR:  Dr. Pulido?

                    DR. PULIDO:  The other thing that I think

          is important is the fact that even with one-year

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

          group of patients?  Wasn't it 10 percent or

          something?

                    DR. ADAMIS:  It was two percent in treated

          and sham alike.

                    DR. PULIDO:  Right, so I mean you are

          already getting to a point where there is a certain

          mortality in these elderly patients.  To continue 

                                                                   191

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

          find a higher mortality rate and I don't know

          whether we are going to find more than what we are

          already finding.

                    DR. DUNBAR:  Is there any additional

          discussion at this time?  If not, at this point

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

          p.m. for the public discussion.

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

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

                                                                   192

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

                              Open Public Hearing

                    DR. DUNBAR:  We are beginning the

          afternoon session of the Dermatologic and

          Ophthalmic Drugs Advisory Committee on Macugen with

          an open public hearing.

                    Both the Food and Drug Administration, the

          FDA, and the public believe in a transparent

          process for information gathering and

          decision-making.  To ensure such transparency at

          the open public hearing session of the advisory

          committee meeting, FDA believes that it is

          important to understand the context of an

          individual's presentation.  For this reason, FDA

          encourages you, the open public hearing speaker, at

          the beginning of your written or oral statement, to

          advise the committee of any financial relationship

          that you may have with the sponsors of any products

          in the pharmaceutical category under discussion at

          today's meeting.  For example, this financial

          information may include the sponsor's payment of

          your travel, lodging, or other expenses in 

                                                                   193

          connection with your attendance at the meeting.

          Likewise, FDA encourages you at the beginning of

          your statement to advise the committee if you do

          not have any such financial relationships.  If you

          choose not to address this issue of financial

          relationships at the beginning of your statement,

          it will not preclude you from speaking.

                    At this point of the open public hearing,

          I will ask speaker number one to please come to the

          podium.  Each speaker will have seven minutes to

          present.

                    MR. GARRETT:  Hi.  My name is Dan Garrett

          and I am with Prevent Blindness America.  My

          organization paid for my own travel to come here

          today and I personally do not have a financial

          relationship with any of the companies pertaining

          to this drug.

                    I mentioned I am with Prevent Blindness

          America.  We are the second oldest voluntary health

          agency in the country.  We represent organizations

          throughout the country that primarily focus their

          efforts on screening, training, advocating, 

                                                                   194

          researching and educating people on the importance

          of good vision care.  We also advocate for

          increased research funding and increased funding to

          the Centers for Disease Control in Washington, and

          we try to impact public policy as it relates to

          saving sight and vision loss.

                    The reason I am here today is not to

          endorse this product but to encourage the committee

          to make the right decision as it relates to the

          science behind this drug.  It might suggest that

          this could prevent further vision loss for people

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

          organization does not endorse the product of

          discussion today.

                    A few thoughts and figures, and I wasn't

          here earlier today so forgive me if these are

          repetitive.  It is important to point out that

          nearly 1.7 million Americans aged 40 and older have

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

          number of blind and visually impaired could

          possibly double.  So, we are talking about a fairly

          significant population.  It is very important that 

                                                                   195

          this committee consider this drug because it has

          the potential to potentially stop vision loss.

          Unfortunately, there is not a miracle drug out

          there yet that prevents AMD but, hopefully, with

          all the science and research that is going on that

          will be in the near future for us.

                    Another interesting statistic, and this

          could particularly hold for people with AMD because

          they are the ones that have most low vision, vision

          impairment is the cause of 18 percent of hip

          fractures, and most people that have AMD are living

          on their own and they have lost their central

          vision so it is very difficult for them to navigate

          their way around their home.  If only one in five

          of those hip fractures were prevented, more than

          440 million dollars could be saved annually so that

          is significant.  So, any type of AMD drug that

          could prevent further vision loss is certainly a

          welcomed addition to the marketplace for patients.

                    My organization, again, advocates

          advancements in treatment of AMD, and I just want

          to say to the committee that I am sure you will 

                                                                   196

          make the right decision on behalf of all the older

          Americans in this country for the people that have

          AMD.  Anything that can prevent further vision loss

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

          Thank you.

                    DR. DUNBAR:  Thank you.  At this point I

          will ask speaker number two to come to the podium.

                    MS. HOFSTADTER:  Good afternoon.  I am

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

          financial ties with the drug company except my stay

          in the hotel and my travel.

                    I was diagnosed with AMD two years ago.  I

          belong to an HMO.  The HMO doctors checked me and

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

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

          called the Jewish Eye Clinic and asked if there was

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

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

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

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

          do not sell your car because we might can help

          you." 

                                                                   197

                    So, I took some lasers, some Visudyne in

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

          legally blind.  Then I was approached by Dr.

          Gonzalez who asked me if I would like to step into

          a clinical trial with Macugen shots.  Well, it was

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

          was sent to Auschwitz and I was experimented on by

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

          choice to make.

                    I didn't think long about it and I thought

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

          got into the clinical trial and I got a Macugen

          shot in my right eye.  It sounds very scary but

          really 20 minutes of discomfort is a small price to

          pay.  After the third shot I gained my sight back

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

          altogether 12 shots and three weeks ago I had my

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

                    And I really want to thank the researchers

          who worked so hard to find a drug like Macugen to

          help us for this dreadful disease.  Thank you.

                    DR. DUNBAR:  Thank you.  Next I will ask 

                                                                   198

          speaker number three to come to the podium.

                    MR. STEVENSON:  My name is Nick Stevenson.

          I am the president of the Association for Macular

          Diseases.  It is the only national support group

          that is solely concerned with both the practical

          and the emotional problems confronted by

          individuals and families endeavoring to cope with

          our particular type of eye disorder.  To do that,

          we publish a newsletter which advises our members

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

          not.  There is an increasing number of scams and

          frauds which are proliferating now not only in

          numbers but in funding as well, and we maintain a

          members hotline where members can always call in

          and we can act as a link between them, their

          problems and the problems that they may face.

                    I, myself, have been legally blind from

          the wet type of macular degeneration for 26 years.

          I have no financial interest in this pharmaceutical

          company or actually any, except that they did pay

          my travel and expenses to come down here.  But what

          I would like very much to emphasize for all of you 

                                                                   199

          is something that many of you, I can understand,

          have already experienced, how difficult and

          understandably difficult it is for a fully-sighted

          person to fully appreciate the enormous subtraction

          from life that loss of vision represents, for some

          far more than for others but, nonetheless, it is

          not something that any of us foresaw in earlier

          years of our lives.  We may have thought of

          disasters overtaking us, such as being struck by an

          automobile or some disease attacking us in a way

          that we found ourselves to be vulnerable.  But the

          loss of vision is something that few of us have

          ever contemplated.  We felt that there was a

          warranty issued on our eyes and we had the full use

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

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

          circumstances appears.

                    Now, it must be admitted that macular

          degeneration varies widely in the degree of

          severity with which it affects individuals.  But

          for those with more severe type, such as this drug

          addresses, they have the problem of not recognizing 

                                                                   200

          the faces of their friends, or their enemies if

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

          in a society where an automobile is as automatic a

          feature as a horse once was out West, or even

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

          taken away.

                    In addition to that, the inability to read

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

          very serious detraction from quality of life.  That

          blue sign over there; it is that entrance right

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

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

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

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

          but they have a cumulative effect and what is very

          difficult for a great many of us to understand

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

          degeneration is a progressive disease.  As the

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

          the dry type or whether we have the wet type.

                    So, it seems to me high time that some

          action was taken to try to avert the further 

                                                                   201

          incidence of macular degeneration in its various

          forms for the people who follow behind us.  It has

          been said of older people that, as they think of

          their lives, the days grow longer and the years

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

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

          finding the cure of polio back in 1954--something

          may appear that will give us some surcease from the

          anxiety, and the apprehensions, and the limitations

          of macular degeneration.  Thank you.

                    DR. DUNBAR:  Thank you.  Now I will ask

          speaker number four to come to the podium.

                    MR. AUGUSTO:  Good afternoon.  I am Carl

          Augusto, president and CEO of the American

          Foundation for the Blind, an organization that is

          dedicated to expanding the rights and opportunities

          of people who are bind or visually impaired in this

          country.  Like Helen Keller before me who devoted

          44 years of her life to the American Foundation for

          the Blind and its causes, I am always grateful to

          speak to governmental officials, corporate America

          and the general public on how we can improve the 

                                                                   202

          lives of people who are blind or visually impaired.

