Friday, August 27, 2004


8:00 a.m.



5630 Fishers Lane

Room 1056

Rockville, Maryland 20852





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

Kimberly Littleton Topper, M.S.




Paula L. Knudson

William Gates, M.D.




Scott M. Steidl, M.D.

Jeffrey Lehmer, M.D.

Vernon Chinchilli, Ph.D.






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




Elaine King Miller, Ph.D.




Peter A. Kresel, M.B.A.




Jonca Bull, M.D.

Wiley A. Chambers, M.D.

Jennifer D. Harris, M.D.




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






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,




DR. STEIDL: Scott Steidl. I am a retina


specialist from the University of Maryland, in




MS. KNUDSON: Paula Knudson, with the


Texas Health Science Center, in Houston.


DR. CHINCHILLI: Vern Chinchilli, Penn




State Hershey Medical Center.


DR. BULL: Good morning, Jonca Bill,


Director of the Office of Drug Evaluation V, in the


Office of New Drugs here, at FDA.


DR. CHAMBERS: Wiley Chambers, Deputy


Director for the Division of Anti-Inflammatory,


Analgesic and Ophthalmic Drug Products.


DR. HARRIS: Jennifer Harris, medical


Officer, same division.


MR. KRESEL: Peter Kresel. I am the


industry representative, Irvine, California.


MS. TOPPER: Kimberly Topper, FDA, the


Executive Secretary for the committee.


DR. MILLER: Elaine King Miller, Amarillo,




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


read the conflict of interest statement.


Conflict of Interest Statement


MS. TOPPER: The following announcement


addresses the issue of conflict of interest with


regard to this meeting and is made a part of the


record to preclude even the appearance of such at




this meeting. Based on the submitted agenda for


the meeting and all financial interests reported by


the committee participants, it has been determined


that all interests in firms regulated by the Center


for Drug Evaluation and Research present no


potential for an appearance of conflict of interest


at this meeting with the following exceptions:


Dr. Jennifer Dunbar has been grated a


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


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


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


and $50,000.


Dr. Jose Pulido has been grated a waiver


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


of stock in the sponsor. The stock is valued from


$5,001 to $25,000.


A copy of the waiver statements may be


obtained by submitting a written request to the


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


of the Parklawn Building.


In the event that the discussions involve


any other products or firms not already on the




agenda for which an FDA participant has a financial


interest, the participants are aware of the need to


exclude themselves from such involvement and their


exclusion will be noted for the record.


We would also like to note that Dr. Peter


Kresel has been invited to participate as a


non-voting industry representative. Dr. Kresel is


employed by Allergan.


With respect to all other participants, we


ask in the interest of fairness that they address


any current or previous financial involvement with


any firm whose products they may wish to comment


upon. Thank you.


DR. DUNBAR: Now we will ask Dr. Chambers


to give an introduction of the issues that we will


review today.




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


me start with welcoming everybody. Good morning.


I want to particularly welcome the advisory


committee members, and the time that they have


taken both to review the material and to both




travel and attend today.




We are here today to discuss Macugen, and


this is the Dermatology and Ophthalmology Advisory


Committee meeting. Those of you who think you


should be some place else, we would welcome the


open seats if you want to give them up.


My name is Wiley Chambers. I am the


Deputy Director for the Division of


Anti-Inflammatory, Analgesic and Ophthalmologic


Drug Products, and it is our Division within the


Office of Drug Evaluation V that will be reviewing


this application today.




This application, unlike many others--or


at least the section that we will be reviewing


today, unlike many others, is part of the


continuous marketing application Pilot 1 NDA


submission which was part of PDUFA 3, which is the


Prescription Drug User Fee Act that was enacted


into law in 2002. This allowed for the


presubmission of individual modules in different




sections that would then be reviewed, and comments


given back. This would not be a final action but


it would be comments on a particular section, with


the goal of speeding ultimate approval of


particular applications by being able to give


interactive comments early on. The action on the


actual NDA will only be taken after all the modules


are submitted and reviewed.




Today's discussion is clinical only. We


are only dealing with the clinical section. We are


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


not dealing with the chemistry manufacturing


section. So, no one should expect that we will


take an action on this NDA today, tomorrow or the


next day because there are other modules which are


being reviewed in their own time course.


The expectation is that we will give


comments back to the sponsor of the application


within approximately six months of the time when


the module was submitted, and so we have scheduled


this meeting to deal with the clinical issues and




our clinical feedback. As you will hear later on,


we have particular questions that are geared toward


this application, but we are looking primarily to


see have we missed anything; are there other areas,


while we are still within the review period, that


we should be looking at further, or are there


issues that you think need to be further explored


before an application would be acted on one way or


the other?




I am going to spend some time today going


through basic clinical trial design issues for


products for macular degeneration in general.




The Division gives guidance as trials are


performed on a way to do a particular trial. We


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


clinical trials. We have tried to give what we


think is a good way to do trials that will give


answers that we can then interpret. We clearly


recognize that there may be additional ways and


there may be reasons to have variance from what we




recommend. But just so that everybody is in the


same page, I am going to go through what we


generally recommend to sponsors of trials so you


know where there are potential differences, which


you may either agree with or disagree with, but


more for informational purposes.


We ask that trials be parallel on design


trials; randomized by person as opposed to


randomized by eye; double-masked, meaning at least


the investigator and the patient are masked to what


treatment they are receiving; and to try to


incorporate dose ranging within the study


development plan. That does not mean every trial


but it means that there be an exploration to dose






The inclusion criteria for at least wet


macular degeneration, using that term as broad as


that is, is that we expect patients to have


choroidal neovascularization documented by fundus


photography and/or angiography. We expect there to


be specific observable features, including




membranes greater than a particular defined size


and with particular diagnostic features such as


leaking on fluorescein, such as leaking on


indocyanine green or ICG, but define a particular


population for which we could then label the






We try to get the trials in total to be as


general as possible while still identifying a


population that the product works for. Patients


with concurrent ocular diseases that may be


associated with choroidal neovascularization we


think should be excluded to avoid any kind of


confounding issues. In this particular case that


generally means excluding people with presumed


ocular histoplasmosis and excluding high myopia,


primarily because these things can also cause


choroidal neovascularization and we want to try and


figure out which disease the product is working on.




We ask for replication. So, we want


safety and efficacy, supported by at least two




independent trials of at least two years duration.


We are looking for robustness in the findings. We


want independent trials, and to that extent we mean


geographically separate so that we know the product


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


just work in Boston or one particular city where


the water supply is unique. These trials conducted


to date were each multicenter trials and so,


obviously, clearly meet that criteria.


Actually, before I go on let me say one


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


trials to go on for two years and we have had


discussions at this advisory committee before about


how long trials should go on for. We have


recognized that endpoints may be acceptable at a


one-year time point but we have asked that trials


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


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


trial will continue to go on for two years and we


will ultimately have that information which we will


factor into our decision. But we believe that,


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




significant portion in the rest of their lives.


Consequently, if the product is showing benefit at


one year we believe we could potentially approve a


product and label it as working for however long it


works for, but we think that duration needs to be


at least one year, but have not been wedded to


anything more than that. If you end up disagreeing


with that, as with anything that I say today,


please feel free to make those comments to us.




The clinical trial program we think should


be able to identify adverse events that occur at


least at a one percent adverse reaction rate.


People may argue that one percent is too low, too


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


have picked. That means you need at least 300


patients studied fully through that to be able to


determine that. We generally recommend at least


500 patients so that we are not dealing with,


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


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


natural age and normal life span, people are not




going to necessarily survive through the


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


other reasons. So, we start out asking for people


to do trials of 500 patients or more.


We like the concentration to be studied


that is going to be marketed, we like


concentrations that are above what is going to be


marketed to be studied to try and exaggerate


potential adverse events so that we can get a


handle of potential adverse events that may occur,


even if they are not going to occur on the final


product that is approved, so that we have some idea


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


frequency of dosing to be at least as frequent as


proposed for marketing. You will see in the trials


we discuss today dose-ranging studies that look at


different concentrations.




The duration, as I mentioned, should be at


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


could be as short as 12 months.






We do not require multicenter trials. It


is certainly easier to enroll larger number of


patients with multicenter trials. Our preference,


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


that there be at least 10 patients per arm per


center. We have set that number so that we can


look at investigator interaction. Now, that is


frequently a difficult thing, to enroll that many


patients per arm per center, particularly if you


have a multi-arm study and you are doing dose


ranging. That dramatically increases the number of


patients you would have at a particular center.


You need to recognize that if we do not


have that many we are probably not going to be able


to look for investigator interaction at any one


particular center. We will do some other things to


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


is there one investigator that is disproportionate


to other investigators really requires more


patients than you will see in these particular


trials. This is not an uncommon problem that we


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




are able to enroll a large number of patients at


any one center you probably wouldn't do a


multicenter trial. So, again, we welcome


suggestions on how to get around this.




Stratification is not necessary. If there


is a chance of imbalance in factors that someone


believes may influence the results, and in this


case there have been discussions about whether


occult versus classic potentially would influence


the results or whether baseline visual acuity would


potentially influence the results. We have


suggested that people stratify so that they have a


higher chance of having an equal distribution


between the individual groups--again, not required.


The hope is that randomization will take care of it


but stratification frequently helps.




Control agent--we have asked that at least


one of the clinical trials that is performed


demonstrates superiority to a control. We have not


defined what that control has to be. It could be




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


lower dose; it could be a different product. By


saying at least one trial has to demonstrate


superiority, that means we also potentially would


accept an equivalence trial. In today's discussion


we are going to deal primarily with superiority


trials but, recognize, we potentially would accept


either a superiority trial or an equivalence trial.


We prefer a vehicle control given our


druthers of different choices, and we prefer that


because it minimizes the bias. There is some


animal evidence--we are not aware of any human


evidence to date but there is some animal evidence


that mechanical manipulation may initiate


inflammatory mediators that may help the condition.


Consequently, by not having something that


simulates that same pathway, there may be some


influence going on by the way you deliver the


product, in this case the intravitreal injection,


that may be a positive effect. But there are


ethical issues, and I am sure we will probably get


into some of that, with giving vehicle controls.




One of the most common reasons cited for


not giving a vehicle control is the risk of


endophthalmitis. We recognize that there is a


theoretical risk of getting endophthalmitis in the


vehicle group. The clinical trials that were


performed here had cases of endophthalmitis that


were in the active control group.


I just want to be on record for stating


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


case of endophthalmitis in the vehicle control


group in any trial that has run that, and there


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


to think it is not unethical to run a vehicle


control. Should we get an endophthalmitis case,


which I am not hoping for anyone, we may change


that opinion but at the present time we continue to


recommend vehicle controlled trials.


We do reluctantly accept sham controls,


but we have put a condition any time we have


accepted sham controls, and that has been that we


have wanted additional doses, in other words, more


than one dose tested to try to aid in the masking




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


these trials today there are multiple doses, in


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


recognize that having a sham increases the chance


of bias influence in the results, although just


having a sham does not necessarily create bias.




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.




Efficacy has been discussed a lot. We


have a number of parameters that we readily accept


as being acceptable. We have other parameters


which we think may in the future be acceptable or


we will be willing to entertain if there is


validation, and validation does not necessarily


need to occur in this particular trial. The thing


that we readily accept as being important is a




change in visual function. So, our guidance to


people when we are having discussions about


clinical trials is that there be statistical


significance in clinical relevance in visual


function at more than one time point. By visual


function we mean visual acuity, visual fields or


color vision.




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






We expect to have dilated seven field


fundus photography sometime during the trial. We


expect to have fluorescein or indocyanine green


depending on what exactly is being studied during


the trial, and we have not specified exactly when


that has to be. We expect dilated ophthalmoscopy


to be performed both for evaluation and for safety


at every visit. We expect a dilated slit lamp exam


for the same reason. We expect to have endothelial


cell counts, not necessarily in every trial but


somewhere within the development plan, and have at


least one study that includes it at the beginning


and end of the trial, and the same thing standard


systemic clinical and laboratory evaluations.




Two meters versus four meters has been a


source of a lot of controversy. It is my


understanding it stems primarily from the


practicality of being able to have exam rooms that


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


would have required 20 foot length and his exam




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


current trend now. People use exam lanes that are


much shorter. But the subject has been studied.


It was the source of a lot of discussion in the


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


as a standard that was published in Ophthalmology


in 1996 for exactly the purpose of discussing what


the best distance is.


It does not mean that you can't


theoretically correct. You know, two meters, four


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


charts smaller so you are looking at the same angle


that gets subtended. The issue is the variability


that occurs when measuring at two meters versus


four meters and the potential for any bias if the


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


down or lock every patient into an exam seat and


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


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


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


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


various seats, if you are leaning backward or




leaning forward, just sitting in your same seat can


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


believe that people are attempting to bias the


results or attempting to lean, and visual acuity is


a very common measure in ophthalmology so everybody


is aware to try to keep people from leaning or keep


that from influencing what goes on. But studies


have been done that show poor reliability at one


meter versus four meters. So, the assumption is


that there is also more variability at two meters


than there would be at four meters. The overall


impact on a particular trial is not known, and the


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


two meters and four meters, which we do not have


data to discuss today.


We think it is more significant for those


trials that have a feature that allows there to be


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


is more of an issue in an equivalence trial than it


is in a superiority trial. These trials that we


are talking of today are superiority trials; they


are not equivalence trials. But there are issues.






Our recommended endpoints to date have all


been, as I mentioned earlier, visual function. We


think at some point in the future we will end up


accepting anatomical changes but we have not yet


found anatomical changes that correlate directly


with visual function. So, currently we readily


accept doubling of the visual angle, which on the


ETDRS chart at four meters would be 15 letters or


more; a halving of the visual angle, in other


words, showing improvement in vision; a quadrupling


of the visual angle, which would be 30 letters or


more. These are all looking at percentage of


patients that have this particular finding because


we think a doubling of the visual angle is a


clinically significant difference that would not


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




We have also been willing to accept a


difference in the group mean. We do not know


exactly how much of a difference in group mean


would be clinically significant so for




consistency's sake we have said we will readily


accept a mean change of 15 letters. That does not


mean that something less than that may not be


statistically significant. We are just not ready


to accept without question anything less than 15






Let me just briefly talk about equivalence


trials just so you know the full scope of what we


have talked about with individual sponsors. We


believe it is possible to do comparison with an


active agent which has already demonstrated


repeated success. Visudyne is currently approved


for predominantly classic choroidal


neovascularization in atrial macular degeneration


and a couple of other things. So, for that


particular indication we would accept an


equivalence trials if one wanted to conduct it.


The way we have set up equivalence trials is that


we have asked that at least 50 percent of the


established treatment effect be preserved so that


95 percent confidence intervals be drawn around




those parameters to protect at least 50 percent of


the treatment effect. Again, it is not a


particular issue for this product but it may be an


issue for other products.


The analyses that we ask to be conducted


always include intent-to-treat with last


observation carried forward and per-protocol with


observed values only. We recognize these as


differences in the data available for analysis.


The intent-to-treat last observation carried


forward is the fullest data set we can obtain. It


is everybody that was randomized in the trial and


it is creating a value for everyone whether real of


extrapolated. A per-protocol analysis is the


minimal data set. It is only those patients that


fully met the protocol and only the values that we


have there.


We don't believe that either one of these


two analyses is the best analysis or is the most


proper or is the most representative. We think


they are extremes and we ask that both be conducted


and we look for differences between these two




analyses. If there are no differences between


these analyses we assume that, regardless of how


much inclusion/exclusion, your results are pretty


much the same and you can accept either one. If


there are differences we ask for additional


analyses to try and explore which one is likely to


be telling a better picture or why it is telling a


different picture.


Other analyses which you would have seen


in the briefing package include things like


worst-case analyses where we treat all dropouts in


the control as being successes and all dropouts in


the test product as being failures. This is not a


correct test. This is not an accurate test. We


are making assumptions in the worst direction to


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


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


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


potential analysis results could be.




