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A Review of Evolving, Evience-Base

Therapeutic Options for Clinical Practice

MaxiMizing Patient

OutcOMes in aMD:

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2 SuPPlEmEnT TO RETinA TOdAy SEPTEmBER 2012

Maximizing Patient Outcomes in AMD

Intended AudIence

This activity was developed for retina specialists andophthalmologists treating patients with AMD.

StAtement of needThis activity is designed to provide clinicians with

practical information about the treatment of AMD andways to best utilize that information in their practice.

LeArnIng objectIveS

At the conclusion of this initiative, participants will dothe following:

Choose therapeutic options for patients withneovascular age-related macular degeneration(AMD) based on new clinical evidence

Establish and utilize new ways to reduce the

treatment burden for patients with neovascularAMD and their caregivers

Discriminate effectively among all therapies availablefor neovascular AMD today

Individualize treatment of neovascular AMDaccording to patients needs

Improve the follow-up care of patients withneovascular AMD

fAcuLty

Allen C. Ho, MD (moderator)Director of the Retina Research Unit

Wills Eye InstituteProfessor of OphthalmologyThomas Jefferson University School of MedicinePhiladelphia, Pennsylvania

Peter K. Kaiser, MDChaney Family Endowed Professor ofOphthalmology ResearchLerner College of Medicine and the Cole Eye InstituteCleveland, Ohio

Richard S. Kaiser, MD

Co-Director of the Retina FellowshipWills Eye InstituteAssociate Professor of OphthalmologyThomas Jefferson School of MedicinePhiladelphia, Pennsylvania

Jonathan L. Prenner, MDClinical Professor in the Department of Ophthalmologyand PediatricsRobert Wood Johnson Medical SchoolNew Brunswick, New Jersey

AccredItAtIon And certIfIcAtIon

The Annenberg Center for Health Sciences atEisenhower is accredited by the Accreditation Councilfor Continuing Medical Education to provide continuing

medical education for physicians.The Annenberg Center for Health Sciences at

Eisenhower designates this enduring material for amaximum of 1.25 AMA PRA Category 1 Credits.Physicians should claim only the credit commensuratewith the extent of their participation in the activity.

There is no charge for this activity. Certificates willbe available online at the Web address noted on theevaluation.

dIScLoSure

It is the policy of the Annenberg Center to ensure

fair balance, independence, objectivity, and scientificrigor in all programming. All faculty and plannersparticipating in sponsored programs are expected toidentify and reference off-label product use and discloseany relationship with those supporting the activity orany others with products or services available within thescope of the topic being discussed in the educationalpresentation.

The Annenberg Center assesses conflict of interest withits instructors, planners, managers, and other individualswho are in a position to control the content of CME/CEactivities. All relevant conflicts of interest that are identified

are thoroughly vetted by the Annenberg Center for fairbalance, scientific objectivity of studies utilized in this activity,and patient-care recommendations. The Annenberg Centeris committed to providing its learners with high-qualityCME/CE activities and related materials that promoteimprovements or quality in health care and not a specificproprietary business interest of a commercial interest.

In accordance with the Accreditation Council forContinuing Medical Education Standards, paralleldocuments from other accrediting bodies, and AnnenbergCenter policy, the following disclosures have been made:

ALLen c. Ho, mdResearch Support Alcon Laboratories

Allergan, Inc.GenentechNEI/NIHNeoVista, Inc.Ophthotech CorporationOraya TherapeuticsPRN PharmaFarm LLCQLT, Inc.Regeneron PharmaceuticalsSecond Sight

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SEPTEmBER 2012 SuPPlEmEnT TO RETinA TOdAy 3


Consultant Alcon LaboratoriesAllergan, Inc.Centocor, Inc.Genentech

Johnson & JohnsonMerck & Co., Inc.NeoVista, Inc.Ophthotech CorporationOraya TherapeuticsPaloma Pharmaceuticals, Inc.PRN PharmaFarm LLCQLT, Inc.Regeneron PharmaceuticalsThromboGenics

Speakers Bureau Alcon Laboratories

Centocor, Inc.GenentechGlaxoSmithKlineNeoVista, Inc.Ophthotech CorporationPRN PharmaFarm LLCQLT, Inc.

Peter K. KAISer, md

Research Support GenentechNovartis PharmaceuticalsRegeneron Pharmaceuticals

Consultant Alcon LaboratoriesArtic Dx, Inc.Bayer CorporationKanghong Sagent

PharmaceuticalsOphthotech Corporation

Shareholder SKS Ocular

rIcHArd S. KAISer, md

Research Support Genentech

Consultant PanOpticaRegeneron Pharmaceuticals

Shareholder Ophthotech Corporation

jonAtHAn L. Prenner, md

Consultant GenentechPanOpticaRegeneron Pharmaceuticals

Shareholder NeoVista, Inc.Ophthotech Corporation

The following faculty for this activity have disclosedthat there will be discussion about the use of productsfor non-FDA approved indications.