                    In my 30-plus years working as a

          rehabilitation counselor and as an administrator in

          agencies serving the blind and visually impaired, I

          have seen first-hand the many difficulties faced by

          those who are losing their vision as a result of

          AMD, age-related macular degeneration.  After

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

          sense of sight, not seeing well enough or seeing at

          all can certainly turn the world upside down for

          those people and their families.  Add to that other

          physical ailments, physical disabilities, personal

          and social hardships that older people, many of

          them, experience the emotional and the functional

          adjustment to vision loss is very, very difficult.

                    Ordinary daily activities become

          challenging, if not impossible.  If you can imagine

          not having the opportunity or not having the

          ability to read the morning newspaper, to drive to

          supermarket to get your groceries, to do your

          personal business, to read your personal mail, to

          cook for yourself--this is what is happening with 

                                                                   203

          so many people losing their vision in this country.

          Moreover, it is difficult to adjust emotionally and

          functionally to a certain level of visual loss if

          that vision worsens next month.

                    One of the first clients that I had as a

          rehabilitation counselor was a gentleman suffering

          from age-related macular degeneration.  He was

          about 50 years old and his deterioration rate was

          steady over the course of time, and he was really

          overwhelmed by this.  His name was Jack.  Jack had

          lost confidence in his capabilities.  He felt that

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

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

          beginning to adjust, I lose more vision and the

          despair sets in again."

                    Well, his visual loss forced him to retire

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

          financial hardship to his family.  He was staring

          at the walls every day and not feeling productive

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

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

          and now he was on my doorstep, wanting answers to 

                                                                   204

          how to live independently.

                    I remember thinking that, gee, if I had

          seen him a little earlier, or if the progression of

          his sight loss was not as significant I might have

          been able to help him realize that he could do his

          job still using alternate techniques or technology.

          But he lost his vision much too quickly and he did

          give up.

                    Now, my blindness is caused by a recessive

          gene disorder and it started when I was very young.

          When I was eight years old I started losing my

          vision and my loss was very gradual over the course

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

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

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

          opportunity to learn the skills that I needed to

          function independently at home and on the job.  I

          had an opportunity to tackle the emotional hurdles

          that inevitably arise with severe vision loss, and

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

          satisfying as anyone's.

                    Now, AMD is the leading cause of severe 

                                                                   205

          visual loss in our country, and this visually

          impaired population will continue to increase as

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

          are outliving our eyes and delaying the effects of

          AMD or stopping the effects of AMD would give

          millions of people more time to adjust emotionally

          and functionally, to locate rehabilitation

          facilities, and to develop the skills that are so

          critical in helping them to function independently.

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

          deterioration would be a blessing.

                    There are services for people who are

          blind or visually impaired.  Low vision services

          that are delivered by specially trained eye care

          professionals enhance the remaining usefulness of

          your vision when you do have vision remaining.

          Other rehabilitation services are available from

          private and public agencies throughout the country

          to help you with personal management skills and

          also vocational skills.  And, assisted technology

          is revolutionizing the way blind and visually

          impaired people function. 

                                                                   206

                    However, there are two problems.  Many

          people with age-related macular degeneration and

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

          programs are available and they may not be in their

          own communities.  Secondly, we don't have the

          funding in this country, federal or otherwise, to

          support sufficient services to meet the growing

          need for services for the increasing population of

          blind and visually impaired people.  So, anything

          we can do to reduce the numbers of this population

          would be helpful in that regard.

                    In closing, blind and visually impaired

          people can live and work with dignity and success

          alongside their sighted peers.  People can adjust

          and learn new skills and also to live

          independently.  But many of them need time to

          develop.  Many of them are not adjusting when their

          vision continues to deteriorate, and without a

          chance to learn to cope with vision loss gradually,

          I am afraid that too many people will be like Jack

          and will give up on themselves before they realize

          that there is help out there that could help them.  

                                                                   207

          Thank you.

                    DR. DUNBAR:  Thank you.  Now I want to

          request that speaker number five come to the

          podium.

                    DR. ROSENTHAL:  I am Bruce Rosenthal,

          Chief of Low Vision Programs at Lighthouse

          International, New York City and Mount Sinai

          Hospital.  My organization paid my expenses.

          However, in the past I have had an unrestricted

          educational grant from Novartis for a booklet on

          vision function.

                    Over 75 percent of the visually impaired

          patients I have examined for the past 30 years have

          a diagnosis of age-related macular degeneration.  I

          have been witness to how the devastating effects

          that progression severe vision loss, especially

          from the neovascular form of the disease, impact on

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

          how severe vision loss affects an individual's

          quality of life, impacts on their independence,

          lowers their self-esteem, and results in

          depression.  In fact, clinical studies have shown 

                                                                   208

          that over 57 percent of people with retinal disease

          have depression.

                    As a clinician, I am very concerned with

          retaining visual function.  Neovascular AMD has the

          effect of destroying vital components of visual

          function.  We are all familiar with visual acuity,

          as well as the importance of preserving it.  But

          other vital components of vision are also

          irreparably destroyed by the effects of AMD.  They

          include contrast sensitivity, and in lay terms that

          is how much a pattern must vary in contrast to be

          seen, and has become increasingly recognized as an

          important factor in influencing the quality of

          life.  We are also interested in retaining usable

          visual field, color perception and stereo-acuity,

          just to name a few.

                    The medical advances, as we all know, that

          have taken place in the past 30 years have been few

          and far between.  However, thermal laser as well as

          PDT have really helped to slow the progression and

          maintain visual function, and one example that I

          will give to you as a clinician is that the early 

                                                                   209

          patients I was seeing with low vision would go from

          20/800 down to light perception.  My patients now

          usually fall in the end stage between 20/200 and

          20/400.  Yet, serious vision loss continues despite

          these interventions, as we know.

                    As Carl Augusto mentioned, we seem to have

          an impact, however, with vision rehabilitation.  As

          a low vision clinician, I have seen that

          individuals with AMD who have access to the latest

          treatments benefit more from vision rehabilitation

          services as well.  These individuals have a greater

          success rate in the use of low vision optical

          prescriptive devices, absorptive lenses, as well as

          high tech and electronic aids.  These people can

          continue to be employed, travel independently,

          manage their own affairs, maintain their own

          residence and perhaps even drive.  Again, I

          recommend that you consider the treatment that will

          help preserve visual function and its benefits to

          society.

                    DR. DUNBAR:  Thank you.  This concludes

          the five members of the public that have registered 

                                                                   210

          to speak at the open public hearing.  However,

          there are some additional members of the public

          that have approached us requesting to speak and,

          time permitting, they will be allowed to come to

          the podium and give two-minute presentations.  So,

          I will ask if there are any other members of the

          general public that wish to come forward at this

          time.  Thank you.  We have someone coming forward.

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

          ophthalmologist in practice, retinal diseases, in

          Baltimore.  I congratulate the sponsors and

          certainly hope that this is approved.

                    I did want to comment that I am concerned

          about the problem of endophthalmitis in terms of

          the fact that the drug is very broadly applicable

          drug that covers all subtypes of choroidal

          neovascularization so it will be used much more

          widely, and the people using it in the community,

          whether they are retinal specialists or

          ophthalmologists who are not retinal specialists,

          because of the more broad range of the indications,

          are selected different than the investigators.  The 

                                                                   211

          investigators, as much as the sponsors, have wanted

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

          investigators are trained extensively and

          controlled much better than the outside area.  So,

          I do think that control of complications,

          particularly endophthalmitis, is important.

                    The second thing is a comment about the

          quality of life.  There was just a discussion about

          contrast sensitivity and visual fields, along with

          the early discussion about ERG and I think these

          types of things should be included in future

          evaluations.  Thank you.

                    DR. DUNBAR:  Thank you.  Are there any

          additional members of the public that wish to come

          forward?

                    [No response]

                              Committee Discussion

                    At this point then we will open up for

          general discussion among the committee members,

          taking into account the presentations we have heard

          from the public.  Are there any comments at this

          time?  Dr. Lehmer? 

                                                                   212

                    DR. LEHMER:  I was going to mention

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

          Mr. Rosenthal, mentioned about contrast

          sensitivity.  A lot of my patients who have the

          same level of visual acuity function very

          differently on similar behavioral tasks in the

          office and when we test their contrast sensitivity

          it varies greatly.  So, it seems like I would

          second the motion of including that as a measure.

                    DR. DUNBAR:  Dr. Chambers?