As a general rule, we ask for alphas to be


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




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


power to detect a difference to be 80 percent or


greater, and we ask that any time anybody looks at


the data, any kind of look any time during the


evaluation that there be an adjustment in the


statistical plan, in other words, correction for


that alpha for any look that occurs. All of our


analyses that you see in any of our data sets will


include these features.




The last one I want to talk about is


pediatrics. There is an agency initiative to try


and include, when possible, pediatric patients in


the drug development of particular products. So, I


am covering it for completeness. In this particular


case, choroidal neovascularization is rarely seen


in pediatric populations and we have not asked the


sponsor of this application or any of the


applications that just deal with choroidal


neovascularization to include pediatric patients


because the population we don't think is relevant


in this particular case. But as a general rule we




do ask for pediatric patients to be included during


the development.


I am happy to take any questions and,


again, I thank everybody for your time, and look


forward to a fruitful discussion.


DR. DUNBAR: Are there any questions at


this point regarding Dr. Chambers' presentation?


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


forum for the sponsor, Eyetech Pharmaceuticals and


I will ask that the sponsor introduce each of their


speakers within their presentation.


Eyetech Pharmaceuticals Presentation




DR. DYER: Good morning.




Today we will discuss the first anti-VEGF


therapy for the eye and the first treatment to


target the underlying biology of neovascular


age-related macular degeneration. Pegaptanib


sodium achieved statistical significance for


clinically meaningful, prespecified primary


endpoint in replicate trials with strong supportive




data in secondary endpoints.


The efficacy was against usual care


controls, and this pharmacological agent also shows


a favorable safety profile and provides a treatment


benefit to many patients for whom no effective


therapy presently exists.




My name is David Guyer. I am from Eyetech


Pharmaceuticals. I previously was professor and


chairman of ophthalmology at the N.Y. School of


Medicine and a practicing ophthalmologist


specializing in macular degeneration.


Also speaking today will be Dr. Tony


Adamis, who was an ophthalmologist on the full-time


faculty at Harvard, and is now with Eyetech. He


ran the ocular angiogenesis laboratory as well.


Our risk/benefit section will be presented by Prof.


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






Neovascular age-related macular


degeneration represents 90 percent of the severe




vision loss from this disease. Many patients note


a loss of independence and inability to read, to


ambulate and to recognize faces of their loved


ones. This occurs because when the disease forms


abnormal blood vessels that leak blood and fluid


waviness or blurred vision can be seen in the


central area that sometimes can lead to a scotoma


or blind area centrally that prevents them from


seeing straight ahead, and in up to a third of


patients clinical depression can be noted.




The devastating effects of this disease


were well summarized in a book by Henry Grunwald,


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


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


Losing Sight, Gaining Insight" Mr. Grunwald said,


"after a lifetime during which reading and writing


have been as natural and necessary as breathing, I


now feel the visual equivalent of struggling for






Macular degeneration represents a major




public health problem and urgent unmet medical


need. It is the most common cause of irreversible,


severe blindness in developed countries.


Ninety-five percent of retinal specialists believe


that macular degeneration represents an epidemic,


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


United States alone, and a prevalence of up to 1.6


million patients with active bleeding. Limited


treatments are available and 85 percent of retinal


specialists are dissatisfied with current treatment






Macular degeneration represents a


progressive disease. Early on in the disease these


whitish-yellow spots, called drusen, occur and


patients can progress to the neovascular form of


the disease which is where pegaptanib is effective.


This is an angiogenic disorder and what happens is


abnormal blood vessels grow behind the retina where


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


untreated, they lead to disciform scarring where


fibrovascular tissue destroys and replaces the




normal rods and cones in the retina. At this


point, usually moderate to severe visual loss is






Let's discuss the therapeutic options


available for patients with neovascular macular


degeneration. In the 1980s, the Macular


Photocoagulation Study Group showed the beneficial


roles of thermal laser photocoagulation. However,


very few patients are suitable for this treatment.


The treatment is most suitable when the abnormal


blood vessel, as seen here on a fluorescein


angiogram, is away from the center of the macula,


in what we call extrafoveal or juxtafoveal


location, because for patients where the blood


vessel is dead center or subfoveal the laser scar


itself can destroy the very tissue we are trying to


save. Unfortunately, most patients with


neovascular macular degeneration have subfoveal


disease where the blood vessel is dead center.




In the year 2000, photodynamic therapy, or




PDT, was FDA approved for patients with subfoveal


predominantly classic angiographic subtype. Thus,


for approximately three-quarters of patients with


neovascular macular degeneration there is no FDA


approved therapy, although there is off-label use,


with some limited CMS reimbursement, presently.


Today we will discuss the first anti-VEGF


therapy for the eye, a pharmacological treatment


that targets the protein VEGF that is responsible


for the hallmarks of all choroidal


neovascularization. Increased levels of VEGF lead


to neovascularization and increased permeability,


which lead to the clinical features of all


choroidal neovascularization, and pegaptanib blocks






VEGF 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.






Pegaptanib sodium is a pegylated modified


oligonucleotide. It has a selective vascular


endothelial growth factor antagonist to isoform


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


aqueous solution in a single-use, pre-filled


syringe, which is important for safety reasons.


The recommended dose is 0.3 mg of intravitreous


injection administered once every 6 weeks.




We will show you today that pegaptanib met


a clinically meaningful primary efficacy endpoint


with statistical significance in replicate,


well-controlled clinical trials, with a favorable


safety profile.




I will now ask Tony Adamis to discuss a


VEGF overview and macular degeneration




VEGF Overview and Macular Degeneration




DR. ADAMIS: Thank you, David and good








In 1971 Judah Folkman first proposed the


targeting of a specific angiogenic factor as a way


to treat disease, and specifically a way to treat


cancer and ophthalmic disease.




It was in 2004, with the completion of


pivotal Phase III trials using Avastin which blocks


VEGF that this theory was in a definitive fashion


proven correct. This drug now was approved this


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


we entered this era of biological anti-angiogenesis






The target in that trial and in our trial


is VEGF, which is an acronym for vascular


endothelial growth factor. Prior to that it was


called vascular permeability factor. Unlike many


other growth factor names, these two are very


appropriate in the sense that they describe the


central biological functions of this protein. VEGF




makes vessels very leaky and VEGF makes vessels


grow. The leaky aspect of it was discovered in


1983 by Harold Dvorak and then the


neovascularization aspect or biology of VEGF was


discovered by Napoleon Ferrara, who has been a


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


Since then, if one conducts a MEDLINE


search, there have been over 11,000 published peer


reviewed articles on VEGF. There is a large body


of knowledge concerning this growth factor. I show


you just one example of that here. This is the


protein structure of VEGF. We now can determine


very precise structure-functional relationships.




The disease we are here to discuss, as


David said, is age-related macular degeneration, a


very prevalent disease in our society and a very


complex one scientifically when one begins to study


it. We are beginning to unravel the earlier stages


of the disease, the stages where Bruch's membrane


is altered and gives you those yellow spots, the


drusen that David showed you in a clinical




photograph. We are also starting to understand the


complex interaction of the different cell layers


with the vasculature. But the area or the phase of


the disease, the late phase of the disease that we


are studying is the neovascular phase where vessels


begin to grow up towards the retina. These vessels


are abnormal and leaky, and they leak fluid and


lipid and they damage the photoreceptors which


sense light, and people lose vision and go blind.


This process, the angiogenic process, has been very


well studied.




As David said, the data indicate that it


is biologically plausible that blocking VEGF would


have a beneficial effect in this disease in a broad


population. When one looks at surgical specimens


or autopsy specimens of patients with the disease,


what is seen is that the common denominator is


VEGF. It is present in all angiographic subtypes


and it is present in all active stages of the


disease. So, therefore, the hypothesis that


blocking VEGF in neovascular MD would have a




broad-base effect has some broad biological






But those are not the only data that we


have. There is a large body of preclinical


evidence, roughly 15 years worth, which is


summarized on one slide here. Let me just briefly


walk you through it. In preclinical models of


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


retina and in the choroid, if one gives a VEGF


inhibitor you can prevent the growth of vessels and


you can prevent the leak that is associated with


those vessels. So, VEGF seems to be required for


those processes.


Similarly, if one looks at those normal


tissues and now introduces VEGF into the system,


either by injecting the protein or genetically


over-expressing it, VEGF in and of itself is


sufficient to produce the neovascularization or


leak that can occur in these tissues.


Then, so that we have some context in


which to interpret those preclinical data, surgical




specimens and autopsy specimens from humans with


actual corneal neovascularization, iris


neovascularization, retinal and choroidal


neovascularization show that VEGF is expressed at


high levels in those tissues at the time when the


vessels are growing and leaking. So, the totality


of the data supports this approach of blocking VEGF


in specifically the disease under study today,


age-related macular degeneration.




It gets a little more complicated in the


sense that VEGF really refers to a family of


related molecules, and I want to talk about one


specifically, VEGF 165 which is the target of






We were faced with the paradox a few years


ago, as we looked at the accumulated data


concerning the role of VEGF in disease and in the


normal state. What we found was that VEGF is


required for the normal formation development of


vessels during development throughout the body. I




am just showing you here two examples. These are


the vessels of the normal colon and these,


obviously, are the normal vessels of the retina.




In the same molecule, VEGF was shown in a


number of definitive studies and laboratories


around the world that VEGF is required for the


abnormal vessels that can grow in the colon, and


this is colon carcinoma, and here is a case of


age-related macular degeneration. So, how is it


that the same protein can cause these vastly


different phenotypes, these different types of


vessels? One set of vessels are normal and they


don't leak and they behave appropriately; another


set looked very different and they behave very






Perhaps, we thought, some of that


complexity is encoded in these different isoforms.


Let me just explain what those are. There is one


VEGF gene but that gene encodes multiple


transcripts or mRNAs for VEGF that have different




sizes that translate into different proteins. So,


one of those major proteins or isoforms is VEGF


165, which just simply means that it is composed of


165 amino acids. Another major isoform, especially


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


could it be that differential expression or


synthesis of these isoforms underlies the


complexity that we see in the vessels in the normal


and the diseased state?




So, in an experiment we conducted and


published last year, we studied the retinal


vessels. We studied the normal retinal vessels


that are developing as the retina forms and we


studied abnormal retinal vessels in a model of


retinopathy prematurity. This is a model where


vessels grow towards the vitreous and leak and are


distinctly abnormal.


What we saw was that when normal vessels


are developing the isoform expression of the two


major isoforms, 120 and 164 which are the rodent


counterparts to human 121 and 165, is roughly equal




during development. But rather strikingly, during


disease when disease vessels are growing there is a


shift to almost exclusive expression of the 164


isoform. So, it was an interesting association


that we saw of 164 with diseased vessels.




But to really get at the causality of 164


in the production of diseased vessels we conducted


the following experiment. In a model of abnormal


vessel growth we gave pegaptanib which blocks just


164 and compared it to a non-selective VEGF


inhibitor which blocks all the isoforms. We saw


that bpth were equally effective in preventing


abnormal vessel growth. Here is the control with


the abnormal vessels, and both are pretty good at


inhibiting that.


We also looked in a model of normal


retinal vessel development and, again, gave


pegaptanib and what we saw was essentially zero


inhibition of normal vessels. We did not affect


normal vessels. Whereas, the non-selective VEGF


inhibitor had a deleterious effect on these normal




vessels in the retina. So, the conclusion we made


was that VEGF 164 may be preferentially associated


with disease and targeting it gives you a much more


selective inhibition in that you are much less


likely to affect normal vessels in the developing


animal. But I will tell you that there has


subsequently been independent support of this,


specifically from UCSF, where this is also perhaps


true in the adult animal.




To be certain of our conclusion because we


used a reagent here, pegaptanib in particular, we


wanted to make sure this conclusion was robust.


So, we created animals genetically that where we


deleted specifically the 164 isoform and these


animals were able to make all the other types of


VEGFs. What we see here is that these animals have


completely normal retinas and normal retinal


vessels and they are no different than animals that


make all VEGF isoforms. In fact, these animals


grow up to a normal age. They can reproduce.


There are no abnormalities we can detect, even




though they cannot make any VEGF 164.




So, how was a drug made that specifically


blocked VEGF 164? Well, pegaptanib is an


oligonucleotide aptamer. It specifically is 28


nucleotide in life. Aptamers are molecules that


will fold in a very specific fashion. They have a


three-dimensional conformation such that they will


bind to the target protein of interest--in this


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


in the case of pegaptanib with a very high


affinity. This binding occurs extracellularly.


The drug does not enter the cell. It is all


happening outside the cell, which is where VEGF is


residing. These features make it act very much


like an antibody but there are some important


distinctions, aside from it not being an antibody;


it is an oligonucleotide.


This class of molecules, in the published


literature and it has been our experience as well,


are quite non-immunogenic. In our preclinical and


in our clinical examination of pegaptanib we have




not seen a single instance when an antibody is


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


remarkable target specificity and this simply


attests to that.




This shows that pegaptanib is very


efficiently binding to human VEGF 165 and murine or


mouse VEGF 164, but there is no significant, or


essentially no binding to VEGF 121 or related


family member of placental growth factor.




So, what we would expect when pegaptanib


is administered to the eye is that you would have


selective VEGF inhibition of 165 which was


associated with pathology and in our animal model


spares the normal vasculature, and we would have


two very important biological responses as a


function of that blockade: vessel growth would be


inhibited, as would permeability, and the thinking


was this would translate to a better visual








The last thing I would like to talk about


is how we chose our dose. This drug is


administered to the eye nine times a year, and


there are three doses that we chose.




Let me show you the data that we had in


hand when we were planning these trials. We knew


from our pharmacokinetic experiments that when


pegaptanib is given to the eye via intravitreous


injection it slowly exits the eye and it can be


measured in the plasma. Actually, the plasma


levels mirror the levels that one sees in the


vitreous. So, by sampling the blood you can infer


what is happening in the eye.


The other important thing that we learned


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


in this rabbit model, you have thousand-fold less


concentration in the plasma than you do in the eye.


In a more relevant primate model we saw that this


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


the plasma than it was in the eye.






We learned from those studies that the


half-life in the primate vitreous is approximately


four days. We also had data that we had collected


in tumor models and in a model of retinopathy


prematurity that when you give pegaptanib


intravenously the amount of pegaptanib that is


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


We also had another inhibitory


concentration that we had determined in vitro in


tissue culture in various assays of calcium


mobilization and endothelial cell proliferation.


The relevant concentration in tissue culture of


pegaptanib that was required to inhibit VEGF was


significantly lower. It was 0.01 mcg/mL or 10




When we started out it was not entirely


clear which of these inhibitory concentrations


would be most relevant when you are injecting the


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


is the most relevant inhibitory concentration, then


a 3 mg dose, given every 6 weeks would sufficient


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




the other hand, this was the relevant


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


0.3 mg dose would actually all three be sufficient


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


perhaps that may translate to a plateau of the dose






To summarize what I have just discussed,


VEGF appears to be an important control point for


neovascularization and vascular permeability, the


pathologies that lead to vision loss in age-related


macular degeneration. Pegaptanib specifically


targets the VEGF isoform VEGF 165, which we believe


is operative in disease. I have shown you data


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


choroidal neovascularization, diabetic retinopathy


and other conditions. And, pegaptanib dosing is


based on pharmacokinetic data which were collected


prior to the conduct of this study.




At this point, Dr. David Guyer will return


and David will talk to you about our clinical




efficacy data from the pivotal trials.


Pegaptanib Clinical Efficacy




DR. GUYER: In this section we will show


you that pegaptanib met a clinically meaningful


primary efficacy endpoint with statistical


significance in independent, well-controlled,


replicate trials, with a favorable safety profile.




The macular degeneration program consisted


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


treatments at 117 sites in 21 countries. The dose


ranges that were studied ranged from 0.25 mg to 3


mg per eye.