Peter K. Kaiser, MD

Jonathan L. Prenner, MD

The following faculty for this activity have disclosedthat there will be no discussion about the use ofproducts for non-FDA approved applications.

Allen C. Ho, MD Richard S. Kaiser, MD

Additional content planners: In accordance with theAccreditation Council for Continuing Medical EducationStandards, parallel documents from other accreditingbodies, and Annenberg Center policy, the following

disclosures have been made.The following have no significant relationship to disclose. Lisa A. Tushla, PhD (medical writer)

All staff at the Annenberg Center for Health Sciencesat Eisenhower have nothing to disclose.

The ideas and opinions presented in this educationalactivity are those of the faculty and do not necessarilyreflect the views of the Annenberg Center and/or its agents.As in all educational activities, we encourage practitionersto use their own judgment in treating and addressing theneeds of each individual patient, taking into account that

patients unique clinical situation. The Annenberg Centerdisclaims all liability and cannot be held responsible for anyproblems that may arise from participating in this activity orfollowing treatment recommendations presented.

This activity is supported by an independent educationalgrant from Regeneron Pharmaceuticals.

This activity is an enduring material and is available inprint or is available as a downloadable PDF. Successfulcompletion is achieved by reading and viewing thematerials, reflecting on its implications in your practice, andcompleting the assessment component.

The estimated time to complete the activity is 1.25 hours.

This activity was originally released in September 2012and is eligible for credit through August 2013.

our PoLIcy on PrIvAcy

Annenberg Center for Health Sciences respects yourprivacy. We dont share information you give us, or havethe need to share this information in the normal course ofproviding the services and information you may request. Ifthere should be a need or request to share this information,we will do so only with your explicit permission. See PrivacyStatement and other information at http://www.annenberg.net/privacy-terms.shtml

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maxiizing Patient

Outcoes in Amd:A Review of Evolving, Evience-BaseTherapeutic Options for Clinical Practice

An expert panel led by Retina TodayChief MedicalEditor, Dr. Allen C. Ho, discusses strategies forobtaining optimal outcomes in patients with age-

related macular degeneration (AMD). In this monograph,Drs. Ho, Jonathan Prenner, Peter Kaiser, and RichardKaiser also provide insights into how they individualizetherapy for each patient with AMD.

Allen C. Ho, MD, is Director of the RetinaResearch Unit at Wills Eye Institute andProfessor of Ophthalmology at Thomas

Jefferson University School of Medicine inPhiladelphia, Pennsylvania. He is Chief MedicalEditor ofRetina Today. Dr. Ho can be reachedat [email protected].

Jonathan L. Prenner, MD, is Clinical Professorin the Department of Ophthalmology andPediatrics at the Robert Wood JohnsonMedical School in New Brunswick, New Jersey.He is the Co-Chief Medical Editor ofNewRetina MD and an assistant editor for the

journal Retina. Dr. Prenner can be reached [email protected].

Richard S. Kaiser, MD, is the Co-Director ofthe Retina Fellowship at Wills Eye Institute

and an Associate Professor of Ophthalmologyat Thomas Jefferson School of Medicine inPhiladelphia, Pennsylvania. He is the Co-ChiefMedical Editor ofNew Retina MD and anassistant editor for the journal Retina. Dr.Kaiser can be reached at [email protected].

Peter K. Kaiser, MD, is the Chaney FamilyEndowed Professor of OphthalmologyResearch at the Lerner College of Medicineand the Cole Eye Institute, Cleveland, Ohio. Heis the Editor-in-Chief ofRetinal Physician. Dr.

Kaiser can be reached at [email protected].

Amd: A groWIng And comPLeX PAtIent

And PubLIc HeALtH ProbLem

DR. HO: Dr. Prenner, would you please provide some

comments on the epidemiology and burden of AMD?DR. PRENNER: AMD is a surprisingly common problem,

which is going to increase in prevalence as the populationages. It is an incredibly impactful disease for patients, oftenreported as the worst medical problem that a patientmight have. One quality-of-life (QOL) study demonstratesthat patients with AMD report lower QOL scores thanpatients with debilitating systemic diseases like chronicobstructive pulmonary disease and acquired immunedeficiency syndrome.1 Based on National Institutes ofHealth data, we project that the advanced form of AMDaffects 2.2 million individuals in the United States, and

while approximately 85% have dry AMD, wet (neovascular)AMD affects 10-15% of the overall AMD population. Thisaccounts for between 220,000-330,000 individuals in theUnited States.2