                    DR. CHAMBERS:  The agency certainly agrees

          they would like to be able to use contrast

          sensitivity as a measure and certainly believe it

          is a measure of visual function.  The difficulty

          with using contrast sensitivity in an assay is

          figuring out which contrast sensitivity is the most

          appropriate, and if you find a difference in one

          frequency versus a different frequency what does it

          mean?  If you have any guidance on which

          frequencies are more important than other

          frequencies, we would love to hear those comments.

                    DR. DUNBAR:  I am interested in the 

                                                                   213

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

          this is insightful because once the drug is

          available to doctors--for example, would a doctor

          perhaps instill it into the anterior chamber for a

          patient with rubeosis?  And, this is a conceivable

          possibility.  Do we know anything about endothelial

          cell toxicity?  This is a question actually for the

          sponsor.

                    DR. ADAMIS:  The question is an important

          one.  We did not look specifically at endothelial

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

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

          there did not appear to be an increased incidence

          of corneal edema.

                    DR. DUNBAR:  Is there any preclinical data

          that might guide us about this question?

                    DR. ADAMIS:  In the preclinical animal

          studies there was no finding of corneal edema as a

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

          my knowledge, specular microscopy was not done.

                    DR. GUYER:  Just as far as a comment on

          other uses, the sponsor right now is presently 

                                                                   214

          looking at other important diseases in trials.  We

          finished our Phase II program of diabetic macular

          edema and actually, hopefully in the fall, we will

          be talking with the agency about putting together a

          Phase III program.  As you mentioned, there are a

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

          we are specifically talking about the indication

          for age-related macular degeneration.

                    DR. DUNBAR:  As a pediatric

          ophthalmologist, I am interested in retinopathy

          prematurity.  Do you have any comments about its

          use in that situation?

                    DR. ADAMIS:  Theoretically it is a drug

          that I think may prove useful in retinopathy

          prematurity but the data that I showed you is that,

          you know, VEGF is required for normal vessel

          formation and the conundrum has always been, well,

          how can you block the bad vessels and leave the

          good vessels alone?  But it look like by targeting

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

          something we would consider doing in the context,

          obviously at some point in the future, as a 

                                                                   215

          clinical trial.  We wouldn't recommend off-label

          use at this point.

                    DR. GUYER:  Also, in addition to

          retinopathy prematurity to look at in the future,

          and we mentioned the diabetic program also, we are

          also presently in a Phase II program for retinal

          vein occlusions and the macular edema that comes

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

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

          if anyone is interested.

                    [Slide]

                    In addition to the diabetic program, we

          presently are studying, as I said, retinal vein and

          also we have a small program with Emily Chiu, of

          the National Eye Institute, on von Hippel Lindau

          tumors because of the increased permeability of

          those lesions.  We are considering, but have not

          started yet, trials for pathological myopia and

          histoplasmosis where, again, choroidal

          neovascularization is associated; sickle cell

          retinopathy; iris neovascularization, as was

          earlier mentioned; and proliferative diabetic 

                                                                   216

          retinopathy.  Those are presently under

          consideration.

                    DR. DUNBAR:  Are there additional comments

          from the committee at this time, especially

          pertaining to the public hearing?

                    [No response]

                    Now I would like to shift our emphasis

          once again to the general discussion that we began

          this morning and see if there are any other

          comments in general from the committee before we

          move on to the questions.  I will poll the

          committee members one by one.

                    Dr. Chinchilli, do you have any additional

          comments?

                    DR. CHINCHILLI:  No, I do not.

                    DR. DUNBAR:  Ms. Knudson?

                    MS. KNUDSON:  No, I do not.

                    DR. DUNBAR:  Dr. Steidl?

                    DR. STEIDL:  No, I don't.

                    DR. DUNBAR:  Dr. Pulido?

                    DR. PULIDO:  No, I do not.

                    DR. DUNBAR:  Dr. Lehmer? 

                                                                   217

                    DR. LEHMER:  No, I don't.

                    DR. DUNBAR:  Dr. Gates?

                    DR. GATES:  None.

                    DR. DUNBAR:  I have no additional

          comments.  Dr. Miller?

                    DR. MILLER:  No.

                    DR. DUNBAR:  And Mr. Kresel?

                    MR. KRESEL:  No, I do not.

                                   Questions

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

          on to a discussion of the individual questions

          posed by the FDA.  I will read the individual

          question and open up the question for general

          disease and at the end of the discussion poll each

          member.

                    The first question reads, has sufficient

          data been submitted to evaluate the efficacy and

          safety profile of pegaptanib sodium?  Excuse me, I

          was operating from an older list.

                    Back to question number one, based on the

          inclusion/exclusion criteria, are there patients

          excluded from the studies that you believe need to 

                                                                   218

          be studied?  Is there any general discussion about

          the inclusion and exclusion criteria?  I am going

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

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

          comments.

                    DR. DUNBAR:  Ms. Knudson?

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

          additional comments.

                    DR. DUNBAR:  Dr. Steidl?

                    DR. CHAMBERS:  Can I interrupt?  Besides

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

          was appropriate--it is at least somebody saying you

          think they were appropriate as opposed to just no

          comments.  Thank you.

                    DR. DUNBAR:  Let's start back again with

          Dr. Chinchilli.

                    DR. CHINCHILLI:  Well, I am not that

          familiar with ophthalmological clinical trials, but

          the criteria seem appropriate to me.

                    DR. DUNBAR:  And Ms. Knudson?

                    MS. KNUDSON:  I think the criteria are

          appropriate and in terms of sufficient data, my 

                                                                   219

          only concern is what we have expressed before,

          long-term use.

                    DR. DUNBAR:  Dr. Steidl?

                    DR. STEIDL:  I don't believe that there

          were patients excluded that need to be studied.

                    DR. DUNBAR:  Dr. Pulido?

                    DR. PULIDO:  I agree with Dr. Chinchilli

          and the other members so far.

                    DR. DUNBAR:  Dr. Lehmer?

                    DR. LEHMER:  I agree that the criteria

          seem appropriate.

                    DR. DUNBAR:  Dr. Gates?

                    DR. GATES:  I am satisfied with the

          inclusion/exclusion criteria.

                    DR. DUNBAR:  I concur with the rest of the

          committee.  Dr. Miller?

                    DR. MILLER:  I concur.

                    DR. DUNBAR:  And Mr. Kresel?

                    MR. KRESEL:  I agree with what the rest of

          the committee has said.

                    DR. DUNBAR:  We will move to question

          number two, visual acuity measurements were 

                                                                   220

          conducted using the ETDRS scale placed at 2 meters

          from the patient.  The validity of the ETDRS scale

          was established based on readings at 4 meters.  Are

          the visual acuity findings sufficiently robust to

          overcome the potential bias introduced by visual

          acuity measurements at 2 meters?  Dr. Chinchilli?

                    DR. CHINCHILLI:  We haven't discussed this

          although it was mentioned by the agency.  You know,

          the fact that there is a control group, the sham

          group, and that you still see differences is

          encouraging.  The question is whether or not there

          is some sort of interaction.  I mean, would the

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

          meters whereas the dosed groups would?  You know, I

          don't know if there is any logical explanation for

          something hypothetical like that happening.  It

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

          hear the ophthalmologists talk about this issue.

                    DR. DUNBAR:  Then I will open this up for

          general discussion before polling each individual

          committee member.  Dr. Lehmer?

                    DR. LEHMER:  I was just going to say I 

                                                                   221

          wanted to hear what the statisticians had to say

          because when we are talking about robustness of

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

          line on are these numbers robust enough to overcome

          that difference.  But I hear what you are saying,

          that this is a comparison between groups that were

          tested under the same conditions so my assumption

          would be that the relative difference would still

          hold up whether it is 2 meters or 4 meters.

                    DR. DUNBAR:  Dr. Chambers?

                    DR. CHAMBERS:  I will just clarify a

          little bit.  There are some differences in other

          areas such as adverse events which might lead

          someone to recognize which group they were in even

          if they were not able to tell from the actual

          procedures, such as some of the floaters, such as

          some of the other many adverse reactions which may

          lead them to, either appropriately or

          inappropriately, believe they were in a group.  The

          concern is that there may be potential unmasking

          because of some of the adverse events that then may

          lead to differences, and the issue that there is 

                                                                   222

          more variability with measurements at 2 meters

          versus 4 meters, although we don't have good

          quantitation on what that is.

                    DR. DUNBAR:  Dr. Pulido?