These are the six trials. EOP1003 and


1004 are pivotal trials, sham-controlled,


double-masked, randomized trials. There were 622


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


in trial 1004 in North America. The other four,


smaller trials were pharmacokinetic trials and


open-label single or multiple dosing trials with,




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




The Phase I/II program showed that


pegaptanib appeared safe in all tested doses and


regimens with no dose-limiting toxicities. There


were no unexpected retinal or choroidal


abnormalities noted by angiography as read by an


independent reading center. As Tony mentioned,


these trials established the dosing regimen based


on pharmacokinetics.




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.




The development of these pivotal studies


was done in conjunction with our expert advisory


panel, whose names are listed on this slide.




The study design was two randomization,




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


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


treatment regimen was every 6 weeks and the


prespecified time point for the primary endpoint


was 54 weeks. PDT, photodynamic therapy, was


permitted per the FDA-approved label at the masked


investigator's discretion. Since shams could have


PDT, this represented a usual care control group.




Independent monitoring was done both by an


independent reading center that confirmed the


eligibility prior to randomization, and an


independent data safety monitoring committee, or






These were the members of the IDMC. It


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






Because of the biology of neovascular


macular degeneration and the mechanism of action of


pegaptanib, we designed a trial with a very wide




range of inclusion criteria which included a broad


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


broad angiographic criteria including all subfoveal


angiographic subtypes; lesion sizes up to and


including 12 total disc areas in size; greater than


or equal to 50 percent of the total lesion size


needed to be active choroidal neovascularization;


and for minimally classic and occult disease


subretinal hemorrhage and/or lipid and/or recent


change in vision was necessary for inclusion.




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.






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.




Stratification at randomization included


study center, a history of prior PDT use and


angiographic subtype.




Our primary efficacy endpoint, which was


prespecified, was the percent of patients losing


less than 15 letters from baseline to week 54, the


same endpoint that was used for marketing approval




of Visudyne.


This is an ETDRS chart where 5 letters


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


change represents a doubling of the visual angle


which is a clinically meaningful change to an


individual patient.




Our primary endpoint used in


intent-to-treat, or ITT, population included


patients receiving at least one treatment and a


baseline visual acuity measurement. The last


observation carried forward, or LOCF, was used to


impute missing data. We will also discuss


supportive visual and angiographic endpoints, as


well as exploratory or subgroup analyses.




This table shows the various study visits.


Of note, a telephone safety check was done 3 days


after treatment. Tonometry or measurement of


intraocular pressure was done both before treatment


and 30 minutes after, and fundus photography and


fluorescein angiography was done at baseline and




weeks 30 and 54.




In order to preserve the integrity of the


masking there were two physicians involved in the


trial. One physician administered the study


treatment and the second physician was involved in


any patient assessments or decisions. Patients


were also masked in that the sham procedure was


identical to the active drug procedure except for


the actual penetration into the vitreous. This


meant that they had application of a lid speculum,


instillation of topical medications,


subconjunctival anesthetic, and pressure against


the globe using a needle-less syringe.


The visual acuity examiners were also


masked to both he treatment arm and also to


previous vision assessments, and the reading center


was not aware of the patient's treatment arm.




This slide represents the patient baseline


characteristics for both trials 1004 and 1003.


What we can see in each trial is that the active




doses and the sham are well balanced with respect


to sex, age, initial visual acuity, angiographic


subtype, prior use of PDT and lesion size. The


only difference between the two trials was that


there was slightly more prior PDT use in trial


1004. That was the North American trial, and that


was because Visudyne was approved and reimbursed


earlier in the United States than in Europe. Out


of 9 possible injections, on average all patients,


treated and sham, received 8.5 of the 9 injections,


and overall there was about a 10 percent rate of


discontinuation in the trial.




We prespecified to use a Hochberg


procedure to account for the multiple doses in this


pivotal trial. As per agreement with the FDA, it


was decided to unmask study 1004 first--that was


the trial that was recruited first, thus, the


results were available earlier--in order to


determine which doses to formally analyze in the


study trial study, 1003.






So, we proceeded to unmask the first


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


67 percent of patients lost less than 15 letters


compared to 52 percent of sham. This hit our


Hochberg adjusted p value at 0.0031. Note that the


1 mg dose had a similar response rate, about 66


percent. The p value was 0.0273. The 3 mg


response rate was higher than the shams at 61


percent, however, it did not hit the necessary p






For this reason, prior to unmasking the


second trial, it was prespecified to the FDA that


only the 0.3 mg and 1 mg doses would be formally


analyzed in the second trial. Then we proceeded to


unmask the second trial, study 1003.




This study showed replication of the


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


percent of the patients in the 0.3 mg dose,


compared to 59 percent of sham, lost less than 15


letters, again hitting our Hochberg adjusted p




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


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


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


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


nominal p value because we decided, as we


mentioned, not to formally analyze it.




So, we can look at the combined data and


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


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


lost less than 15 letters compared to 55 percent of


the shams, and for all of these active treatment


groups we had low nominal p values.


It is important to emphasize that for the


0.3 mg group we were able to show independent


replication in two trials of a statistically


significant effect in a prespecified clinically


significant primary endpoint.




I would like to turn now to some


supportive visual angiographic analyses. There are


a variety of ways of looking at various visual




outcomes that are standard for reassurance that the


treatment effect for showing the primary endpoint


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


were in favor of pegaptanib which gives us


confidence in this treatment effect. Because the


independent trials had the same protocol and


demographics, and because we prespecified it in our


statistical plan, we will present these as pooled






This graph shows the percent responders


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


show that the active treatment group had a


treatment effect over sham not only at our primary


endpoint at 54 weeks, but at every studied time


point the active treatment group did better than


the sham.




This is a graph of mean change in visual


acuity. Again, the active treatment group is here,


the sham or usual care group showing a progressive


decrease in vision, and the difference at 54 weeks




was approximately 50 percent in favor of the active


treatment group.




This treatment effect was early and


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


first visit after the first injection the


pegaptanib groups had already distinguished


themselves from the controls and, as we can see


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


with the low nominal p value. This sustained


itself throughout the 54-week course of treatment.




Sham eyes were twice as likely to suffer


severe vision loss than actively treated patients,


as shown in this graph of percent of patients with


severe vision loss. We can see the sham controls


with severe vision loss compared to the


active-treated groups.




At week 54, again, there was a low nominal


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


sham, with progression to severe vision loss which




is 30 letters or 6 lines.




This also was seen for legal blindness in


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


see that more sham eyes progressed to 20/200 vision


or worse compared to actively-treated groups.




Patients on pegaptanib were also more


likely to maintain and/or gain visual acuity. This


graph shows the prespecified endpoints of


maintaining or gaining vision that is greater than


or equal to zero lines gained, as well as greater


than or equal to 3 lines gained. These other two


endpoints were not prespecified but we can see


again in all cases a treatment effect for


maintaining or gaining vision compared to sham.




The next few slides will show the


distribution of visual acuity change at baseline


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


0.3 mg group. This was the range of visual


acuities at baseline. Yellow is the 0.3 mg group




and blue is the sham.




After 54 weeks in the trial we can see


that more patients in the 0.3 mg treated group than


sham had good visual acuities and more patients


with sham than treated patients had poorer visual


acuity. So, the shift in distribution was in favor


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


less than 0.0001.




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


the 1 mg group. This is the baseline visual acuity


distribution and at 54 weeks again we can see more


1 mg treated patients than sham having relatively


good visual acuities and more shams than treated


eyes having poorer vision. Again, this shift in


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


value of less than 0.0001.




Finally, we can see that for the 3 mg


group also. Here is the baseline distribution and


at 54 weeks again more 3 mg patients had better




visual acuities than shams, and more shams had


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


treated patients.




This is a graph of the cumulative


distribution function of vision. What it shows on


the bottom is the change in visual acuity up to


week 54 and the cumulative proportion on this axis.


This shows the robustness of the data as it uses


all of the data points for 54 weeks.


What we can see first is this S-shaped


curve. This is the blue sham patients. You can


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


15 letters which was our primary endpoint, moderate


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


talked about, represents severe vision loss, and we


can see the zero or higher time point which


represented maintaining vision. What we can see is


that, whether we are talking about preventing


vision, maintaining vision or gaining vision, there


has been a shift in distribution, a shift in the


distribution of the sham patients in all active




treatment arms to the right, suggesting benefit in


all areas. The area between the lines which


represents this improvement was highly


statistically significant for all three doses, for


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


0.0001 again; and the 3 mg dose 0.0017.




I would like to now turn to the


exploratory or subgroup analyses.




It is important to emphasize that this


study was powered to test for statistical


significance in the overall study population, that


is, to test for the primary hypothesis or primary


endpoint of all subjects. Nevertheless, it is


important to explore various baseline


characteristics such as lesion composition, lesion


size, baseline vision, age, sex and pigmentation of


the iris.




Despite a reduced ability to draw


statistical conclusions because of decreased sample




size, in some cases as small as 18 patients,


multiple subgroup analyses which can both lead to


false positives and negatives--despite this no one


subgroup drove the overall effect, as we will show






We will first look at the 0.3 mg and 1 mg


doses as was described in the FDA briefing book.


We have also analyzed and prepared the 3 mg dose


and if people are interested later we can show you


that. We will present this using pooled data


because it was prespecified and we will show the


individual trials after.




Here we can see for the pooled data at the


0.3 mg dose that in all cases of all patient


characteristics the 0.3 mg active treated group did


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


consistent with the biology of this disease and the


mechanism of action of pegaptanib, for all


angiographic subtypes, predominantly classic,


minimally classic and occult, as seen here; also,




initial baseline visual acuity, size of the lesion,


race and pigmentation of the iris.




Here we can see for severe visual


loss--the first graph was moderate visual loss or


primary endpoint, but we can see that the


conclusions we made are supported by severe visual


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


The blue are the sham so all had more severe vision


loss than actively treated 0.3 mg group for all


patient characteristics. So, this supports our


primary analysis.




Turning to the 1 mg group, we can see the


same thing, that in all patient characteristics the


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


that this information is supported by severe vision


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


the actively treated 1 mg dose.




Let's now turn to the individual trials.


Individual trials which are under-powered




inherently have more variability. Nevertheless, we


can make the same conclusion, that no one subgroup


drove the overall efficacy. Again, for trial 1004


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


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


we can see support for using severe visual loss as


another important clinical endpoint.




For trial 1003, with the 0.3 mg dose we


can see the same thing.




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


trial 1004, that in all cases the treated groups


did better than the controls and this was supported


by the severe vision loss in 1004 again.




And, in trial 1003, again, for moderate


vision loss treated patients did better than the


blue shams and support with severe vision loss


where shams did worse than actively treated


patients for progression to severe vision loss.






In order to be sure there were no


important subgroup relationships, we also performed


a multiple logistic regression to identify any


potential factors either influencing the outcome or


modifying the treatment effect. Subgroups and


interactions of subgroups with treatment were






These are some of the subgroups that we


evaluated, age, angiographic subtype, use of PDT,


sex, race, lesion size, status of


smoker/non-smoker, subretinal hemorrhage, the


fellow eye vision loss and lipid.




We found for the 0.3 mg dose that no


factors were identified as significant treatment


effect modifiers for 0.3 versus sham, and no


factors except treatment with pegaptanib were


identified as significantly influencing the


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


of treatment.






For the 1 mg group we again found that no


factors were identified as significant treatment


effect modifiers versus sham, and for pegaptanib at


1 mg there was a relationship between treatment


with pegaptanib, again at 0.0001, and age which


favored patients with less than 75 years of age.


This is not to say that older patients did not do


better. It just said that there was a favor for


younger patients even both appear to respond.




What can we conclude from these


exploratory or subgroup analyses? First, we have


shown that the treatment benefit appears


well-distributed among a broad patient population.


Second, the efficacy is not consistently


concentrated in or absent from any particular


patient subgroup. No one subgroup drove the


overall efficacy.




The 0.3 mg dose represents the lowest


studied efficacious dose and it met its primary


efficacy endpoint with statistical significance in




independent replicate trials, as we have shown you.


The efficacy was substantiated in every clinically


meaningful endpoint tested. We have seen the


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


show no additional benefits over 0.3 mg. Tony will


shortly show you that there was no safety


difference between 0.3 mg and 1 mg as well.


However, theoretically we all know that a lowest


dose yields the lowest systemic concentration. So,


the sponsor advisory board and independent data


monitoring committee endorsed the 0.3 mg dose as a


dose that should be selected.




I would like to turn now to angiographic


findings. We have mentioned to you that we believe


there are two mechanisms of action for pegaptanib,


anti-angiogenesis and anti-permeability. As I will


now show you, we have anatomical confirmation for


both mechanisms of action that support the visual


findings we have shown you today.


Let's first look at the anti-angiogenesis.


Here is a patient in the trial with predominantly




classic neovascularization that showed virtually


complete regression. The white large area is the


neovascularization. You can see it has almost


completely regressed after 54 weeks of treatment.


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






What we can see is that there was a


decrease in the lesion size that had a low nominal


p value in favor of active treatment for the 0.3


and the 1 mg dose. So, we have anatomical


confirmation or support for anti-angiogenesis as a


mechanism of action that supports the visual






The second mechanism of action that we


described was anti-permeability. Here is another


patient in the trial that had significant cystoid


macular edema with neovascular disease. We can see


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


a lot of permeability. After 54 weeks of treatment


we can see a great decrease in the permeability.






Again, we can show that leak size over


time was less for treated groups than for shams.


The p values here are noted.




In addition, we can look at the change in


leakage to week 54 as a sign of anti-permeability


action, and we can see that very similar to visual


distribution curves I showed you earlier, we can


see again that there was less leakage noted more


often in actively treated 0.3 mg patients than in


sham, and more leakage noted in shams than in


actively treated eyes. This change in distribution


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


have anatomical confirmation for anti-permeability


as an important mechanism of action that supports


the visual findings.




I would like to now turn to photodynamic


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


have a historical perspective of the use of PDT in


this trial so you can understand some of the




challenges we faced when we were designing this




At the time of starting the trial PDT was


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


certainly ethical considerations that required that


PDT be permitted in patients with predominantly


classic disease. However, the PDT usage pattern


was not yet known.




So, what we decided to do was to create


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


What that meant was that patients had to have


predominantly classic disease and the masked


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


masked physician determined if the patient was


eligible for PDT per the FDA label and then whether


that PDT was recommended for that individual


patient. If so, the treatment was administered per


the FDA label.


Now, to ensure that these strict rules


were being followed, we had a reading center review


the usage pattern and we found that 92 percent of




the time the reading center agreed with the


appropriate use of PDT in this trial.




PDT use could occur three ways: prior to


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


actually, any combination of the three. It is


important to emphasize that overall the use of PDT


was extremely low. Three-quarters of patients were


never exposed to PDT in the study eye at any time


in the time trial.




Let's examine each one of these three


scenarios in detail. First let's talk about prior


PDT which was stratified and was balanced at


randomization. Also, notice the small numbers


again, emphasizing very little PDT use in the


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


was stratified and balanced.




Baseline PDT is the second scenario, and


the baseline PDT use was again very similar among


the groups. We can see here that for the active




treated groups 10-13 percent of patients had PDT at


baseline compared to 14 percent for shams and,


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


patients per subgroup.




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.






We need to ask was there increased PDT use


in pegaptanib patients relative to sham that could


suggest that some of the pegaptanib efficacy was


derived from PDT?




The answer to this question was no. As we


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


PDT in active treated patients compared to sham.




The second important question about


post-baseline PDT use is was there an increase in


the average number of PDT treatments in pegaptanib


patients relative to sham?




Again the answer is no. As we can see


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


active treatment eyes compared to sham.




The third important question, which will


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


was there evidence of any adverse events with the




co-administration of photodynamic therapy and


pegaptanib that could lead to a drug-to-drug


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


just a few minutes.