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

          possible way of getting around this problem?  I

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

          Because there is a concern, could future studies be

          requested to be at 4 meters from the start for the

          small chance that there may be a problem?

                    DR. CHAMBERS:  It is the agency's

          recommendation that they be at 4 meters to avoid

          the issue even coming up.  Were we talking about a

          single letter we probably wouldn't be asking this

          question either.  We would say, well, that is

          definitely within what the variation is.  You may

          choose to believe, well, it takes 16 meters before

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

          so we think there is enough robustness in the

          findings and robustness in differences in visual

          acuities that, while we would have not like to have

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

                                                                   223

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

          to deal with it as best they can.

                    DR. DUNBAR:  Dr. Pulido?

                    DR. PULIDO:  Though it would have been

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

          to be enough robustness of the data that I accept

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

          way you had said it?

                    DR. CHAMBERS:  I did not want to put words

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

          examples of the type of information we are looking

          for in comments.

                    DR. PULIDO:  That would have been the way

          I would have said it without you having said it.

                    [Laughter]

                    DR. DUNBAR:  I have a question for the

          agency.  Was this an agreed upon aspect of the

          protocol prior to commencing the clinical trials,

          or was this a point that came up in the analysis

          later on?

                    DR. CHAMBERS:  The agency, having had the

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

                                                                   224

          protocols were written for ETDRS and has always

          assumed that if someone wrote ETDRS that they meant

          that they would do visual acuities at 4 meters.  We

          have come to find out since that time that that is

          not the interpretation necessarily in the whole

          community and so there were clinical trials that

          were started using the charts but moving them to

          different distances and people continued to call it

          ETDRS even though it does not meet the technical

          protocol of ETDRS.  In this particular case we were

          aware of the difference after the trials had

          started.  To the extent we were aware of them

          before the trial start, to the extent that we were

          aware of them during the trials, we have made those

          comments but in some cases we are aware that there

          were trials that started before we were able to

          comment on it.  Then you would be caught with the

          equal question of do you change the protocol in

          midstream or do you run the protocol the way it was

          started, even if you would have preferred to do it

          a different way?

                    I will let the sponsor comment on their 

                                                                   225

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

          do fully understand it--is to continue the

          protocol, at the point that you recognize there is

          a difference, the way it was written so that you

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

          changed the protocol.  What would have happened had

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

          the data that we have.  We obviously don't

          encourage it in the future but this is what we

          have.

                    DR. DUNBAR:  I have a question for the

          sponsor.  Was every center done at 2 meters?  Were

          they all uniform throughout the protocols?

                    DR. GUYER:  Could I have slide 14 up,

          please?

                    [Slide]

                    First, yes, they were all standardized.  I

          think Dr. Chambers summarized very nicely in the

          morning the difficulties with 2 meters versus 4

          meters.  When we started the trial our thought

          process was, first, that historically other trials

          were done at 2 meters, most of the other trials 

                                                                   226

          were for this condition.  Part of the reason was

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

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

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

          more patients to see at the baseline visions and at

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

          meter.

                    But certainly the FDA has presented very,

          very good information why 4 meters should be

          considered as well.  There is no perfect testing

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

          said it very well, that the key factor is if

          masking is good and if you have some kind of rigid

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

          move, then 2 meters is certainly a good testing

          parameter.  The real potential biases at 2 meters

          have to do with two things.  One is accommodation

          which, obviously, in this population because of

          presbyopia is not an issue.  The second is the

          leaning that Dr. Chambers mentioned.

                    Now, we have randomization which certainly

          helps.  So, we would hope that good randomization 

                                                                   227

          and masking should be equal between sides.  But we

          also have some very important quality control

          information.

                    [Slide]

                    We had very vigorous training and

          monitoring of the visual acuity examiners before

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

          over 450 audits performed in all of the centers

          throughout the world.  And, one of the questions

          that was looked at was, was proper patient

          positioning, such as leaning, prevented by the

          acuity examiners?  You can see that in these 469

          audits, 98.3 percent of the examiners did use

          proper patient positioning, which comforts us that

          at least based upon this quality control we don't

          believe that the patients were leaning forward.

                    We also have good evidence of proper

          masking.  All groups, the active groups as well as

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

          that suggests that masking was good.  Similarly for

          discontinuation rates and reasons, which you can

          see in the FDA briefing book. 

                                                                   228

                    [Slide]

                    Actually, when we did a trial for macular

          degeneration a number of years ago we devised this

          measuring stick which also must be used at every

          examination.  Here you can see a visual acuity

          examiner to actually remind the visual acuity

          examiner always to be sure that the patient is at

          the right distance and that the patient doesn't

          lean forward.  This, I think combined with the

          quality control, helps us.

                    Also, in Dr. Chambers' questions about

          masking and floaters, which is a very good

          question, we actually have looked to try to give us

          some comfort that there was no difference in the

          responder rate of patients who had floaters and

          didn't have floaters.

                    [Slide]

                    This shows that whether the patients had

          floaters or didn't have floaters we see an active

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

          the data from as many possibilities of potential

          unmasking and did not see anything.  So, we have 

                                                                   229

          some comfort I think by the quality control and by

          the good masking in the trial that 2 meters was

          probably not an issue.  But we certainly share with

          the agency that in future trials 4 meters are

          preferred.  We wish more study centers, as Dr.

          Chambers mentioned, had 4-meter testing which has

          also been part of our thought process, that it is

          difficult to get 117 centers with rooms that big.

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

          testing after these discussions.

                    DR. DUNBAR:  Thank you.  Are there any

          other general comments for discussion before

          individual polling of the committee members?  If

          not, I will ask each committee member to answer the

          question are the visual acuity findings

          sufficiently robust to overcome the potential bias

          introduced by visual acuity measurements at 2

          meters?  Dr. Chinchilli?

                    DR. CHINCHILLI:  Yes, I believe the data

          are reliable even though the measurements were

          taken at 2 meters.  I was comforted by some of

          these quality control issues that the sponsor 

                                                                   230

          addressed and was prepared to address.

                    DR. DUNBAR:  Ms. Knudson?

                    MS. KNUDSON:  I will echo what Dr.

          Chinchilli said.

                    DR. DUNBAR:  Dr. Steidl?

                    DR. STEIDL:  Yes, given the significance,

          the audits presented and randomization, I am

          comfortable with them.

                    DR. DUNBAR:  Dr. Pulido?

                    DR. PULIDO:  I am comfortable with the

          robustness of the data.

                    DR. DUNBAR:  Dr. Lehmer?

                    DR. LEHMER:  I am comfortable with the

          robustness of the data.

                    DR. DUNBAR:  Dr. Gates?

                    DR. GATES:  I am also satisfied.  In

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

          always ask them to lean forward for these different

          tasks, and with this randomization not picking on

          any particular segment of the patient population, I

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

          physically able or not able.  So, with this 

                                                                   231

          randomization I am very satisfied with the

          robustness.

                    DR. DUNBAR:  I concur with the other

          comments to this point.  Dr. Miller?

                    DR. MILLER:  Based on what Dr. Chambers

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

                    DR. DUNBAR:  And Mr. Kresel?

                    MR. KRESEL:  I agree with the rest of the

          committee.

                    DR. DUNBAR:  We move to question number

          three, has sufficient data been submitted to

          evaluate the efficacy and safety profile of

          pegaptanib sodium for the treatment of the

          neovascular form of AMD?  If not, what additional

          data are needed?  I would like to open this for

          general comments and discussion.

                    [No response]

                    Then I will begin by polling Dr.

          Chinchilli.

                    DR. CHINCHILLI:  You have to start over

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

          discussions we had this morning, it sounded to me 

                                                                   232

          as if some of the committee members want to see

          more data on long-term safety and use and

          continuation, you know, how long is it necessary to

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

          period of time we need to have data to assess

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

          to make a judgment on that but it seemed like it

          was a concern to many of the committee members.

                    DR. DUNBAR:  I will ask you to address

          each part of the question, the first being has

          sufficient data been submitted to evaluate efficacy

          and safety profile?

                    DR. CHINCHILLI:  Yes, I sort of glossed

          over that.  Yes, I believe it has.

                    DR. DUNBAR:  You mentioned the additional

          data part as well.  Any further comments on that?

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

          else.

                    DR. DUNBAR:  Ms. Knudson?

                    MS. KNUDSON:  I think from what I have

          read and heard that sufficient data is available,

          and additional data I would like to see is how long 

                                                                   233

          would a patient need to use this; how much safety

          is there after several years of use.  Those are my

          concerns.

                    DR. DUNBAR:  Dr. Steidl?

                    DR. STEIDL:  Well, there is a lot of

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

          think that additional data is required ultimately.

                    DR. DUNBAR:  Dr. Pulido?

                    DR. PULIDO:  Yes, I believe that

          sufficient data has been submitted to evaluate the

          efficacy and safety profile, and it appears to me

          very efficacious and safe.  I do believe that

          postmarketing surveillance for ERG, visual field

          and subsequent vision would be worthwhile in a

          subgroup of patients.

                    DR. DUNBAR:  Dr. Lehmer?

                    DR. LEHMER:  I feel that there is

          sufficient data to show the efficacy and safety

          within the parameters of the study, and would echo

          the comments of Dr. Pulido.

                    DR. DUNBAR:  Dr. Gates?

                    DR. GATES:  I also believe sufficient data 

                                                                   234

          has been submitted for efficacy and safety.

                    DR. DUNBAR:  I concur with the comments of

          the rest of the committee about sufficient data for

          efficacy and safety, and I concur with Ms. Knudson

          that some type of postmarketing surveillance for

          long-term efficacy be continued.  Dr. Miller?

                    DR. MILLER:  I concur with regard to the

          data for efficacy and safety, however, I am really

          concerned, as you have also mentioned, with regard

          to how long a patient should be taking this

          particular medication.

                    DR. DUNBAR:  Mr. Kresel?

                    MR. KRESEL:  I think sufficient data has

          been submitted to evaluate efficacy and safety for

          one year, and I will leave it to my ophthalmology

          colleagues to determine if longer-term data is

          needed.

                    DR. DUNBAR:  Question number four reads,

          are additional analyses of the current data needed

          to understand the efficacy or safety of pegaptanib

          sodium for the treatment of the neovascular form of

          AMD?  Dr. Chinchilli? 

                                                                   235

                    DR. CHINCHILLI:  I mentioned this, this

          morning, about the time to treatment failure.  I

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

          particular situation here but, you know, it would

          be interesting to see Kaplan-Meier survival curves.

          I think there was one point where the sponsor had

          flashed a slide up there and then took it off

          because they were addressing some other issue with

          that question.  But I think the agency in

          particular should consider this for future studies

          for future sponsors.  I mean, the disease is one

          that is progressive so you are going to reach the

          point where it has progressed to the point of

          concern which, everybody has been telling me, is

          greater or equal to 15-letter loss from baseline.

                    So, I think it should be analyzed in that

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

          affect this particular situation with this

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

          additional analyses now but I think the analyses I

          am proposing would be more accurate and not rely so

          much on data imputation. 

                                                                   236

                    DR. DUNBAR:  I wonder if this can be the

          answer to our question about how long the drug

          should be taken.  It seems like this type of

          analysis might answer that question.  DR.

          CHINCHILLI:  That is possible, yes.

                    DR. DUNBAR:  Dr. Pulido?

                    DR. PULIDO:  Point of clarification, there

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

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

          think it is going to change what we have found but

          since the question is out there to either the FDA

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

                    DR. DUNBAR:  Will you repeat the question?

                    DR. CHINCHILLI:  Do you have the

          Kaplan-Meier survival curves?

                    DR. CHAMBERS:  We have not chosen to ask

          for it because we have information, not on this

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

          indicative of what you see at year one and at year

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

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

          month three and month six is frequently in the 

                                                                   237

          wrong direction for what you see at one year and,

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

          analysis because we see them reverse.

                    DR. CHINCHILLI:  But you can use the

          Kaplan-Meier survival curve to get a more accurate

          indication of what is happening at one year.  I

          agree if you think three months and six months is

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

          curve to get a better estimate of what is happening

          at one year because it accounts for all the

          censoring, the dropouts and the terminations that

          occur.

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

          take people out as a single event and allow them to

          either come in or come back out as they go through

          that endpoint, I absolutely agree.  I am just going

          through the reason why we have not in the past used

          that because we did not want an answer that

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

          the point is that is potentially confusing.  We

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

          nine months.  In some cases with some drugs it 

                                                                   238

          hasn't made a difference.  With this particular

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

          early on does appear to be continuing later on.

          That is just not true of every particular product

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

          and when not to.  But I absolutely understand what

          you are talking about.  We just have not looked at

          those particular analyses and I don't know if the

          sponsor has or has not.

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

          show it?

                    DR. CHAMBERS:  By all means.

                    [Slide]

                    DR. GUYER:  This is the Kaplan-Meier

          estimate of the first observed loss of 15 letters

          of vision with ITT and, again, it is consistent

          with the other endpoints we showed you earlier

          today, that the active treatment groups at all of

          these data points with time show a treatment effect

          compared to the sham.

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

          other questions regarding this? 

                                                                   239

                    DR. PULIDO:  No.

                    DR. DUNBAR:  Dr. Chinchilli?

                    DR. CHINCHILLI:  No, that is what I wanted

          to see.   DR. DUNBAR:  Okay.  In our

          polling we kind of moved back to a general

          discussion.  Dr. Chinchilli, you indicated that

          that satisfied your question?

                    DR. CHINCHILLI:  Yes, it did.  That was

          the additional analysis I would like to see but,

          again, I didn't expect to see anything different

          than that but it is still nice to see it, and that

          the sponsor had considered it.

                    DR. DUNBAR:  Ms. Knudson?

                    MS. KNUDSON:  I will pass on the question

          of analysis of the data.

                    DR. DUNBAR:  Dr. Steidl, are there

          additional analyses you would like to see?

                    DR. STEIDL:  No, my impression is that

          additional analyses won't change the efficacy and

          safety profile.

                    DR. DUNBAR:  Dr. Pulido?

                    DR. PULIDO:  No additional analyses are 

                                                                   240

          needed.

                    DR. DUNBAR:  Dr. Lehmer?

                    DR. LEHMER:  I agree, no additional

          analyses are needed.

                    DR. DUNBAR:  Dr. Gates?

                    DR. GATES:  No additional analyses are

          needed.

                    DR. DUNBAR:  I concur.  Dr. Miller?

                    DR. MILLER:  I concur.

                    DR. DUNBAR:  And Mr. Kresel?

                    MR. KRESEL:  I concur.

                    DR. DUNBAR:  Moving to question number

          five, has the concomitant use of PDT therapy with

          pegaptanib been explored sufficiently?  Are there

          concerns with using this product concomitantly with

          PDT therapy?  I would like to open this for general

          discussion.  No additional general comments at this

          time?  If not, as I poll you individually just

          please try to address the two parts of this

          question.  Dr. Chinchilli?

                    DR. CHINCHILLI:  Well, I think it was a

          good idea to not make exclusions in the study for 

                                                                   241

          PDT therapy.  Given that situation, I thought the

          sponsor did a reasonable job of analysis to account

          for that.  So, I think, you know, that is a hard

          one to answer for a statistician.  It hasn't been

          explored sufficiently.  You know, we are never

          satisfied.  So--

                    DR. PULIDO:  You have proven that already!

                    [Laughter]

                    DR. CHINCHILLI:  I don't think I will get

          invited back.  You are going to kick me back to my

          other committee, I know that.

                    You know, the designs were reasonable.  In

          the inclusion criteria it was good to see that they

          included that since PDT therapy seems to be

          something that is important for this disease.  So,

          I think I have answered the first question.

                    Are there concerns with using this product

          concomitantly with PDT therapy?  You know, given

          the circumstances and the way the trials were

          designed, I thought the sponsor showed that, given

          all those limitations, the sham group was the one

          that ended up having to have more PDT therapy, 

                                                                   242

          showing efficacy for the product.  It didn't seem

          like there were safety concerns.  I didn't see any

          issue.  Although the numbers were small, there

          didn't seem to be any safety issues when it was

          used concomitantly.  But, you know, the trials

          weren't designed specifically to look at that.

                    DR. DUNBAR:  Ms. Knudson?

                    MS. KNUDSON:  I am comfortable actually

          answering yes to the first and I have no problem

          with the second personally.

                    DR. DUNBAR:  Dr. Steidl?

                    DR. STEIDL:  I think it has been explored

          sufficiently and I don't have concerns about

          concomitant use.  I think we would all like to know

          ultimately if there is a synergistic effect.  That

          is what is ultimately going to be an issue.

                    DR. DUNBAR:  Dr. Pulido?