In summary, pegaptanib met a clinically


meaningful primary efficacy endpoint with


statistical significance in replicate, independent,


well-controlled clinical trials.




I will now ask Tony to come up and discuss


our clinical safety database.


Pegaptanib Clinical Safety




DR. ADAMIS: This is the entire safety


database. This includes the patients from the


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


that the total clinical experience to date includes


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


which 7,500 are intravitreous injections that we


can monitor for the safety. There is a slight


imbalance that you will see in that there are more




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


is because that was the dose that was used


throughout most of the Phase I/II program. In


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


those earlier programs as well.




The overall safety is shown here. As


regards any adverse events, you can see it is


balanced between all treatment arms and sham.


There is an imbalance in the serious adverse


events. These are largely injection related, and


we will talk about those in depth in a moment.


The discontinuations, you will note, due


to adverse events are low. They are one percent in


both the treated and the sham arms. Similarly, the


death rate is balanced to two percent.




Looking at the death rate just a little


more closely, we can see that there is no evidence


here of a dose response.




Let's look at the most frequent non-ocular




serious adverse events. This is a busy slide but


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


good balance between the treated and the sham arms


and, secondly, there is no clustering within a


system organ class. This is rather diffuse. These


conditions are age appropriate. The mean age of


this population is 77 years old that we studied.


These people had a number of concomitant illnesses.


Fifty percent of them had hypertension; 25 percent


were on statins; 20 percent had cardiac disease.


So, we believe it is representative of the






We looked particularly for VEGF


inhibition-related adverse events as these have


been reported with other non-selective inhibitors


given intravenously at higher doses. We were happy


to see that there were no signals here. The most


sensitive signal, the one that has been picked up


with other non-selective inhibitors in smaller


trials than ours, less powered but nevertheless it


was evident, was hypertension. You can see here




that the rate of adverse events is 10 percent both


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


there for that very sensitive signal of VEGF


inhibition. Thromboembolic adverse events are


similarly balanced, as are ischemic coronary artery


disorders, heart failure and serious hemorrhagic


adverse events.




Why is it that we did not see any of these


VEGF inhibition-related phenomena? There is a


number of reasons. Some of these are theoretical,


some are real but in aggregate they provide I think


an argument. Pegaptanib is, as I said, selective


for VEGF 165 so the other major isoform 121 is


never blocked. So, all VEGF is never blocked with


pegaptanib, even if you gave it at very large


concentrations. It just does not bind to VEGF 121.


Secondly, the concentrations that we see


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


magnitude less in the plasma and those


concentrations are below the inhibitory


concentration that our models have told us both for




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


believe that these are levels that are below the


ability of pegaptanib to affect VEGF levels in any


sort of substantive way.


Third, as I just said, there was an


absence of sensitive VEGF inhibition signals, the


most sensitive being hypertension which I showed


you but also in our 1006 trial, where we looked


carefully at proteinuria, again there is no


evidence that this drug is inducing proteinuria in


either our clinical population or in our


preclinical models.


Then, the report recently of


thromboembolic adverse events occurring in cancer


patients on chemotherapy and receiving Avastin--we


think there are a couple of very different things


about our population and that population that was


studied. Number one, cancer in and of itself


predisposes patients to thromboembolic phenomena.


They have indwelling catheters; they are bedridden;


and the cancer itself alters the clotting system.


Secondly, some chemotherapy has been shown to be




vascular toxic, to be prothrombotic. There is a


published literature on that.


So, add these two hits to the vasculature


and then block all VEGF to prevent the endothelium


from healing itself, one can have a theoretical


basis for understanding now why thromboembolic


phenomena may be more prevalent in a population


with cancer and chemotherapy. That is not age


related macular degeneration. This is a very


different population that is not, by and large, on


chemotherapy and do not have cancers.




Let's look at the ocular adverse events.


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


these events in a little more detail. They are


listed here, those that occurred greater than or


equal to 10 percent of patients on either


pegaptanib or sham. You can see that there is a


slight imbalance in eye disorders, and we will talk


about these, and you see a number of various


adverse events listed here.






Let's talk about them in more detail,


number one that was listed on the previous slide


being eye pain. These patients receive nine


intravitreous injections over the course of a year.


It is rather remarkable actually that two-thirds of


them never reported a single instance of pain. Of


those patients, approximately the one third that


did report pain, it was mild or moderate in


character in 99 percent of them, and only one


patient exited this trial describing an adverse


event of pain.


The other important thing to note here is


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


was significantly higher than what is seen in the


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


that these patients experienced--one conclusion you


can draw is that it may be due to the preparative


procedure prior to the injection of the drug. As


you recall, these patients have a speculum placed


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


have a subconjunctival anesthetic injection. These


things may have contributed to the lion share of




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


obviously, there is a difference here. The


remainder of it here can well be ascribed to the


actual intravitreous injection itself.


Of those patients who reported pain, it


was in a minority of their injections, two in both


the treated and the sham arms, and the median time


to resolution was two to three days which is the


time of the follow-up phone call.




With regard to vitreous floaters, there


was more than an imbalance here. It was 33 percent


in the treated arms versus 8 percent in the sham.


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


between the sham eye and the fellow eye so some of


this may be due to the preparative procedure but a


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


likely due to the act of giving an intravitreous


injection itself. When giving a 90 mcL volume


injection into the eye, in the average human a


volume of 4 mL, you are displacing the vitreous and


it is perhaps not surprising that as a function of




that you are going to induce floater. These


floaters never were severe. All of them were


characterized as mild to moderate. No patient left


the trial because of floaters. It was in a


minority of injections, 1 to 2 injections, that


these were reported, if they ever were reported,


and the median time to resolution was 3 days in the


treated arms versus 7 days in the sham arms.




We looked at cataract very carefully. We


specifically looked at cataract in only the aphakic


eyes. One-third of these patients approximately


were pseudophakic. What we saw was that across all


treatment arms there was a slight imbalance, with


30 percent of the eyes having an adverse event of


cataract versus 26 in the sham arm. This slight


imbalance may be partially explained by the fact


that the phakic fellow eye also had a slight


imbalance, 17 percent in the treated versus 15


percent in the sham arms.


But we looked at this a little more in


depth. The type of cataract that one would expect




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


has been amply described in the literature, is


posterior subcapsular cataract. So, when we looked


for that specific type of cataract grading, you can


see there is zero difference. It is 11 percent in


both the treated and the sham arms.




Nuclear cataract was similarly well


balanced. In fact, if you remove the eyes that


were vitrectomized, which we will talk about in a


minute, vitrectomy can cause a nuclear sclerotic


cataract to accelerate. This is 18 percent in both


arms and there is, indeed, a slight imbalance in


cortical of 18 versus 15 percent.


One piece of objective data we have is


that the vast majority of these patients came in at


baseline with cataract and only 3 patients


underwent elective cataract surgery over the 54


weeks of the trial in the treatment arms.




Anterior chamber inflammation was another


adverse event. You can see here that there is an




imbalance slightly with 14 percent occurring in


study eyes versus 6 percent in the sham eyes, and


there were zero reports in the fellow eyes. None


of these cases of anterior chamber inflammation


were characterized as severe. All of them were


mild to moderate and we believe they were largely


due to the active intravitreous injection and not


to the drug itself. The reports of inflammation


were all moderate and self-limiting and did not


increase during the course of the trial. In fact,


there was a slight trend to decrease, arguing that


there wasn't a sensitization to the molecule here,


in fact, supporting that this was due to the


injection itself. The median time to resolution


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


of inflammation.




We looked at interaction potentially with


PDT and specifically at ocular adverse events. You


can see here that the majority of patients did not


have the combination of PDT and pegaptanib, but of


those who did we looked very carefully at the event




rates and the important thing to consider here is


the event rate difference in the sham arms


plus/minus PDT, and does that difference change in


any sort of meaningful fashion when the PDT is


given together with pegaptanib. The answer is that


from these data there doesn't appear to be a


difference in those two measures. The same is true


with vitreous floaters. There is a slight


difference here and there is really no difference


here in the treatment arms.




But let's look at it another way. This


assessment is looking to see if there was a report


of an adverse event at any time during the 54


weeks. For instance, if the patient had PDT at


baseline but had an adverse event at 54 weeks it


would be captured and presented in these data. We


thought we would try to look at this a little more


carefully and see if there was a better temporal


relationship. So, now we are looking at data of


patients who had PDT plus/minus 2 weeks around an


injection of pegaptanib. These events may more




likely signify some sort of interaction and, again,


there are no alarming signals here.


When one looks at eye pain there is very


little difference here and there is very little


difference here between the sham and the treatment


arms. The same is true for corneal epithelium


disorders. For these two specific adverse events


one can postulate a mechanism as to why that is.


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


the injection which can affect the epithelium and


perhaps cause pain. On top of that is a near


temporal relationship the placement of a contact


lens for doing the PDT, and one could understand


why there might be a slight increase here. Again,


no patients dropped out because of any adverse


events related to a combination of PDT and the use


of pegaptanib.




Now let's concentrate a bit on ocular


serious adverse events. The three most common we


are going to discuss in detail here are


endophthalmitis, retinal detachment and traumatic




cataract. The ones below occurred at a very low


event rate. When the narratives in the cases were


looked at in depth there really did not appear to


be an association with the use of pegaptanib so we


will not discuss them further here unless you wish


to discuss it later in the question and answer




Endophthalmitis occurred in 12 patients


over 54 weeks. That translates to a relative risk


of 1.3 percent of patients developing


endophthalmitis over the course of one year of


therapy. So that we could compare our rate to the


published literature this was converted to a per


injection rate of 0.16 percent. What we learned is


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


within the published norm and reported norm in


cases of endophthalmitis in patients receiving


intravitreous injected therapeutics.


As important as the rate is what happened


to these patients, what was the outcome. One


patient lost severe vision in this trial as a


function of their endophthalmitis, 1/12, which




translated to a rate of 0.1 percent over the course


of the year. Seventy-five percent of the patients


who developed endophthalmitis elected to stay in


the trial.


Traumatic cataract--you can see there were


five cases of it and there were five cases of


retinal detachment, of which three were


rhegmatogenous in nature.




I show you here the specific details of


all 12 cases of endophthalmitis. What you can see


here are the starting visions, the visions prior to


the event, and the change in vision from just prior


to the event which probably most accurately


captures the visual loss related to the


endophthalmitis itself. What you can see is the


one patient who lost 11 lines as severe vision




Let me just tell you anecdotally what


happened. It was a protocol violation. It turns


out this patient had an active lachrymal sac


infection prior to the development of the




endophthalmitis and the injection of the mediation,


and had an active lachrymal sac infection after the


event of endophthalmitis. The patient should never


have been enrolled because that was an exclusion




The other patients, as you can see, were


treated aggressively and their visual outcomes tend


to be perhaps a bit better than what you would


expect for a case of endophthalmitis. In fact,


there are some patients here who gained one or two


lines of vision.




How were these patients diagnosed, and


were we able to identify the endophthalmitis


relatively early? This slide shows you exactly


what happened. Three patients were identified in


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


injection. Eleven patients presented to their


physician's office with complaints, and this


happened between days two and five. Two patients


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


The endophthalmitis cases I am describing here are




the 12 in the first year and the ones that have


occurred subsequent to that which I am going to


talk about.




We have been following the endophthalmitis


issue very carefully and I would like to provide


you with an update on where we are beyond the


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


year 0.16 percent of injections, or 1.3 percent of


patients, developed endophthalmitis. In the


second, and now some patients have entered the


third year of this trial, there have been five


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


there has been one case in our Phase II diabetic


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


now, it is 18 cases of endophthalmitis with a


denominator of over 14,500 injections, and the rate


now is reduced somewhat to 0.12 percent per




In the first half of this trial when we


saw the case reports of endophthalmitis we convened


an expert panel of ophthalmologists and retinal




specialists who work in the endophthalmitis area


and we decided that we needed to heighten the


awareness of the need for strict adherence to an


aseptic protocol when one is giving an


intravitreous injection. In fact, there was a


letter sent to IRBs and a formal protocol


modification mandating the use of a sterile drape,


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


we did these things and we analyzed what the


potential effect could be, what we saw was that


prior to that protocol modification being adopted


at all sites between August of 2001 and May of 2003


the rate was 0.18 percent, and after that protocol


modification the rate has now fallen to 0.03




Can we ascribe the decrease in the rate to


the change in the protocol? Not necessarily.


There was more than one variable that was changing


here. At the same time that we instituted this


protocol modification and heightened awareness


about the aseptic technique there was a dramatic


uptake in the number of intravitreous injections




being given for off-label use in diabetic macular


edema with steroids, triamcinolone in particular.


So, the knowledge base and the experience of retina


physicians increased rather dramatically at the


same time that we saw a drop in our rates.




The visual outcome for the cataract cases


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


7 lines of vision, it was ascribed to progression


of macular degeneration. All of these patients, in


fact, had successful cataract surgery.




The visual outcome of the retinal


detachment cases is shown here. All of these were


successfully repaired and you can see the cases of


rhegmatogenous detachment which most likely were


injection related. The visual outcomes were quite






Intraocular pressure was examined. As I


said earlier, it is not surprising if one injects


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




transient rise in pressure. In fact, in


ophthalmology it is common with almost all


procedures that pressure spikes tend to occur.


Well, they occurred here and the transient rise in


mean intraocular pressure at the first prespecified


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


treatment arms.


It is important to note that the mean


intraocular pressure returned to pre-injection


levels one week following the injection, which was


the next visit, and that 90 percent of patients,


approximately 90 percent of patients, never had a


spike above the prespecified threshold of 35 mm and


any patient who did have a spike was not allowed to


leave the physician's office till the pressure was


below 30 mm.


Very importantly, there was no evidence of


a persistent increase in intraocular pressure over


one year. The drug did not seem to alter the


outflow of the eye in any way. In those patients


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


spike was it because somehow the drug was altering




the outflow mechanisms, and if that was the case


you would expect to see an increased incidence


during the course of the trial as it progressed.


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


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


fact, may have been dropping slightly.




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.




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




choroidal vasculature as a function of the drug


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


that deviated from the natural history of


age-related macular degeneration and no alterations


in the normal vessels.




The safety update, which was just


concluded in the past week by the independent data


monitoring committee, has reviewed 100 percent of


the patients through month 18 of this trial and 97


percent through month 24, and there have been no


deviations from sort of the pattern of adverse


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


the trial. There have been no new safety concerns


except perhaps for a slight increase in the number


of retinal detachments. There were 6 that were


reported in the second year of this trial.




To summarize the non-ocular safety, there


was a very low discontinuation rate due to adverse


events. It was one percent and it was balanced in


the treated and the sham arms. Non-ocular serious




adverse events appeared to be similar in rate and


character between pegaptanib and sham, and the


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


population was similar between pegaptanib and sham.




As regards ocular safety, I think what we


can conclude is that the majority of the ocular


adverse events were judged to be procedure related.


They were transient and mild in character and


largely self-limiting. There was a low


discontinuation rate due to ocular adverse events


and the serious adverse events were infrequent.


They were rarely associated with severe vision loss


and were mostly procedure related. Finally, there


were mild transient and predictable, manageable


increases in intraocular pressure but no evidence


of a long-term rise in intraocular pressure.




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


practicing retinal specialist at the Massachusetts


Eye and Ear Infirmary, will come and discuss the


risk/benefit profile for pegaptanib.




Pegaptanib Benefit/Risk Profile


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


Dunbar, members of the advisory committee, ladies


and gentlemen, with your permission I would like to


introduce myself a little more fully and my


perspectives so that you can have the clearest


context in which to place my remarks.




With regard to this study, while it was in


progress I was invited to be a member of the safety


committee and later became its chair. At the


conclusion of the study I was asked to be a member


of the scientific advisory board. I perform a


virtually identical role for the Alcon Corporation,


chairing their safety committee in the evaluation


of their anecortave product. I also advise them on


surgical themes and instrumentation as well.