                    DR. PULIDO:  I agree with my esteemed

          colleague to my left.

                    DR. DUNBAR:  Dr. Lehmer?

                    DR. LEHMER:  I don't feel that the numbers

          involved were large enough but, again, the study 

                                                                   243

          was not designed to specifically look at answering

          this question.  So, with regard to the lack of

          difference between the groups, I guess within the

          small numbers that were shown I would have to say

          that there doesn't appear to be enough concern for

          further study of this.  So, I guess I would have to

          just caution about the fact that there are small

          numbers but the data that they do have don't raise

          a sufficient concern for me.

                    DR. DUNBAR:  Dr. Gates?

                    DR. GATES:  Yes to the first question; no,

          to the second.

                    DR. DUNBAR:  I concur with the rest of the

          committee.  I think that it was comforting that

          both the agency and the sponsor numbers, even

          though they were small numbers, they agreed in the

          ways that they looked at this and so I concur.  Dr.

          Miller?

                    DR. MILLER:  I concur but I was concerned

          about the small numbers but I will concur with

          everyone else.

                    DR. DUNBAR:  Mr. Kresel? 

                                                                   244

                    MR. KRESEL:  I think the design of the

          study tends to answer the question, and when you

          have an all-comer study, you know, you mimic

          real-world use and I think that answers at least

          the question of the safety of using the two

          products together.  It wasn't designed or intended

          to talk about any additional efficacy parameters so

          if people have questions about that they may want

          to look into that at a later date, but it certainly

          answers the question on the safety of using the two

          products together.

                    DR. DUNBAR:  Question number six reads, do

          the route and/or frequency of administration of the

          drug raise any concerns that are not addressed by

          the studies?  Is there any general discussion about

          this question?

                    [No response]

                    Then we will move on to individual

          polling, starting with Dr. Chinchilli.

                    DR. CHINCHILLI:  I don't feel qualified to

          answer this.  I would like to hear the

          ophthalmologists respond to this.  Do I have to 

                                                                   245

          give an answer?

                    DR. DUNBAR:  No.

                    DR. CHINCHILLI:  Thank you.

                    DR. DUNBAR:  Ms. Knudson?

                    MS. KNUDSON:  Of course, I feel similarly

          to Dr. Chinchilli but I would like to say that if,

          indeed, this is the route and if, indeed, it is the

          amount of time between injections that patients

          will actually be going through, I wondered to

          myself whether people would be willing to come back

          that frequently for an invasive procedure.  Then I

          thought, well, these are highly motivated patients

          and they probably would be.  So, I am all right

          with this.

                    DR. DUNBAR:  Dr. Steidl?

                    DR. STEIDL:  Well, I guess maybe more so

          than others here I believe the route and the

          frequency are a big issue and do raise significant

          concerns but, in the spirit of the question, I do

          think they were raised by the studies and they were

          discussed by the company.  So.

                    DR. DUNBAR:  Dr. Pulido? 

                                                                   246

                    DR. PULIDO:  Just one question to the FDA,

          were less often injections evaluated, i.e., every

          three months?  And, can I ask the company if they

          have any data on less often injections?

                    DR. ADAMIS:  Let me tell you briefly about

          what we are doing because we would like to limit

          the number of injections as much as possible.

          There is the ongoing 1006 study which is a

          pharmacokinetic study where we are looking at

          various doses, trying to determine what the

          relevant half-life in the vitreous is in people.

          Recall, when we designed the study we used the

          monkey half-life of four days.

                    The other thing we are doing is we are

          determining in the laboratory the relevant

          inhibitory concentration when you administer this

          via intravitreous injection.

                    Once we have those two pieces of data in

          hand, if there is evidence that we can dose less

          frequently or there is a more optimal way that is

          certainly something that the sponsor is willing to

          consider.  But right here, today, what we have is 

                                                                   247

          that the 0.3 at every six weeks appears to be safe

          and effective.

                    DR. PULIDO:  In that case, as far as the

          route and frequency of administration, I think

          until new data shows it can be done less frequently

          the data is acceptable to me.  Again, I do have the

          long-term concerns that I have mentioned before

          because of the neurotrophic effect of VEGF.

                    DR. DUNBAR:  Dr. Lehmer?

                    DR. LEHMER:  I think the concerns have

          been addressed adequately.  I know with regard to

          injecting acyclovir agents for CMV retinitis it

          seemed we were jumping to implants fairly quickly

          and this population that was studied were highly

          motivated, possibly more highly motivated than

          patients who are not participating in a clinical

          trial.  So, there may be less enthusiasm or less

          compliance with coming in for every six-week

          injections but I think within the realm of the

          study I don't have any concerns.

                    DR. DUNBAR:  Dr. Gates?

                    DR. GATES:  No additional concerns. 

                                                                   248

                    DR. DUNBAR:  I think it is interesting

          that in the study the sponsor has shown that they

          were able to retain well greater than 90 percent of

          their participants even when they were receiving

          between 8-9 injections.  So, yes, of course, there

          are concerns for anyone receiving multiple

          intraocular injections, however, to the best

          possible in a clinical trial situation, I think

          they have been addressed.  Dr. Miller?

                    DR. MILLER:  Yes, I would agree that they

          have been addressed but, at the risk of being an N

          of 1 study myself, I am a motivated person and I am

          concerned that someone would have to go through the

          discomfort so many times.  So, I just wonder if

          there isn't a way of delivering it some other way,

          other than through an injection, but I am not an

          ophthalmologist.  Thank you.

                    DR. DUNBAR:  Mr. Kresel?

                    MR. KRESEL:  I agree with Dr. Dunbar.  I

          think certainly there is data for nine injections

          in the first year and there will be data very soon

          for 18 injections cumulatively.  How many 

                                                                   249

          injections a patient can endure over time

          cumulatively I don't know, but patients tend to

          vote with their feet and so in the end you find

          that out anyway.  So, I think that for now the data

          is adequate.

                    DR. DUNBAR:  Question number seven reads,

          endophthalmitis was observed in approximately two

          percent of patients in these studies.  What is the

          optimal follow-up needed to minimize the impact of

          potential endophthalmitis cases?  Is there any

          general discussion about this before the individual

          polling?

                    DR. CHINCHILLI:  Well, I am not quite sure

          I understand the question.  I mean, are we talking

          about optimal follow-up in the individuals who have

          been diagnosed with endophthalmitis or are we

          talking about the general population?  I mean, it

          is not clear what the agency is asking.

                    DR. CHAMBERS:  Let me clarify.  We are

          potentially talking about if we were to approve

          this product and attempt to label it.  Because this

          is an event that could occur, we are looking at how 

                                                                   250

          frequently we should be recommending people come

          back.  Endophthalmitis is more easily treated early

          rather than late.  Are there recommendations on how

          often people should come back to be observed?

          Obviously, in the first week is when the cases were

          observed.  Are there signs that we should be

          putting in the labeling that should be warning

          patients on things to look out for that should

          suggest that they see somebody earlier rather than

          later?  Basically, we are looking as much as

          possible for additional labeling comments.

                    DR. DUNBAR:  Dr. Lehmer?

                    DR. LEHMER:  It seemed to me that all the

          cases of endophthalmitis presented within one week.

          Was that correct?  It is always an issue if

          something is relatively infrequent, such as this,

          should everybody be screened, say, two days or

          three days afterwards?  It seems like when the

          potential risk is high, as it is in

          endophthalmitis, that it is worth doing that.

                    DR. DUNBAR:  I think it was interesting

          that the sponsor designed their study so they had 

                                                                   251

          telephone follow-up at three days, and they did

          pick up a significant number of those cases through

          that telephone follow-up.  I was trying to compare

          this in my mind to, say, a cataract surgery where

          maybe a patient will be seen at day one and day

          seven and that is another procedure with the risk

          for endophthalmitis.  However, the extra precaution

          of the three-day follow-up seemed to provide

          benefit because their patients also did better in

          general than patients with endophthalmitis.  I

          wonder what the rest of the committee members think

          about this.

                    DR. PULIDO:  I think that many were found

          at four days.  So, was it that they called at three

          days and that they noticed that they were having a

          problem and so they came back on day four?

                    DR. DUNBAR:  Maybe the sponsor can comment

          on this.

                    DR. ADAMIS:  If we could call up slide

          128, just to remind the audience?

                    [Slide]

                    Three of them were picked up on their 

                                                                   252

          phone call at days three and four.  There were two

          questions we asked them:  "How are you feeling?

          And, "how is your vision?"  That is how they were

          captured.

                    Eleven, the majority, walked in on their

          own, went back to the doctor's office, between days

          two and five.  Then, the remaining two were during

          the one-week follow-up exam.  That is how everybody

          was diagnosed.  It was actually the one-week

          period.

                    DR. DUNBAR:  Dr. Gates?

                    DR. GATES:  Do you have an idea how many

          people you called and screened that were negative

          on that day-three phone call?

                    DR. ADAMIS:  Everybody was supposed to get

          called so presumably everybody else was negative.

                    DR. DUNBAR:  Are there any comments from

          the committee about the specific recommendation?

          Mr. Kresel?

                    MR. KRESEL:  Going back to my earlier

          pragmatic approach because I do write labeling, it

          seems to me that probably somebody should have a 

                                                                   253

          recommendation and probably some patient

          educational material so that patients will

          understand what to look for and call their

          physician.  If 11 of them showed up in the office

          on their own, they were probably told by their

          investigator that if you have these particular

          problems you should call me.

                    So, we probably should recommend some kind

          of patient education.  It seems like a rather

          simple, more pragmatic approach.  You are certainly

          not going to expect a busy office to be calling

          every patient all the time.  So, having patients

          understand what to look for and knowing when to

          call probably makes more sense.

                    DR. DUNBAR:  Are there any specific

          recommendations of signs or symptoms that the

          committee wishes to have included in the labeling?

          For example, say, a patient had their family member

          read the labeling to them like patients sometimes

          are wont to do if they are not feeling well?  Any

          specific recommendations for the agency?  Dr.

          Steidl? 

                                                                   254

                    DR. STEIDL:  I don't have any because some

          endophthalmitis can present with a quiet looking

          eyes, some without pain.  I have a lot of patients

          walk in, not realizing that they have lost

          significant vision.  And, maybe this is a

          particular type of population and maybe with the

          right education you can prevent that to some

          degree, but I think if we rely on the patient it is

          dangerous.  As far as specific recommendations, I

          don't know, you have a sudden enough

          endophthalmitis on day one or day four--it can

          happen any time.  So.  Phone calls I guess in lieu

          of everyday exams might be reasonable.  I am not

          really sure.

                    DR. DUNBAR:  Should the labeling mirror

          the study design with visits at one day, a phone

          call at three days and visit at one week?  Or,

          should the labeling provide--you were mentioning

          there was a patient education component, there is a

          physician examination component, and it seems like

          to protect patients the labeling should reflect

          both of these, as was designed in the study.  Dr. 

                                                                   255

          Lehmer?

                    DR. LEHMER:  The comments have been made

          that the outcomes of these endophthalmitis cases

          were very good compared to, say, postoperative

          endophthalmitis after cataract surgery and maybe

          that is because of the rigorous follow-up and maybe

          that should be the new standard.  I know there is

          no FDA label saying everybody should get examined

          one day after cataract surgery, but I suppose it

          would be easier to make it a standard if the

          recommendation to change the protocol was to make

          it a more surgical approach, meaning a sterile

          field.  Then perhaps a recommendation for a

          follow-up should also be more along those

          lines--this is a surgical procedure and a day-one

          check or phone call and a week-one check would be

          appropriate.

                    DR. PULIDO:  I disagree.  The volume of

          patients would be extraordinary on day one.  If we

          are going to increase the follow-up, I think

          following protocol and having a phone call at day

          three would be probably more acceptable to the 

                                                                   256

          patients.  For some of these patients it is hard to

          come back.  It is not as surgically invasive as

          other procedures.  I don't recall right off the top

          of my head how many came back at day one with

          endophthalmitis in this group but I think it was

          only one.  To pick up one case, you would have

          tremendous hardship for these patients.  I think if

          you want to go that route, a phone call at day

          three and then follow-up at week one would be much

          better both for the patient and for the volume of

          cases.

                    DR. DUNBAR:  I would like to recommend

          that the sponsor and the agency work together to

          include education in the label, such as to return

          if symptoms of redness, pain and vision loss--very

          brief endophthalmitis education and to incorporate

          some agreed upon follow-up schedule.  Are there any

          other general comments?

                    DR. MILLER:  I would disagree with that.

          I think that. I think we need to remember that some

          people don't always have someone there to read for

          them.  So, if there is a way of getting the 

                                                                   257

          information to them and making sure that they know

          what to look for before it happens, that would be

          helpful.

                    DR. DUNBAR:  If there is no more general

          discussion let's resume the individual polling.

          Dr. Chinchilli, have I already begun with you?

                    DR. CHINCHILLI:  Sure, you did!  It sounds

          like some sort of form of education is necessary or

          follow-up by the ophthalmologist's office.  So, I

          really don't know what to recommend but obviously

          this is of major concern so some form of follow-up

          or education is necessary and I just can't make a

          recommendation.

                    DR. DUNBAR:  Ms. Knudson?

                    MS. KNUDSON:  I think it is quite clearly

          physician and patient education material that needs

          to be developed.  And, if patients can't read or

          don't have someone to read to them, they could have

          an audio tape which would describe what they need.

          That is not very expensive to do and it would be

          very simple.

                    DR. DUNBAR:  Dr. Steidl? 

                                                                   258

                    DR. STEIDL:  I agree with Dr. Pulido that

          probably more than one exam in a week is going to

          become prohibitive.  I think a phone call is

          reasonable.  The materials that we have for

          Visudyne are useful, and I think that, you know,

          when Visudyne was just coming out there were a lot

          of these meetings that explained to doctors how to

          manage their patients and I think this has to be

          impressed on them, how this needs to be done for

          patient education.

                    DR. DUNBAR:  Dr. Pulido?

                    DR. PULIDO:  I agree with Dr. Steidl.

                    DR. DUNBAR:  Dr. Lehmer?

                    DR. LEHMER:  I would still advocate the

          one day.  I don't know many of our cataract surgery

          colleagues who have given up examining their postop

          patients one day afterwards.  I think part of the

          message we might be sending by having a phone call

          be the only thing between treatment day and one

          week postop is that perhaps this is a fairly benign

          procedure, and knowing that a lot of surgical

          procedures are being considered by optometrists 

                                                                   259

          these days we have to realize what kind of message

          we may be sending with our labeling.  But I would

          agree that at a least a phone call on day three and

          an exam one week later is necessary.

                    DR. DUNBAR:  Dr. Pulido?

                    DR. PULIDO:  Again, maybe I am missing

          something, Dr. Lehmer, but there was one case that

          I see here of endophthalmitis, in the chart on page

          47, on day one.  So, we are going to not pick up

          the vast majority of cases by seeing the patient on

          day one.  What is it that we are going to pick up

          on day one?

                    DR. LEHMER:  Well, that is true of this

          population, which is not thousands of patients.  We

          would, therefore, pick up several patients over the

          population of the United States that would be

          patients receiving this treatment.

                    DR. DUNBAR:  Dr. Gates?

                    DR. GATES:  I recommend the phone call at

          day three with the specifics on redness,

          sensitivity, vision deterioration and pain to be in

          that phone call, so to speak, as a protocol.  I 

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          also concur with the one week postop visit.  I

          think that is a good compromise between the two

          positions and I think that is appropriate with the

          standard of care of other intraocular surgeries.

                    DR. DUNBAR:  I would like to recommend

          that very specifically patient education be

          addressed with the same sentence that Dr. Gates

          said, redness, pain, loss of vision, and that

          physician education with follow-up at least at the

          three-day and seven-day time periods be suggested.

          Dr. Miller?

                    DR. MILLER:  I would like to strongly

          recommend that we have the patient education

          component as you have discussed.

                    DR. DUNBAR:  Mr. Kresel?

                    MR. KRESEL:  I think a combination of

          patient and physician education and follow-up

          visits is necessary.  I will leave the timing to

          the ophthalmologist.  But I would point out that

          finding one case in a thousand is not an

          insignificant number.

                    DR. DUNBAR:  Question number eight reads, 

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          are there adverse experiences that are of

          particular concern for this product?  We will start

          with general discussion.  In the absence of any

          comments, we will move to individual polling with

          Dr. Chinchilli.

                    DR. CHINCHILLI:  Well, I didn't see any in

          the safety tables provided, other than the

          endophthalmitis--anything that looked drastically

          different from the sham group.  So, I don't see

          anything to comment on for that one.

                    DR. DUNBAR:  Ms. Knudson?