Finally, I am a consultant to the Iridex


Corporation serving as a member on the safety


committee for the transpupillary thermotherapy


trials and their PTAMD or laser for drusen trial.


I hold no equity in any of these companies nor any




of their competitors.




I would like to also share four


perspectives that will inevitably influence my


remarks and may be helpful to you also in your


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


the pegaptanib safety committee. Secondly, I have


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


interest in endophthalmitis and the effects of


administration of intravitreal medications. I am,


as introduced, an academic in the field of retinal


diseases and therapy. But perhaps most importantly


and most germane is that I have a very active


retinal practice at the Massachusetts Eye and Ear


Infirmary and care for many patients with macular






As has been said, neovascular AMD is quite


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


visual acuity driving privileges frequently become


impossible for a patient. At 20/80 or worse


difficulty is even present in trying to read large




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


level of definition of legal blindness at which it


is difficult to recognize faces and independent


function is threatened.




How extant is this problem in the world


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


comprehensive studies recently reported by the Eye


Diseases Prevalence Research Group, they looked at


studies in the United States, Western Europe and


Australia over an 11-year period.




Based on their analysis, it is the leading


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


40 years or older. You see that slightly over half


are due to age-related macular degeneration.




They then applied their model to the U.S.


Census data for both 2000 and projected to the


future. In a morning filled with numbers, I will


spare you all the numbers here, but using a


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




worse as visually impaired, there are 3.3 million


Americans with visual impairment today. In the


future there will be approximately 5.5 million


American with visual impairment at some level,


again slightly over half, due to age-related


macular degeneration. So, it is clearly a problem.




As such, it merits our highest attention


as physicians, researchers, etc. to try to find


treatments and even cures. This slide is color


coded and it lists the candidate therapies for


neovascular subfoveal age-related macular


degeneration. Therapies which have demonstrated


effectiveness in replicate clinical trials are


shown in yellow. We have laser photocoagulation,


photodynamic therapy with Visudyne and the data you


have just heard on pegaptanib. The great majority


of interventions are listed in white, which


indicates ongoing study with various degrees of


promise, and it includes surgical options, as you


see here and a variety of other laser treatments,


as well as other pharmaceuticals, many of which are




nearing the end of their clinical trials. There


are also some abandoned therapies that were


ineffective and combination strategies, as you see


in the lower right, are becoming of increasing






Looking at the established therapies,


there are two. One is photocoagulation with


thermal laser which has been effective in


extrafoveal, juxtafoveal and subfoveal lesions.


However, in subfoveal lesions this therapy has been


abandoned due to the immediate destruction of


central vision following treatment and is no longer


in clinical use. Photodynamic therapy with Visudyne


is approved for subfoveal predominantly classic






In addition, evolving clinical practice,


in a hope to provide improved care for patients


with macular degeneration, has led to a new


accommodation therapy which has become widespread.


That is the combination of a PDT treatment with




Visudyne in association with an intravitreous


induction of triamcinolone in the peri-PDT period.


This treatment has had some very promising early


pilot results but the literature is quite minimal


at present. Nevertheless, it has become a common


treatment in clinical practice.




Intravitreous injections are quite common


in my world as a retinal specialist. They were


employed and were actually the pathway to great


success in the therapy of endophthalmitis, and are


still continued widely in use for that indication.


We also utilize intravitreal injection as a


treatment of retinal detachment, as well as


administering agents for CMV retinitis. However,


there has been great expanded use recently in


office practice of intravitreal injections as


regards the use of triamcinolone acetodine for


diabetic macular edema, retinal vein occlusions,


uveitis, as I have just mentioned, in association


with photodynamic therapy.






Pegaptanib represents the potential for a


new approach, a pharmacotherapy, and what are the


advantages of pharmacotherapy? They are both


general and specific. In general, pharmacotherapy


offers the prospect of treatment at a molecular


level with improved targeting of the disease


process and, more importantly, limitation of the


collateral damage that invariably occurs with


larger scale interventions such as surgery or




Pegaptanib quite specifically is based on


very extensive basic science into the most widely


accepted, central disease processes in AMD, namely


neovascularization and leakage, with consistency


across multiple experimental models and studies.




As a member of the safety committee, we


looked for three specific areas in great detail.


One, were there any potential systemic side effects


from receiving an anti-VEGF medication? Secondly,


were there intraocular drug-related side effects


from this VEGF medication? Thirdly, were there any




mechanical side effects or complications from the


intravitreal injection procedure itself?




We did find serious ocular adverse events


related to the injection procedure. As you have


heard, there were 12 cases of endophthalmitis.


This incidence rate is quite comparable to that in


published series for intravitreal injection with


the other forms of intravitreal injection therapy


that I have mentioned previously. One of these


patients had severe visual loss. Nine of the


patients continued in the study and elected to


continue receiving study medication. Finally,


after protocol modifications, the incidence is


clearly trending downward.


There were five cases of retinal


detachment, which were repaired and some were


related to the underlying macular degeneration


itself. Traumatic cataract was seen in five cases


and all were surgically repaired without sequelae.




So, in these 22 serious ocular events, we




considered them in the context of 7,545


intravitreous injections performed in 1,190


patients by 117 centers worldwide, and many of


those centers had more than one injector. We felt


that this denominator indicated substantial safety


for this procedure.


We also found no evidence of systemic side


effects, no evidence of ocular drug-related side


effects, and the majority of other adverse events


were mild and transient within the eye. The


serious ocular adverse events were infrequent and


manageable. So, we concluded that there was a very


favorable safety profile that, in addition, may be


further improved by education and additional






If we look at severe vision loss, again to


understand the context of these adverse events, if


a patient presented to the trial and received sham,


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


per year of suffering severe visual loss. When


they were enrolled in the pegaptanib group that




risk was reduced to 9.5 percent per year.




In the endophthalmitis, retinal detachment


and cataract serious ocular events that we saw, the


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


of vision, was 0.1 percent, indicating substantial


order of magnitude less risk from endophthalmitis


than from the real problem here which is the


macular degeneration itself.




Regarding efficacy, you have heard a


detailed presentation and I will just summarize.


There was significant reduction in moderate and


severe vision loss compared with sham. There was


promotion of vision stability and gain in a


proportion of patients. There was efficacy with


broad-based entry criteria including a range of


subfoveal neovascular AMD lesions. And, the


benefit of intravitreous pegaptanib therapy was


early and sustained.




As we have seen, in this slide baseline




visual acuity is on the left. Sham is indicated in


purple and pegaptanib in grey. At 54 weeks there


is a definite shift in the 0.3 pegaptanib group to


preservation of better vision on the left of this


chart compared to the visual acuities observed with






I am not a biostatistician but I will try,


for myself and for all of us, to place these


results in some kind of a wider context. What


could this mean? No one knows exactly how many new


subfoveal neovascular lesions occur a year, but


120,000 per year of new treatment-eligible patients


is probably a reasonable estimate. If those


patients were to behave similar to the gathered


group enrolled in this trial, we could make some


statements, and here they are:


Pegaptanib potentially prevents severe


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


vision, in 15,000 additional patients per year in


the United States compared with usual care, based


on a 57 percent reduction in the rate of severe




vision loss with pegaptanib.




Secondly, reaching a level of 20/200 or


worse within the treated eye, we could call that


blindness in the treated eye. Pegaptanib


potentially prevents treated-eye blindness in an


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


again compared with usual care, based on a 38


percent reduction in the rate of treated-eye


blindness with pegaptanib.




In conclusion, from the perspectives


available to me and now available to you, I have


concluded that pegaptanib will have a significant


impact on AMD in regard to both individual patients


with AMD lesions that would become amenable to


treatment and, secondly, in its effects on visual


function and its preservation in the aging U.S.




The positive results in this trial


indicate the beginning, and not the limit, of


pharmacotherapy for AMD. I agree with the




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.




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




eye. In this particular trial the investigator


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


there would be active disease that was eligible for


the trial, the doctor would make that decision. If


we look at slide D-82--




--here we can see some of the baseline


characteristics. In two-thirds of the patients


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


patient was treated in both eyes at the same time.


But in the lifetime of a patient there could be


some overlapping times where they have an active


lesion and the second one becomes active. Some


patients are fortunate enough not to get it in


their second eye but, unfortunately, if they live


long enough many will.


DR. CHINCHILLI: Thank you.


DR. DUNBAR: Dr. Pulido?


DR. PULIDO: A superb presentation; very


interesting results. Just two questions. Number


one, glaucoma was not an exclusion criterion in the


study. So, some of the patients had glaucoma and




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


chronic injections on the small subgroup of


patients that had glaucoma?


DR. GUYER: I will let Tony answer that.


DR. ADAMIS: We were interested in that


question as well. Slide OS-31.




We looked specifically at patients with a


history of ocular hypertension and/or glaucoma, and


then followed their pressures throughout the entire


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


in their intraocular pressure as a function of




DR. PULIDO: The other question probably


is to you as well. There are some recent


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


delivery with retrograde transported Lentivector


prolongs survival in a mouse ALS model. Here is


another one: mural protection of ischemic brain by


VEGF is critically dependent on proper dosage.


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


assumption that VEGF and VEGF 165 is specifically a




cytokine for angiogenesis, but there is more data


to show that there is an independent effect


directly on neural tissue, separate from its


angiogenic effect. ERG was not a part of this


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


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


So, considering the neuroprotective


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


angiogenesis is important, critical to take care of


this significant problem in patients. But my


concern is the long-term chronic dosaging


considering that there is an independent effect of


VEGF as a neuroprotective agent.


DR. ADAMIS: As always happens in science,


what seems very straightforward becomes more


complex, and what you quote is absolutely correct.


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


But what has been learned in about the last five


years is that neural cells have VEGF receptors and


VEGF may be neuroprotective for certain tissues.


Certainly, in the ALS model that is the most


convincing story to date. Whether the effect is




direct or not is still being debated in the


scientific world, but it may well be direct because


of the VEGF receptor on the neural cells.


We were interested in this as well. Even


before we got into the scientific question as part


of our preclinical safety testing, there was a


9-month dog study where the dogs received 3 mg


injections every 2 weeks bilaterally. Then they


had ERGs done and there were no abnormalities seen


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


but, more importantly, recently we examined this


issue and looked specifically at the isoform story.


We presented a paper at ARVO last spring where we


showed that in a model of retinal ischemia if one


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


you can in fact induce some neural apoptosis. But


when we gave pegaptanib in the exact same setting


there was no induced apoptosis. So, again getting


at this thesis, the important thing with pegaptanib


I think is that you are sparing some VEGF to allow


it to have its physiological or perhaps these


rescue functions that can occur in the eye. So,




that gave us an additional measure of comfort that


we are not going to have neural toxicity.


DR. PULIDO: But the question still arises


have you done long-term ERG studies on these




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


not done those in these patients.


DR. DUNBAR: Mr. Kresel?


MR. KRESEL: My disclaimer is that I am


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


even an appropriate way to ask this but I am going


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


at endophthalmitis which, you know, obviously is


one of the things that people have concern about,


and referred to a decrease in patients that was


only five cases in years two and three. My


question is how many patients continued therapy


that far? So, did the number of patients decrease


and, therefore, the percent not go down? Because


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


did go down.


DR. ADAMIS: It is a fair question. The




number of patients was decreased in the second


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


injection basis. That accounts for any loss of


patients and those were the rates that I presented


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


Slide 129.




Just to show you the data, you can see


that prior to the amendment on a per injection


basis it was 0.18 percent, and then post the


amendment it was 0.03 percent but with that


additional confounding variable of a lot of


off-label steroid injections going on.


DR. DUNBAR: Dr. Gates?


DR. GATES: In the context of the cases of


endophthalmitis, could you expand on the initial


injection technique versus some of the changes that


you made secondarily? Because draping oftentimes


means different things to different people.


DR. ADAMIS: Correct. The details of the


injection procedure are on a slide but let me see


if I can recite them from memory for you, the




changes. There was a requirement for the


installation of an antibiotic drop or dilated


povidone-iodine prior to the amendment. Then,


after the amendment the drape that was specified is


a clear plastic one that adheres around the lids


and the lashes, and then the placement of the


speculum, and then also asking for a


povidone-iodine flush to be done, and then patients


received postoperative antibiotics. So, what we


tried to instill there was a sense of uniformity in


the procedure. There was more latitude prior to


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


memory, that were instituted.


DR. DUNBAR: We have more than one-year


data, but would you anticipate that the patients


will continue every six-week intravitreal


injections for the rest of their lives?


DR. ADAMIS: That is an important


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


second year of the design. We want to know,


obviously, about the safety in the second year and


then an important question was do people need to be




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


is one of randomized discontinuation to try to get


to an answer as regards that very important


question, do people need another nine injections?


DR. DUNBAR: Dr. Lehmer?


DR. LEHMER: I noticed in the data that


most of the p values were significant, at least in


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


mg doses, and for the higher dose there was less


incidence, at least in the tables and graphs, of


statistically significant levels. Are there any


conclusions you have drawn about that? Is more not


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.




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




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




issues, theoretical safety issues, we believe that


the 0.3 mg dose has met the requirements to be an


effective treatment here.


DR. DUNBAR: Dr. Miller?


DR. MILLER: Thank you. In terms of the


number of patients that have been in the trials,


are you comfortable or is the model sufficient


enough to tell us that there are no adverse risks


related to the population? For example, with Vioxx


we now know that after a period of time there are


now people that are coming up with cancer, that it


is causing cancer in some of them. Have you given


it to enough patients so that you would know if


there were rare cases where other problems would be




DR. ADAMIS: The population studied was


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


ophthalmology trial. But for very rare events, and


this is a problem faced with all clinical trials,


that show up in patients on the order of one in


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


in these types of trials to detect in a very




air-tight manner those signals.


That being said, with the power we have,


and we do have some significant power according to


the guidelines Dr. Chambers talked about earlier,


we were happy to see with all three doses that


there wasn't any evidence of toxicity, either


systemically or in the eye, related to the drug.


But we will never know with absolute certainty for


those very, very rare events.


DR. MILLER: Thank you.


DR. GUYER: Also as Dr. Chambers


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


higher dose, 10 times higher than the dose that we


believe is the correct dose, gives us some comfort


that a dose 10 times higher has been studied in


many patients. So, that gives us more comfort than


in many other trials.


DR. MILLER: Thank you.


DR. DUNBAR: Ms. Knudson?


MS. KNUDSON: I was just curious about the


necessity for pregnancy tests and two forms of


birth control when your animal data indicated no




problems and you are dealing with a very elderly


population. What was the necessity for this?


DR. ADAMIS: That is the miracle of modern


medicine. There are people over age 50 having


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


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


reason for that.


MS. KNUDSON: Two forms of birth control?


DR. ADAMIS: That is the standard protocol


in clinical trials.




MS. KNUDSON: Did you pay for them?


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






DR. DUNBAR: Are there any additional


questions? Dr. Steidl?


DR. STEIDL: Thank you for a superb


presentation. I think I understand some of the


rationale behind the 15-letter vision loss, the


primary endpoint. I understand the comparison to


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




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


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


they agree with me.


I guess one of the things that I really


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


could see, only one paragraph devoted to quality of


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


may notice more in the treated eye than if the


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


feelings are, your comfort is with this. As


physicians, we often think it is good for the


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


perspective on this what have you gotten from your




DR. ADAMIS: Sure. First, I would also


mention that this difference, as we mentioned


earlier, is against a usual care control and


actually provides for approximately three-quarters


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


we think that that is very, very important, in


addition to the fact that the primary endpoint was


supported by every secondary visual angiographic




endpoint that we saw. So, that gives us great


confidence in our endpoint. Slide number Q-2,






We agree that it is very important to look


at quality of life measurements, and we did using


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


validated measure. It was only measured in one of


the trials, in trial 1004 which was the North


America trial. Because validated foreign language


versions were not consistently available we did it


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


significantly under-powered. We could not pool the


data. The results were not statistically


significant but there were trends that favored


pegaptanib treatment. As I said, it was


under-powered really to detect the small but


potentially meaningful differences between groups.