                    MS. KNUDSON:  I agree with Dr. Chinchilli.

                    DR. DUNBAR:  Dr. Steidl?

                    DR. STEIDL:  I guess I have stated my case

          about endophthalmitis and, in fact, Dr. Liss'

          points, who came up and spoke, were well taken that

          although I think Visudyne has been well managed I

          think there are a lot of ophthalmologists who might

          consider doing this, people who don't normally do

          this type of thing in the community, particularly

          if there is a lot of hype about it.  People are

          coming to their office, saying do you do this?  

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          And, they have to say they don't.  I am just

          concerned about the risk in the hands of people who

          are not commonly doing this.  But in general I

          think the adverse experiences have been well

          discussed and addressed by the company.

                    DR. DUNBAR:  Dr. Pulido?

                    DR. PULIDO:  I guess the only other one

          that would be of concern is the retinal detachment

          and, again, patient education regarding signs and

          symptoms of retinal detachment would be worthwhile.

                    DR. DUNBAR:  Dr. Lehmer?

                    DR. LEHMER:  I don't have any additional

          concerns.                DR. DUNBAR:  Dr. Gates?

                    DR. GATES:  No concerns.

                    DR. DUNBAR:  In echoing the previous

          comments, I was interested to read that the retinal

          detachment patients seemed like they were high risk

          patients for retinal detachments, patients with

          lattice degeneration or multiple small holes.  I am

          wondering if there should be a precautionary

          statement in the label addressing this.  It seems

          like common knowledge among ophthalmologists, 

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          however, those patients certainly are at an

          increased risk for any retinal detachment and

          disturbing the vitreous in those cases could tip

          them over the edge.  Dr. Miller?

                    DR. MILLER:  Yes, I have a concern that

          was I guess an echo of what was mentioned earlier

          about potential individuals who don't do the

          procedure every day or who might not be as

          knowledgeable.  How would we address that for the

          patients' benefit?  Is there something that the

          agency or the sponsor can do to address that issue?

          I am asking Dr. Steidl.

                    DR. DUNBAR:  Dr. Steidl?

                    DR. STEIDL:  Well, I am probably not the

          right one to answer that, but these things do tend

          over time to work themselves out to some degree.  I

          just think that by anticipating the problem in the

          way it is presented, marketed and the information

          is disseminated to the doctors who are going to do

          this initially we can, to some extent, circumvent

          some of these problems but I think you can't

          completely.  So, I don't really have an answer. 

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                    DR. DUNBAR:  If only the federal

          government could instill personal ethics in every

          doctor in the United States!  Mr. Kresel?

                    DR. KRESEL:  A comment on that, I am sure

          the sponsor will be doing all kinds of educational

          programs because it is to their advantage to have

          the drug used properly and have patients be

          successful on it.  So, I am sure there will be all

          kinds of training programs out there.  I don't have

          any additional concerns.

                    DR. DUNBAR:  Question nine reads, vascular

          endothelial growth factor, 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.

                    (a), Has the adverse event profile of the

          two randomized Phase III trials raised any concern

          over the possible systemic effects of this therapy?

                    (b), Is there additional monitoring that 

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          should be in place for patients on pegaptanib

          sodium therapy?  Is there any general discussion on

          this two-part question?

                    [No response]

                    Returning to the individual polling with

          Dr. Chinchilli?

                    DR. CHINCHILLI:  Well, with respect to

          part (a), I think it is prudent to be concerned

          about possible systemic effects.  Obviously, with

          the one-year data we were shown there wasn't any

          evidence of that, but there certainly can be

          cumulative effects over time so, again, I think

          what we described in one of the earlier questions

          in terms of having long-term follow-up and

          long-term data, you know, that certainly should be

          monitored in terms of there being some systemic

          effects.

                    DR. DUNBAR:  How long do you think it

          should be monitored?

                    DR. CHINCHILLI:  I have no idea.  I don't

          know.  In my experience with other diseases,

          administered locally and not systemically, it was 

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          important to do that as well with those other

          situations, to monitor systemically because there

          could be buildup; there could be transference into

          systemic compartments.  So, I would say it needs to

          be done but I am not an expert.  I can't really

          comment on how long that should be followed.

                    Then, in terms of part (b), I have sort of

          touched on that but I really don't know what else

          to say, what additional monitoring there should be.

                    DR. DUNBAR:  The sponsor mentioned that

          the earliest indication of some systemic effect may

          be blood pressure.  Should there be labeling that

          says the patient should be monitored for blood

          pressure effects of the medicine?

                    DR. CHINCHILLI:  That sounds reasonable.

                    DR. PULIDO:  On the other hand, this is a

          population that is hugely at risk for having

          elevated blood pressure, and to stop a medication

          that may be helping their vision with the

          off-chance that the blood pressure elevation was

          from the medication and not their normal disease

          and normal lifetime I don't think is appropriate.  

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          So, I think the amount in the systemic circulation

          is so small that something like that would just not

          be very reasonable.

                    DR. DUNBAR:  Are there any additional

          generalized comments before we resume the

          individual polling?

                    [No response]

                    Ms. Knudson?

                    MS. KNUDSON:  I would just go back to my

          concern for long-term monitoring.  I would find out

          more about the effects of the drug and the effects

          on the people who are taking it.

                    DR. DUNBAR:  Dr. Steidl?

                    DR. STEIDL:  My answer to (a) is it does

          not raise concerns.  I think the systemic profile

          looks reasonably safe and has been well studied.

          And, I don't think that additional monitoring, from

          my point of view, is needed with regard to the

          whole issue of approval but there are a lot of

          things I would love to see--again, is there an

          additive effect of PDT; quality of life issues; ERG

          data.  If that can be added in any form at some 

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          point, it would be useful.

                    DR. DUNBAR:  Dr. Pulido?

                    DR. PULIDO:  Has the adverse event profile

          raised any concerns?  No.  Is there additional

          monitoring that should be in place for patients?

          Just what I have mentioned prior.

                    DR. DUNBAR:  Dr. Lehmer?

                    DR. LEHMER:  My answer to part (a) is no,

          and I agree with Dr. Pulido on part (b).

                    DR. DUNBAR:  Dr. Gates?

                    DR. GATES:  No systemic concerns, and no

          on the second part also.

                    DR. DUNBAR:  I concur that there are no

          systemic concerns, and additional monitoring for

          any specific things like blood pressure or liver

          enzymes or kidney function tests should be

          monitored.  The items mentioned by the previous

          committee members I think would be useful.  Dr.

          Miller?

                    DR. MILLER:  No to part (a).  The second

          part, just the long-term follow-up with regard to

          the patients. 

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                    DR. DUNBAR:  Mr. Kresel?

                    MR. KRESEL:  No to part (a) and just

          long-term follow-up on (b).

                    DR. DUNBAR:  This concludes the individual

          questions for the advisory committee.  At this

          point in time, are there any other generalized

          comments from any member of the advisory committee?

                    [No response]

                    Are there any additional comments that the

          agency wishes to make?

                    DR. SELEN:  Arzu Selen.  One comment I

          would like to make is about the systemic

          bioavailability.  I believe that there has been

          some discussion on this and, yes, indeed, there

          isn't a lot of drug circulating the systemic

          circulation.  Nevertheless, given such a huge

          molecule, there is some bioavailability from

          intravitreal administration.  Even though levels

          are low, it is still detectable.  I guess I have to

          compliment the company on the quality and quantity

          of the pharmacokinetic data they have submitted.

          Based on this, it looks like the drug in humans has 

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          a half-life somewhere around 10 days, and also

          ranges from 2-19 days in individuals.  So, you

          know, there is considerable amount of drug

          remaining after a single dose.  Nevertheless, the

          levels that you are looking at are at 0.3 mg and

          the dose was studied at 3 mg.

                    So, given that, it seems to me that there

          is a big margin there but, at the same time, there

          is also some evidence of non-linearity.  So, taking

          all of that together, I think the part that comes

          into play is the clinical results and that was what

          Dr. Harris presented and that review did not show

          any big flags.  But I think it is still an

          important thing to perhaps continue looking at and,

          you know, not just to overlook at this time anyway.

          Thank you.

                    DR. DUNBAR:  Thank you.  Are there any

          additional comments from the agency?

                    [No response]

                    Then, at this time I would like to thank

          each and every one of you for coming today to

          discuss Macugen, and this will be the conclusion of 

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          the advisory committee for today.

                    [Whereupon, at 2:35 p.m., the proceedings

          were adjourned.]

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