Slide Q-3.




We can see some of these differences. It


is important to mention that a 5 or more difference




in the LS mean is considered potentially to be


meaningful. So, anything between 0 and 5 is


probably not meaningful. What you can see here are


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


dose, and this has to do with color vision,


peripheral vision, distance vision, social


functioning and role limitations. So, these strong


trends, despite a very under-powered sample, give


us some confidence that the QOL, very much as the


angiography and the other secondary visual


endpoints, also supports the primary endpoint, and


we are getting significant benefit for these


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


chart, but actually benefit that is important to


them in the real world to help them get around.


DR. DUNBAR: Thank you very much. At this


point we will take a 15-minute break and begin


again at 10:30.


[Brief recess]


DR. DUNBAR: We will begin the agency


presentation by Dr. Jennifer Harris.


FDA Presentation




DR. HARRIS: Good morning.




I am Dr. Harris and I was the primary


medical reviewer for Macugen.




I am not going to repeat everything that


the sponsor has presented to you; I am just going


to try and bring up the salient points to try and


give you an idea of how we went through the


application and what we thought was important to


present this morning.


I will go briefly over the study design;


the efficacy results for each individual study so


you can see what replicated itself and what did not


replicate itself; conclusions about the efficacy; a


safety overview of the combined study, the pooled


study overview. There are a couple of specific


safety concerns that we want to talk about a little


bit more and the sponsor discussed a little bit


this morning but we just wanted to go over those


again. Then conclusions about the safety and then


we are going to briefly go through the questions




that we are going to pose to the advisory committee


and, of course, you will see them again after






Again, there were two Phase III studies,


1003 which was an international study, and 1004


that was done predominantly in North America.




Both trials were randomized,


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


dose-ranging, multicenter trials. Within the


trials patients received intravitreous injections


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


54 weeks. These trials were actually 2 years in


duration. The data that we will be looking at


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


the 54-week time period these patients were






This is just a little schematic, just to


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


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




data is probably sometime soon I think, this month


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






Subjects that were enrolled in these


trials were over the age of 50. They had subfoveal


choroidal neovascularization secondary to AMD. The


total lesion size was less than 12 disc areas, and


greater than 50 percent of the lesions had to be


active CNV. The best corrected visual acuity had


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


you have heard, were allowed to have PDT before


entering into the trial and they were also allowed


to have PDT during the trial. Prior to the trial


they could not have had anymore than one prior


photodynamic therapy treatment, and the patients


could not have had any previous subfoveal laser






The primary efficacy endpoint, again, was


a proportion of patients who lost less than 15


lines of visual acuity from baseline at 54 weeks.




Those are considered responders. Secondary


efficacy endpoints were the proportion of patients


gaining greater than 15 letters of vision,


proportion of patients gaining more than zero


letters of vision, and a mean change in visual






Just to give you an idea of the subject


disposition, there are approximately 612 patients


in the 1003 study that were randomized to


treatment. Approximately 53 percent of these


patients discontinued. As you can see, it was


pretty well distributed. The treatment groups were


consistent, with approximately 10 percent or so of


patients discontinuing in each of the treatment






For the second study, 1004, we see the


same thing. The distribution of patients enrolled


was approximately the same in each treatment group,


including sham and, again approximately 10 percent


or so of the patients discontinued therapy.






I am showing you this, not that I think


that you can probably read it but just to give you


an idea of who was enrolled and to show you really


that the groups were well balanced. They were very


well balanced between all three active treatment


arms, including the sham. The demographics of


patients that were enrolled in the 1003 trial were


consistent with patients who actually had the




I also wanted you to note down at the


bottom that patients with all subtypes of


neovascular AMD were enrolled. There was a


substantial number of patients with predominantly


classic and occult lesions that were enrolled in


the trial.




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.






Now I will go into the efficacy results.


Before we go to the efficacy results I want to just


put up this slide to show you how corrections were


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


trials we did not go into these trials with one


optimal dose and, therefore, you know if you have


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


0.05 value and you can determine whether the drug


works or not. We went into the Phase III trials


and we had three different doses so we had to find


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


use the Hochberg procedure to actually control for


these multiple comparisons.


With the Hochberg procedure, each of the


treatment groups was compared to sham and if all


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


were considered to have three active doses. If


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


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


values was less than 0.0167, then we had one active


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




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


results you may see some 0.05 or even 0.025 and


that may or may not mean that that was actually


statistically significant.




This is the primary efficacy result for


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


the 0.3 mg dose there was approximately 67 percent


treatment effect versus 53 percent of the sham


group. This was a statistically significant


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


treatment effect is about 14 percent over sham.


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


treatment effect versus 53 in sham. However, this


did not meet our pre-required p value.




For study 1003 we have similar results


and, again, the 0.3 mg group shows approximately a


73 percent treatment effect versus 60 percent of


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


also seen that the 1 mg group was also


statistically significant with a 75 percent




treatment effect versus 60 percent.


So, it appears that both the 0.3 mg and


the 1 mg group have approximately a 15 percent


treatment effect over sham, with the 0.3 mg


replicating its results in both trials and the 1 mg


dose did not replicate these results.




You have seen this graph before. This


shows you what was happening to the patients'


visual acuity in study 1004 throughout the first


year of the study. What we see is that all


patients continued to lose vision in all treatment


groups, including sham, throughout the first year


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


the patients in the sham group lose vision at a


higher rate than those in the other three active


treatment groups.




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




to lose vision at a faster rate than those in the


Macugen treatment group.




We have a chart similar to the sponsor's


in that we looked at a subgroup analysis. The


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


one particular group that is actually driving the


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


if we look at all the subgroup analyses that were


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


lesion size, baseline demographics and male/female,


what we see is that for each subgroup analysis the


0.3 mg group shows a higher response rate than the


sham group in each of the subgroups.




This was repeated in study 1003 where,


again, the 0.3 mg group shows a higher response


rate in all of the subgroup analyses over sham.




We also wanted to take a look at lesion


size, basically because of the proposed mechanism


of action of Macugen, and that is to inhibit




endothelial cell growth. So, we wanted to see


whether that was, indeed, happening. What we


noticed was that actually the total lesion size for


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


the total leak size, continues to increase for all


treatment groups. Even in patients receiving


Macugen, lesion size does increase but it does


appear that it increases to a lesser degree in the


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


that it does increase in size.




The same thing was seen in the 1003 study


where, again, the total lesion size for all


treatment groups did increase in size, however, for


the 0.03 mg group it does seem to increase to a


lesser degree than in the sham group.




As you have heard, patients who entered


the trial were allowed to get photodynamic therapy,


which is an approved therapy for AMD. So, our


question became were we really seeing an effect of


Macugen or were we just really seeing the effect of




patients receiving an already approved therapy?


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


chart you see here is the number of patients who


actually got on-study photodynamic therapy


treatment in study 1004. We see that approximately


the same amount of patients actually received


photodynamic therapy in all treatment groups,


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.




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




see that there were approximately half as many


patients who received PDT in the international


study versus the American study. That could be


based on practice patterns across the ocean.




We also wanted to look at not so much what


percentage of patients got photodynamic therapy but


were more patients in one group or the other


receiving more treatments? As we look at this


chart for study 1004, we are looking at the total


number of photodynamic therapy treatments. We see


that there is substantially less number of


treatments that were given in the 0.3 mg group


versus that given in the sham group.




For study 1003 the results are similar.


While there is not that big of a difference between


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


were less photodynamic therapy treatments given in


the 0.3 mg treated group.




Lastly, we wanted to look at the results




and say, well, it looks as though the same


percentage of patients were receiving photodynamic


therapy; it looks as though the same number of


treatments were given. Well, did that make any


difference in terms of the responder analysis, the


primary efficacy endpoint?


So, what you are looking at here is the


responder analysis at month 12 for four different


groups, the first group being the group that


received no photodynamic therapy either before the


trial or during the trial. The second one are


those patients who only received pre-study PDT.


The third is a group that received on-study


photodynamic therapy only. The fourth group are


those patients who received pre-study and on-study


photodynamic therapy. The last line here is for


reference so you remember what the primary efficacy


results were for all patients that we just looked




What we noted, which was good, is that the


majority of the patients who entered the trial


never had any confounding or problems with




photodynamic therapy, and that their results


actually were pretty consistent with the overall


results. In terms of the number of patients who


received photodynamic therapy either before or


during the trial, or both before and during the


trial, those numbers were so small that we really


can't make any conclusions about whether receiving


photodynamic therapy before or during the trial has


any effect on the efficacy results.




Similar results were seen for study 1003,


where we looked at the number of patients who


actually received photodynamic therapy. They are


extremely small and no conclusions can be drawn


from using concomitant PDT therapy. The results


for those patients who received no photodynamic


therapy, again, were consistent with the overall


efficacy results.




We were curious, I mean, our primary


efficacy endpoint is really those patients who lose


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




the disease process, that patients will continue to


lose vision so those patients who lose less than 15


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


we wanted to know was there any possibility that


you could actually gain vision if you use this


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


gained greater than 15 letters of vision.


If you look at study 1004, actually there


is a statistically significant increase in patients


who actually gained vision in the 0.3 mg group and


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


results were not replicated in the 1003 study where


you see no statistically significant gain in






So, in terms of our efficacy conclusions,


we believe that Macugen 0.3 mg does reduce the risk


of vision loss in patients with neovascular


age-related macular degeneration. But keep in mind


that there is only approximately a 15 percent


treatment effect over sham, and that there is no


clinically meaningful increase in vision seen in




patients during the first year of using Macugen.




The sponsor has presented all of the


safety results. I am not going to go back through


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


similar events were seen in all treatment groups


and no dose-dependent adverse events were seen.


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


act of giving an intraocular injection itself and


no so much to the drug. The majority of adverse


events, things like eye pain, superficial punctate


keratitis, floaters, iritis are those things that


we commonly seen with intraocular injections of any






But there are two safety concerns that we


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


endophthalmitis again and also a little bit about


systemic VEGF inhibition and what that could mean.




In the database we had there were 16 cases


of endophthalmitis. What we heard this morning is




that actually there are 2 more cases. I guess


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


of those 16 cases occurred in the pegaptanib sodium


treated patients, and none of the cases were in the


sham treated patients. All 16 cases occurred


within one week of injection.




So, I took a look at what kind of


organisms were actually coming out of the


endophthalmitis samples. We see that of the 16


cases, the overwhelming majority are those types of


organisms that are commonly seen around the lid or


around the ocular area--coagulase negative Staph.,


Staph. epi. There were about 6 cases that were


actually negative on the samples. So, it stood to


reason that maybe the problem was with the


injection procedure and the sponsor did take a look


at that and made some changes.




The original procedure called for the


patients to get 2-3 drops of 50 percent saline


diluted, 10 percent povidone-iodine or they could




receive 1 drop of topical antibiotic.




An amendment was made in the protocol


after I think 12 cases of endophthalmitis, and it


was changed so that patients would undergo a more


sterile preparation procedure, similar to most


intraocular surgeries, and patients would be


prepped and draped similar to intraocular surgery


and patients would receive either pre-injection


topical antibiotics for 3 days prior to injection


or 5 percent povidone-iodine flush immediately


prior to injection.




So, what happened to the endophthalmitis


cases? Well, we saw in the database that actually


13 of the 16 cases occurred before the protocol


amendment. Three of those 16 cases occurred within


3 months after the protocol amendment. This is


actually wrong now because I guess there have been


2 additional cases since that time. Based on the


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


of endophthalmitis 3 months after the protocol was








I just want to touch a little bit on


systemic VEGF and what that could or could not mean


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


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


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


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


circulation, mainly because it plays an active role


in cardiac angiogenesis. This is important in


collateral blood vessel formation in patients with


myocardial ischemia. It is also an important


vasodilator and it helps to maintain coronary


artery blood flow and helps maintain patency of


coronary arteries.




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--




arrhythmia; atrial fibrillation which could be an


early indication of myocardial ischemia;


bradycardia; chest pain; coronary artery disease,


not just those cases where patients obviously came


into the study with a known diagnosis but those


patients who were diagnosed with coronary artery


disease during the trial; and myocardial


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


well, is there a problem? Could we actually have


these systemic anti-VEGF effects based on the


intravitreal injections? What you see here on the


chart is that actually all the numbers are pretty


small across all the groups, and there is no real


indication that the intravitreal injection of


pegaptanib will have any systemic anti-VEGF






Just for completeness, in terms of the


death rate, there were approximately 25 patients


who did die during the study, approximately the


same in each study, and the majority of causes were


actually things like cardiovascular events,




malignancies and they were pretty typical of the


age of the population that we were studying. So,


we think those events were really due to the


population and not actually to the drug.




In terms of safety, similar events were


seen in all treatment groups. The most frequently


occurring adverse events related to the intraocular


injection itself and not to the drug. The risk of


endophthalmitis appears--and I have to emphasize


"appears" since there may be more cases that we


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


and there does not appear to be an apparent


increase in the risk associated with systemic


anti-VEGF activity.




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




patients excluded from the studies that you believe


need to be studied?


Visual acuity measurements were conducted


using the ETDRS scale at 2 meters. The validity of


the ETDRS scale was established based on ratings at


4 meters. Are the visual acuity findings


sufficiently robust to overcome the potential bias


introduced by visual acuity measurements taken at 2






Has sufficient data been submitted to


evaluate the efficacy and safety profile of


pegaptanib sodium for the treatment of the


neovascular form of AMD? If not, what additional


data are needed?


Are additional analyses of the current


data needed to understand the efficacy or safety of


pegaptanib sodium for the treatment of the


neovascular form of AMD?


Has the concomitant use of PDT therapy


with pegaptanib been explored sufficiently? Are


there concerns with using this predictive




concomitantly with PDT?




Do the route and/or frequency of


administration of the drug raise any concerns that


are not addressed by the studies?


Endophthalmitis was observed in


approximately 2 percent of patients in the studies.


What is the optimal follow-up needed to minimize


the impact of potential endophthalmitis cases?


Are there any other adverse experiences


that are of particular concern for this product?


VEGF has been shown to be an important


component in the development of collateral vessels


in ischemic heart disease. Inhibition of VEGF in


the systemic circulation could present a


theoretical increased risk of symptomatic


cardiovascular disease in the target population of


elderly patients with AMD. Has the adverse event


profile of the two randomized Phase III trials


raised any concern over the possible systemic


effects of this therapy? Is there additional


monitoring that should be in place for patients on




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




maybe it would be better answered by the company,


when one looks at the serum levels, is that the


total amount of the drug that is being measured or


is that the unbound free form that is being




DR. ADAMIS: It is the total level.


DR. DUNBAR: Dr. Lehmer?


DR. LEHMER: Are there known levels for


VEGF or VEGF inhibition that are clinically


significant from the cardiovascular current




DR. ADAMIS: The short answer is no in


humans. The longer answer is that the most


sensitive signal of systemic VEGF inhibition is


hypertension. In the Avastin trials they picked it


up in their colon cancer, the renal study, their


lung cancer study, and some of those were much


smaller studies than ours and there was no evidence


of hypertension as a function of use of pegaptanib


in our study. So, I guess whatever that level


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


well below that.




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




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




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




DR. ADAMIS: It is an area that we are




very interested in, in the laboratory of the


sponsor. So, we are working on alternative


formulations to see if we can get an extended


release profile in implantables of that sort. I


think ultimately that may end up being an




DR. DUNBAR: Ms. Knudson?


MS. KNUDSON: I just don't seem to


understand why the DSMB permitted the trial to


continue with the sham arm when at every point it


appears the sham arm is inferior to every drug dose


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


it, which continually advances and one should treat




DR. ADAMIS: Yes, the data safety and


monitoring committee, their charge was to monitor


for safety. But the point you raise is a very


important one. So, in this randomized,


discontinuation trial design we actually allow


people who discontinue the drug and lose two lines


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


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




on sham for two years.


DR. DUNBAR: I have a question for Dr.


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


presentation that 6/16 endophthalmitis patients had


sterile endophthalmitis. I wonder, with your


experience with endophthalmitis, if you could tell


us do you think that these patients had infectious


endophthalmitis that were culture negative, or do


you think that that may be more of inflammatory




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


for both of those things, that is inflammation


after injection or specifically infections, we


found really no evidence of a widespread


inflammatory effect at all. In studies of


endophthalmitis in general, for example after


cataract or other forms of ocular surgery,


invariably large studies always find that


approximately two-thirds will be culture positive


and one-third are, inexplicably, culture negative.


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


will be organisms that have just not been




successfully collected by the culture technique.


Perhaps the specimen was too small; perhaps the


laboratory didn't plate it properly, or something


of that nature. Some of them may be fastidious


organisms that are difficult to culture. But


clinically I think we treat those cases as presumed


infectious. The patients had acute presentations


and they were invariably managed with TAP and


antibiotic injection. So, I think that they mirror


my clinical experience with endophthalmitis cases,


except somewhat for their outcomes which were


surprisingly somewhat better. They suggested


somewhat better visual outcomes than we might see


in clinical cases that, for example, would occur in


another context, after cataract or something like


that. Have I answered your question?


DR. DUNBAR: Thank you. Dr. Gates?


DR. GATES: Any conclusions as to that?


Is it a smaller bacterial load perhaps with this




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


phenomenon. Certainly, these patients were




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




plausible hypothesis that it may be having somewhat


of an anti-inflammatory effect as well and you get


less standard damage that occurs when neutrophils


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




DR. DUNBAR: Dr. Chinchilli?


DR. CHINCHILLI: Yes, I have a question


for the agency. In the briefing document you


showed the results from the worst-case analyses. I


notice that in your presentation you really didn't


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


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


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


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


they are in the briefing document, or am I reading


too much into that?


DR. CHAMBERS: We do a large number of


analyses, which are neither shown in the briefing


document nor shown in the presentation, to try to


look at the robustness of the findings. We thought


it instructive to give what potentially is a bottom


lower limit and include it in the briefing document




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


magnitude could be of inclusion or exclusion of


different findings, but since it does not


necessarily represent an accurate finding we didn't


think, from a time perspective, that it was worth


continuing to present in a presentation.


DR. CHINCHILLI: Well, I think it is


highly inaccurate. I know you try to look at the


bounds but I think they are highly inaccurate


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


get into this now, but I do have some


recommendations about analyses, endpoints and


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


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]




Now we have a decision about our agenda


because we have significantly more time with our


morning session than we expected. It is imperative


that we start the open public hearing as it is


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


their voice in this matter. We have two options.


One is that we can take a longer lunch period and


then start the agenda for the afternoon as


previously published. Or, we can begin to answer


some of the FDA questions now and start our lunch


closer to the scheduled time and then have the


public hearing at 1:00 p.m.


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


questions now and then we will, of course, begin


the public hearing at 1:00 p.m.


DR. CHAMBERS: We would like to hear some


general discussion as opposed to just going through


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


some of the time this morning, just a general


discussion of the different topics that are on


there and then specifically go through questions






DR. DUNBAR: Then we will start with Dr.


Chinchilli in terms of general discussion from the




DR. CHINCHILLI: Well, I mentioned this in


my previous question and I would like to talk about


the endpoint that is used and the analysis. I


don't quite understand why the analysis was done


this way, and then looking at the briefing


documents I see that this is the way the FDA


recommends the analysis be done. But there is


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


would be better to reverse the definition, to look


at someone who fails, someone who is a treatment


failure who has 15 or more letter loss and then


look at the time to occurrence of that event. This


way you would better handle the dropouts and the


censoring that occurs.


Now, I realize the subjects in these


particular studies come into the study every six


weeks so you don't have a nice continuum for


determining when this treatment failure takes


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




failure time process. It would just get away from


looking at these extreme cases, the worst-case


scenario that the agency likes to look at in terms


of bounding the results. It just seems to me that


that would be a better approach to the analysis,


that is, to reverse the definition and talk about


treatment failure and look at time until treatment


failure occurs, and doing time to event analyses.


That would be a much more accurate analysis, I


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


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


there is some reason I am missing that that is not


a good approach. And, maybe the company would like


to comment on that as well.


DR. CHAMBERS: We are certainly open to


looking at a number of different types of analyses


and different ways of doing it. The general


recording of visual acuities has been every three


months, not every six weeks. Consequently, you


have set fixed time points when you are getting the


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


at every three months, we have not thought as being




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




DR. CHINCHILLI: I agree. I mean, the


dropouts in these two trials was between 10-12


percent so that is not extreme. But I think you


are going to have trials where you may see more




dropouts, a higher rate than that, and all these


cases that you are proposing for analysis all


involve some form of data imputation. If you look


at the treatment failure approach and time to event


analysis, you know, you account for that censoring


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


current methods. You know, I think I am getting


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


with me the way the outcome is constructed and all


these analyses are performed that involve some form


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


it makes a bit of difference with these two


particular trials here but in general it is not


really good methodology.


DR. CHAMBERS: We certainly are interested


in additional comments you have along that,


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


have some type of bias and some type of assumptions


in the way it is presented, including the methods


you are discussing.


DR. DUNBAR: Dr. Lehmer?


DR. LEHMER: I just want to make sure I




understand correctly that, with regard to the


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


presented, being the most inclusive; the


per-protocol analysis being the most exclusive. As


I understand from the briefing, when the two were


compared there were no significant differences and,


therefore, that is why we are using the


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


as possible to get the safety data. Is that a


correct interpretation of why we are using the


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.




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




was 1,208 and that represents the largest


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


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


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


sponsor's definition, that received study drug and


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


The per-protocol was all of the ITT patients that


had an observed post-baseline vision and no major


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


much smaller group because they observed the


protocol perfectly and also had an observed time


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


Then you have a week 54 observed which are the


actual patients who received the study drug and had


a baseline vision and also a week 54 vision, and


that is 1,085.




Just to illustrate further maybe some of


the differences, E-102 shows again, starting with


the all-randomized where you start with 100 percent


of your population, going down to week 54 where you


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








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


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


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


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


medication and baseline visual acuity occurred,


which is in our briefing book. Very importantly,


you can see that they are all the same. Slide






We can see that on the left we have the


ITT population using an LOCF, which is in the


sponsor's briefing book, and we have the


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


the FDA briefing book. Then we have some of the


extremes, the per-protocol observed and the week 54


observed. Then you can see that we have very


robust data and that the sensitivity analysis and


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


statistically significant change. So, any way you


look at it, either extreme, we see robustness of




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




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


effective vitreous concentrations that are weeks,


it would seem with that trend that it is quite


possible that this may be needed for a while beyond


the study time period. You know, somebody


mentioned the 0.16 percent per injection in


endophthalmitis rate. If you multiply that times


nine it gets pretty close to what was seen. I


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


then if you start thinking about doubling the time


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


view, it is getting pretty scary.


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


point of view, as sterile endophthalmitis because


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


infectious cases that don't come back positive. I


am wondering if that seems like a logical


assumption, that if this is to carry on we could


assume that the endophthalmitis rate would grow




DR. ADAMIS: Yes, I think your


interpretation of the data is correct and,




obviously, the cumulative risk increases as a


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


this responsibility seriously, is to make sure that


the injection procedure, which may be a modifiable


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


We were fortunate in the second year after the


amendment to actually see that rate go down and,


subsequent to the amendment that occurred last May,


it is down to 0.03 percent per injection.


The other aspect of it that is equally


important is the visual outcome. That is, if this


event happens, are these patients being diagnosed


rapidly and being treated appropriately, and then


doing everything you can to preserve the vision as


a function of getting the infection. I think our


investigators did a rather superb job in the sense


that everybody was diagnosed within a week.


Everybody got intravitreal antibiotics. Over half


of them had vitrectomies and you saw the visual


outcomes. I will tell you that the visual outcomes


in the second year with the additional cases are


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




data presented today. But your thesis is correct


that the more you use the drug, there obviously is


an incremental risk over time that increases.


DR. DUNBAR: Dr. Pulido?


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


using intravitreal injections, but the alternative


is the present forms of treatment or systemic


medication that also increase the risk. It is a


small risk but I would rather take that risk than


give something that has systemic effects.


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


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


the context of the potential benefit. So, the


reduction in severe vision loss is greater than 50


percent and the severe vision loss we saw as a


function of endophthalmitis was 0.1 percent. On


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


the benefit outweighs the risk.


DR. DUNBAR: Dr. Lehmer?


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


data are very impressive. Along the lines of what


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




Obviously, we are not able to really assess that


based on the numbers, but taking this information


forward, seeing what are the clinicians going to do


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


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


with macular degeneration, do we use Macugen? Do


we use PDT? Do we use both?


I suppose if patient recruitment were


going to start now we would see a much larger


percentage of the European community using PDT


since it has been approved there and there has been


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


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


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


impact of PDT.


DR. GUYER: I think that is a very


important point. One of the things that was


important to us when we designed this trial was to


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


possible. That is why we allowed photodynamic


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


lot about combination use or anything like that,




but I agree with you that certainly future trials


will be able to address those issues and it is




DR. DUNBAR: Mr. Kresel?


MR. KRESEL: I guess being the pragmatic


industry representative, I will ask the question


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


lot of discussion about endophthalmitis and I think


you gave a really good answer as far as how the


patients were treated and how they were followed


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


know, they came back to see the physician at these


intervals. So, would you recommend in labeling


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


tracked and, in fact, appropriately diagnosed and




DR. ADAMIS: The optimal follow-up I think


still remains to be determined. One of the things


we have done is we have given grants to specialists


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


a preferred practice recommendation. The only


thing we can say is what we did and what the




results were. I think it is still an open question


as to which variables that we changed, and we


changed multiple and, as I said, the steroid


injections were taking place at the same time in


another population--which of those factors is the


most important still remains to be determined and I


think a lot more work needs to be done in that




So as regards to what we will recommend,


it is still being decided. Until we hear back from


the experts we obviously will tell people what we


have been doing and the results that were


associated with that.


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


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


the last three or four years there has been a


tremendous experience in the retinal world with the


use of off-label intravitreal steroids because


there is such an unmet medical need not only for


this disease, macular degeneration, but also for


diabetic macular edema. So, I actually think there


was a tremendous learning curve for retinal




physicians learning the best way to do intravitreal


injections. That occurred. We talked about the


protocol amendment and we hope that that had some


effect. But I think also equally important may be


that the retinal doctors had a very, very good


experience of the best way to practice intravitreal


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




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






But having participated in both the data


safety committee and also this panel, I am quite


convinced that the protocol modifications had a


very real effect on reducing the incidence of


endophthalmitis, and I am confident that incidence


can be kept low and probably be even further


reduced with appropriate education of both patients


and physicians, as well as appropriate training.


DR. DUNBAR: Dr. Pulido?


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


recent article I believe in The American Journal of


Ophthalmology. It included people from Baskin


Palmer, looking at the incidence of endophthalmitis


following intravitreal triamcinolone injections,


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




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


never have been known when these trials were begun,


but intravitreal injections have become quite


commonplace in retinal practice now with off-label


use of triamcinolone and the incidence which has




been reviewed shows that it is substantially


higher. Although I believe that that incidence, in


fairness, is decreasing as physicians treat the


injection technique with additional seriousness and


care. But, actually, a detailed review has been


made available to this review committee and showed


that the rate of endophthalmitis following


intravitreal injection with pegaptanib was well


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


for intravitreal medication administration across


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






DR. DUNBAR: Recently several of the


comments reflected not so much concerns about the


statistical significance of the efficacy of the


drug but, rather, concerns for the future.


Previously Dr. Bull mentioned that the committee


can make Phase IV recommendations for plans for the


future, for future studies. What is the mechanism


for this? And, perhaps this is an appropriate time


for the committee to discuss some of these future




DR. BULL: That would fundamentally fall


under recommendations for additional studies. If


these are data deficiencies that you might see as


impacting marketing of the product, it would argue


against whether or not you feel the data is


sufficient at this point in terms of the efficacy


assessment. If these are data needs that need to


be obtained in a systematic way, they can certainly


not hold up marketing of the product if you feel


there is sufficient efficacy in terms of what you


have seen.


We realize this is an incomplete data set




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


given the earliness of where we are in this


submission. In fact, there are modules in the NDA


that have not come in and have not been vetted by


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


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


terms of the re-randomization. There are a number


of sort of outstanding assessments here that I


think certainly have significant implications for


further work. But I think things that need to be


looked at systematically certainly have the


potential of being addressed in Phase IV.


DR. DUNBAR: Dr. Pulido?


DR. PULIDO: Just for clarification, that


could be a postmarketing surveillance. For


instance, study ERG could be postmarketing,


following marketing approval surveillance in that




DR. BULL: You mean is post-approval?




DR. BULL: Potentially but, again, as I


said there is a huge caveat here that we are still




very early in the review of this application and


there are a number of other aspects, particularly


from chemistry manufacturing issues, that will need


to be addressed and other things that will impact


the totality of our assessment of the data.


DR. DUNBAR: Dr. Chambers and then Mr.




DR. CHAMBERS: Let me just clarify, the


range of different options includes additional


Phase III trials, additional Phase IV clinical


trials, as well as postmarketing commitments,


postmarketing monitoring. There is going to be a


certain amount of postmarketing monitoring that


automatically goes with any new drug product. But


what you are describing would probably more


accurately be done as actual controlled clinical


trials because you want, obviously, a baseline as


well as continued follow-up in order to look for


any potential changes. That is probably better


done with a control group and making sure you have


everybody in your trial.


DR. DUNBAR: Mr. Kresel?




MR. KRESEL: I guess my question isn't


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


rest of the committee because it is not one for me


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


and I have heard people commenting on how long can


we use this drug and what are the consequences, I


guess I would like to hear the committee weigh in


on how much follow-up post-approval the committee


thinks is appropriate, for planning purposes. That


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


years of data pretty soon. How much data does the


rest of the committee think is appropriate to


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




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




the question still in my mind is interpretation.


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


you do see something, is that necessarily the drug


product or is that the disease going on? And you


don't know the answer to that.


DR. PULIDO: Then you would have to do the


trial you were considering.


DR. DUNBAR: Taking a step back to Mr.


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


committee members if there is any sense among the


committee to build a consensus of how long the


company should study the drug for the future after


this they finish this planned two-year period. Not


so much requesting additional data such as the


visual field and ERG that Dr. Pulido mentioned, but


just to continue the clinical trial, is there any


sense among the committee? Dr. Lehmer?


DR. LEHMER: In the PDT studies there was


a physical endpoint of no leakage. Is there a


similar endpoint with regard to this study looking


for that type of endpoint or stabilization of


vision? I think we have to have some kind of




clinically meaningful endpoint on which to base the


answer to that question of how long do we carry the


study for and, therefore, how long do clinicians


expect to carry on the treatment.


DR. GUYER: In the photodynamic studies


there was continued leakage. When they decided to


retreat they would do a fluorescein angiogram to


determine that. But over the course of the year,


similar to what we have seen, there was still


leakage occurring and that us the disease, and Tony


can perhaps give us some hypothesis for why.


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


data will be very, very important in the sense that


we will learn more about two years of therapy


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


mentioned earlier, I think what is nice about the


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


a patient who has significant disease with large,


scarred, poor vision obviously wouldn't be


necessarily a good candidate to continue treatment.


Someone that might not have any leakage, as you


say, could be used as a clinical endpoint for




perhaps stopping treatment, and people who are


actively bleeding would continue.


But it is important to say that really the


only recommendation we can make is this clinically


important finding is based on one year or 54 weeks


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


more and it would be dangerous to try to speculate


that less treatment could give the same effects.


So, we believe that clinical judgment would be


very, very important in determining long-term




DR. DUNBAR: Dr. Pulido?


DR. PULIDO: The other thing that I think


is important is the fact that even with one-year


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


group of patients? Wasn't it 10 percent or




DR. ADAMIS: It was two percent in treated


and sham alike.


DR. PULIDO: Right, so I mean you are


already getting to a point where there is a certain


mortality in these elderly patients. To continue




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


find a higher mortality rate and I don't know


whether we are going to find more than what we are


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.]






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




connection with your attendance at the meeting.


Likewise, FDA encourages you at the beginning of


your statement to advise the committee if you do


not have any such financial relationships. If you


choose not to address this issue of financial


relationships at the beginning of your statement,


it will not preclude you from speaking.


At this point of the open public hearing,


I will ask speaker number one to please come to the


podium. Each speaker will have seven minutes to




MR. GARRETT: Hi. My name is Dan Garrett


and I am with Prevent Blindness America. My


organization paid for my own travel to come here


today and I personally do not have a financial


relationship with any of the companies pertaining


to this drug.


I mentioned I am with Prevent Blindness


America. We are the second oldest voluntary health


agency in the country. We represent organizations


throughout the country that primarily focus their


efforts on screening, training, advocating,




researching and educating people on the importance


of good vision care. We also advocate for


increased research funding and increased funding to


the Centers for Disease Control in Washington, and


we try to impact public policy as it relates to


saving sight and vision loss.


The reason I am here today is not to


endorse this product but to encourage the committee


to make the right decision as it relates to the


science behind this drug. It might suggest that


this could prevent further vision loss for people


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


organization does not endorse the product of


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




this committee consider this drug because it has


the potential to potentially stop vision loss.


Unfortunately, there is not a miracle drug out


there yet that prevents AMD but, hopefully, with


all the science and research that is going on that


will be in the near future for us.


Another interesting statistic, and this


could particularly hold for people with AMD because


they are the ones that have most low vision, vision


impairment is the cause of 18 percent of hip


fractures, and most people that have AMD are living


on their own and they have lost their central


vision so it is very difficult for them to navigate


their way around their home. If only one in five


of those hip fractures were prevented, more than


440 million dollars could be saved annually so that


is significant. So, any type of AMD drug that


could prevent further vision loss is certainly a


welcomed addition to the marketplace for patients.


My organization, again, advocates


advancements in treatment of AMD, and I just want


to say to the committee that I am sure you will




make the right decision on behalf of all the older


Americans in this country for the people that have


AMD. Anything that can prevent further vision loss


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


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






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




speaker number three to come to the podium.


MR. STEVENSON: My name is Nick Stevenson.


I am the president of the Association for Macular


Diseases. It is the only national support group


that is solely concerned with both the practical


and the emotional problems confronted by


individuals and families endeavoring to cope with


our particular type of eye disorder. To do that,


we publish a newsletter which advises our members


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


not. There is an increasing number of scams and


frauds which are proliferating now not only in


numbers but in funding as well, and we maintain a


members hotline where members can always call in


and we can act as a link between them, their


problems and the problems that they may face.


I, myself, have been legally blind from


the wet type of macular degeneration for 26 years.


I have no financial interest in this pharmaceutical


company or actually any, except that they did pay


my travel and expenses to come down here. But what


I would like very much to emphasize for all of you




is something that many of you, I can understand,


have already experienced, how difficult and


understandably difficult it is for a fully-sighted


person to fully appreciate the enormous subtraction


from life that loss of vision represents, for some


far more than for others but, nonetheless, it is


not something that any of us foresaw in earlier


years of our lives. We may have thought of


disasters overtaking us, such as being struck by an


automobile or some disease attacking us in a way


that we found ourselves to be vulnerable. But the


loss of vision is something that few of us have


ever contemplated. We felt that there was a


warranty issued on our eyes and we had the full use


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


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


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




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




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




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




so many people losing their vision in this country.


Moreover, it is difficult to adjust emotionally and


functionally to a certain level of visual loss if


that vision worsens next month.


One of the first clients that I had as a


rehabilitation counselor was a gentleman suffering


from age-related macular degeneration. He was


about 50 years old and his deterioration rate was


steady over the course of time, and he was really


overwhelmed by this. His name was Jack. Jack had


lost confidence in his capabilities. He felt that


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


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


beginning to adjust, I lose more vision and the


despair sets in again."


Well, his visual loss forced him to retire


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


financial hardship to his family. He was staring


at the walls every day and not feeling productive


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


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


and now he was on my doorstep, wanting answers to




how to live independently.


I remember thinking that, gee, if I had


seen him a little earlier, or if the progression of


his sight loss was not as significant I might have


been able to help him realize that he could do his


job still using alternate techniques or technology.


But he lost his vision much too quickly and he did


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




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.




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.




Thank you.


DR. DUNBAR: Thank you. Now I want to


request that speaker number five come to the




DR. ROSENTHAL: I am Bruce Rosenthal,


Chief of Low Vision Programs at Lighthouse


International, New York City and Mount Sinai


Hospital. My organization paid my expenses.


However, in the past I have had an unrestricted


educational grant from Novartis for a booklet on


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




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




patients I was seeing with low vision would go from


20/800 down to light perception. My patients now


usually fall in the end stage between 20/200 and


20/400. Yet, serious vision loss continues despite


these interventions, as we know.


As Carl Augusto mentioned, we seem to have


an impact, however, with vision rehabilitation. As


a low vision clinician, I have seen that


individuals with AMD who have access to the latest


treatments benefit more from vision rehabilitation


services as well. These individuals have a greater


success rate in the use of low vision optical


prescriptive devices, absorptive lenses, as well as


high tech and electronic aids. These people can


continue to be employed, travel independently,


manage their own affairs, maintain their own


residence and perhaps even drive. Again, I


recommend that you consider the treatment that will


help preserve visual function and its benefits to




DR. DUNBAR: Thank you. This concludes


the five members of the public that have registered




to speak at the open public hearing. However,


there are some additional members of the public


that have approached us requesting to speak and,


time permitting, they will be allowed to come to


the podium and give two-minute presentations. So,


I will ask if there are any other members of the


general public that wish to come forward at this


time. Thank you. We have someone coming forward.


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


ophthalmologist in practice, retinal diseases, in


Baltimore. I congratulate the sponsors and


certainly hope that this is approved.


I did want to comment that I am concerned


about the problem of endophthalmitis in terms of


the fact that the drug is very broadly applicable


drug that covers all subtypes of choroidal


neovascularization so it will be used much more


widely, and the people using it in the community,


whether they are retinal specialists or


ophthalmologists who are not retinal specialists,


because of the more broad range of the indications,


are selected different than the investigators. The




investigators, as much as the sponsors, have wanted


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


investigators are trained extensively and


controlled much better than the outside area. So,


I do think that control of complications,


particularly endophthalmitis, is important.


The second thing is a comment about the


quality of life. There was just a discussion about


contrast sensitivity and visual fields, along with


the early discussion about ERG and I think these


types of things should be included in future


evaluations. Thank you.


DR. DUNBAR: Thank you. Are there any


additional members of the public that wish to come




[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?




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




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


this is insightful because once the drug is


available to doctors--for example, would a doctor


perhaps instill it into the anterior chamber for a


patient with rubeosis? And, this is a conceivable


possibility. Do we know anything about endothelial


cell toxicity? This is a question actually for the




DR. ADAMIS: The question is an important


one. We did not look specifically at endothelial


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


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


there did not appear to be an increased incidence


of corneal edema.


DR. DUNBAR: Is there any preclinical data


that might guide us about this question?


DR. ADAMIS: In the preclinical animal


studies there was no finding of corneal edema as a


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


my knowledge, specular microscopy was not done.


DR. GUYER: Just as far as a comment on


other uses, the sponsor right now is presently




looking at other important diseases in trials. We


finished our Phase II program of diabetic macular


edema and actually, hopefully in the fall, we will


be talking with the agency about putting together a


Phase III program. As you mentioned, there are a


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


we are specifically talking about the indication


for age-related macular degeneration.


DR. DUNBAR: As a pediatric


ophthalmologist, I am interested in retinopathy


prematurity. Do you have any comments about its


use in that situation?


DR. ADAMIS: Theoretically it is a drug


that I think may prove useful in retinopathy


prematurity but the data that I showed you is that,


you know, VEGF is required for normal vessel


formation and the conundrum has always been, well,


how can you block the bad vessels and leave the


good vessels alone? But it look like by targeting


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


something we would consider doing in the context,


obviously at some point in the future, as a




clinical trial. We wouldn't recommend off-label


use at this point.


DR. GUYER: Also, in addition to


retinopathy prematurity to look at in the future,


and we mentioned the diabetic program also, we are


also presently in a Phase II program for retinal


vein occlusions and the macular edema that comes


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


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


if anyone is interested.




In addition to the diabetic program, we


presently are studying, as I said, retinal vein and


also we have a small program with Emily Chiu, of


the National Eye Institute, on von Hippel Lindau


tumors because of the increased permeability of


those lesions. We are considering, but have not


started yet, trials for pathological myopia and


histoplasmosis where, again, choroidal


neovascularization is associated; sickle cell


retinopathy; iris neovascularization, as was


earlier mentioned; and proliferative diabetic




retinopathy. Those are presently under




DR. DUNBAR: Are there additional comments


from the committee at this time, especially


pertaining to the public hearing?


[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




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?




DR. LEHMER: No, I don't.


DR. DUNBAR: Dr. Gates?


DR. GATES: None.


DR. DUNBAR: I have no additional


comments. Dr. Miller?




DR. DUNBAR: And Mr. Kresel?


MR. KRESEL: No, I do not.




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


on to a discussion of the individual questions


posed by the FDA. I will read the individual


question and open up the question for general


disease and at the end of the discussion poll each




The first question reads, has sufficient


data been submitted to evaluate the efficacy and


safety profile of pegaptanib sodium? Excuse me, I


was operating from an older list.


Back to question number one, based on the


inclusion/exclusion criteria, are there patients


excluded from the studies that you believe need to




be studied? Is there any general discussion about


the inclusion and exclusion criteria? I am going


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


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




DR. DUNBAR: Ms. Knudson?


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


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




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




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




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




more variability with measurements at 2 meters


versus 4 meters, although we don't have good


quantitation on what that is.


DR. DUNBAR: Dr. Pulido?


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


possible way of getting around this problem? I


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


Because there is a concern, could future studies be


requested to be at 4 meters from the start for the


small chance that there may be a problem?


DR. CHAMBERS: It is the agency's


recommendation that they be at 4 meters to avoid


the issue even coming up. Were we talking about a


single letter we probably wouldn't be asking this


question either. We would say, well, that is


definitely within what the variation is. You may


choose to believe, well, it takes 16 meters before


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


so we think there is enough robustness in the


findings and robustness in differences in visual


acuities that, while we would have not like to have


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




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


to deal with it as best they can.


DR. DUNBAR: Dr. Pulido?


DR. PULIDO: Though it would have been


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


to be enough robustness of the data that I accept


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


way you had said it?


DR. CHAMBERS: I did not want to put words


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


examples of the type of information we are looking


for in comments.


DR. PULIDO: That would have been the way


I would have said it without you having said it.




DR. DUNBAR: I have a question for the


agency. Was this an agreed upon aspect of the


protocol prior to commencing the clinical trials,


or was this a point that came up in the analysis


later on?


DR. CHAMBERS: The agency, having had the


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




protocols were written for ETDRS and has always


assumed that if someone wrote ETDRS that they meant


that they would do visual acuities at 4 meters. We


have come to find out since that time that that is


not the interpretation necessarily in the whole


community and so there were clinical trials that


were started using the charts but moving them to


different distances and people continued to call it


ETDRS even though it does not meet the technical


protocol of ETDRS. In this particular case we were


aware of the difference after the trials had


started. To the extent we were aware of them


before the trial start, to the extent that we were


aware of them during the trials, we have made those


comments but in some cases we are aware that there


were trials that started before we were able to


comment on it. Then you would be caught with the


equal question of do you change the protocol in


midstream or do you run the protocol the way it was


started, even if you would have preferred to do it


a different way?


I will let the sponsor comment on their




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


do fully understand it--is to continue the


protocol, at the point that you recognize there is


a difference, the way it was written so that you


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


changed the protocol. What would have happened had


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


the data that we have. We obviously don't


encourage it in the future but this is what we




DR. DUNBAR: I have a question for the


sponsor. Was every center done at 2 meters? Were


they all uniform throughout the protocols?


DR. GUYER: Could I have slide 14 up,






First, yes, they were all standardized. I


think Dr. Chambers summarized very nicely in the


morning the difficulties with 2 meters versus 4


meters. When we started the trial our thought


process was, first, that historically other trials


were done at 2 meters, most of the other trials




were for this condition. Part of the reason was


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


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


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


more patients to see at the baseline visions and at


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




But certainly the FDA has presented very,


very good information why 4 meters should be


considered as well. There is no perfect testing


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


said it very well, that the key factor is if


masking is good and if you have some kind of rigid


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


move, then 2 meters is certainly a good testing


parameter. The real potential biases at 2 meters


have to do with two things. One is accommodation


which, obviously, in this population because of


presbyopia is not an issue. The second is the


leaning that Dr. Chambers mentioned.


Now, we have randomization which certainly


helps. So, we would hope that good randomization




and masking should be equal between sides. But we


also have some very important quality control






We had very vigorous training and


monitoring of the visual acuity examiners before


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


over 450 audits performed in all of the centers


throughout the world. And, one of the questions


that was looked at was, was proper patient


positioning, such as leaning, prevented by the


acuity examiners? You can see that in these 469


audits, 98.3 percent of the examiners did use


proper patient positioning, which comforts us that


at least based upon this quality control we don't


believe that the patients were leaning forward.


We also have good evidence of proper


masking. All groups, the active groups as well as


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


that suggests that masking was good. Similarly for


discontinuation rates and reasons, which you can


see in the FDA briefing book.






Actually, when we did a trial for macular


degeneration a number of years ago we devised this


measuring stick which also must be used at every


examination. Here you can see a visual acuity


examiner to actually remind the visual acuity


examiner always to be sure that the patient is at


the right distance and that the patient doesn't


lean forward. This, I think combined with the


quality control, helps us.


Also, in Dr. Chambers' questions about


masking and floaters, which is a very good


question, we actually have looked to try to give us


some comfort that there was no difference in the


responder rate of patients who had floaters and


didn't have floaters.




This shows that whether the patients had


floaters or didn't have floaters we see an active


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


the data from as many possibilities of potential


unmasking and did not see anything. So, we have




some comfort I think by the quality control and by


the good masking in the trial that 2 meters was


probably not an issue. But we certainly share with


the agency that in future trials 4 meters are


preferred. We wish more study centers, as Dr.


Chambers mentioned, had 4-meter testing which has


also been part of our thought process, that it is


difficult to get 117 centers with rooms that big.


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


testing after these discussions.


DR. DUNBAR: Thank you. Are there any


other general comments for discussion before


individual polling of the committee members? If


not, I will ask each committee member to answer the


question are the visual acuity findings


sufficiently robust to overcome the potential bias


introduced by visual acuity measurements at 2


meters? Dr. Chinchilli?


DR. CHINCHILLI: Yes, I believe the data


are reliable even though the measurements were


taken at 2 meters. I was comforted by some of


these quality control issues that the sponsor




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




randomization I am very satisfied with the




DR. DUNBAR: I concur with the other


comments to this point. Dr. Miller?


DR. MILLER: Based on what Dr. Chambers


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


DR. DUNBAR: And Mr. Kresel?


MR. KRESEL: I agree with the rest of the




DR. DUNBAR: We move to question number


three, has sufficient data been submitted to


evaluate the efficacy and safety profile of


pegaptanib sodium for the treatment of the