The prevalence of advanced AMD in the United Statesis high, and our specialty has become, in part, defined bythe management of this disorder. This prevalence is goingto increase to nearly 3,000,000 people by 2020, which willcorrespond to 300,000-400,000 patients with wet AMDas the baby boomer population ages.2 Interestingly, asubstantial part of that growth is in the 85+ age group. As aresult, we are going to be treating a more significantly aged

population with this disease as well.In short, the prevalence of AMD is significant and is

going to rise dramatically. The literature suggests thatwet AMD affects a comparable number of individuals inEurope, and the demographic trends there are similar.2Recent survey data suggest that there is a growth in thecare of AMD, with two-thirds of physicians reporting anincreasing number of injections performed over the last 12months.3

Were all very busy clinicians, seeing a lot of patients withAMD. Id like to ask my fellow panelists: Are youre seeingmore patients with the disease or treating more often? Is

the treatment burden increasing in your practices?

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DR. PETER KAISER: I dont know if its increasing.I think in the past, most general ophthalmologistsand even family practitioners looked at AMD as anuntreatable disease. So a patient coming in with diseasemight not get referred to a retina specialist. I think thepublic awareness of the anti-vascular endothelial growth

factor (VEGF) therapies has changed this notion. Now,general ophthalmologists and even primary care doctorsare sending us AMD patients earlier and earlier. So, theproportion of patients that we can actually treat asopposed to, say, a dry patient or a disciform-scar patient,is going up.

DR. HO: Retina specialists have been amazingly adeptat expanding their capacity to treat these patients, and ifyou have a disease that is growing in a growing segmentof the population, that increases the number of thosepatients in your practice.

DR. RICHARD KAISER: Weve had to make logisticalchanges to our practices. Weve had to adapt our actualoffice structure to accommodate these patients so thatwe can (1) move them through in an expedited fashion;(2) present to them the data that we have in a concisepackage; and (3) still give them as much TLC as wepossibly can. But the increased number of patients in ouroffices does stress the system a little bit. However, I thinkweve been good at adapting to that.

We all have been practicing long enough to rememberwhen all we had was laser for AMD patients. There is

nothing more rewarding than being able to actually helppeople. Weve had to evolve our approach to patientswith the advancement of technology, but the reward iswell worth it.

ScreenIng And monItorIng Amd In

PAtIentS And In tHe PoPuLAtIon

DR. HO: Please tell us how you screen forand monitor AMD.

DR. PRENNER: As we have discussed, the incidenceand prevalence of AMD is very high in the populationover age 65, and appropriate screening is critical to help

identify those patients at risk for the disease. An annualexamination by an experienced ophthalmologist isperhaps the most effective means of screening for AMD.Modifiable risk factors include hypertension, cholesterolcontrol, and control of smoking and obesity, but manyof the risk factors for AMD are not modifiable.4

The findings of the screening exam will help determine,in large part, the risk of developing advanced AMD anddictate the need for nutritional supplementation. As faras the pace of follow-up goes, we know that patientswith intermediate dry AMD, advanced dry AMD, or wetAMD in 1 eye are at very high risk for development of

wet AMD in the other eye. This high-risk population

may benefit from examination by a retinal specialist.5,6Subclinical wet AMD is also not uncommon; weve allseen patients who are asymptomatic with wet AMD, andthese patients are best treated before they develop visualdysfunction. These patients can be missed without thehigh resolution and multifaceted imaging modalities that

retina specialists specifically utilize.At-home screening devices are now coming online,where patients can monitor themselves in a sensitiveand automated way for development of advanced AMD.Well-educated patients have started to ask about theseat-home screening approaches as they are becomingcommercially available.

DR. HO: Those points about at-home screening andmonitoring are interesting because our care and ourassessments of patients are staccato and intermittent.Does anyone want to comment on their experience

with some of the new digital devices that might behelpful in the future for home screening/monitoring?

DR. PETER KAISER: I was recently involved in 2 studieslooking at home-based monitoring of AMD: (1) ForeseeHome device and (2) an iPhone-based app in whicha patient could do a vision test on the smartphone. 7,8Both of these at-home tests measure vision changesand metamorphopsia, and clinical studies are ongoingevaluating whether, once a patient is being treated forwet AMD, can that patient be followed at home sothat he/she only needs to come into the office when areinjection is needed? At this point, both tests are still

unreliable in terms of predicting when a patient wouldrequire reinjection. They appear to be more reliablein predicting the crossover from dry to wet AMD, butimprovements in the algorithm may make the tests evenbetter.

DR. RICHARD KAISER: I believe we need to look atscreening from a more global health care perspective.Should we be screening patients before they developdry disease? Should we be screening patients that havea family history of AMD? What are we going to do ifthey are identified? Can our health care system afford

to provide services for these patients, because yourenow talking about millions of patients at risk for AMD?We still do not have any treatments for the dry formother than nutriceuticals, which can only slow down theprogression of the disease. Once patients have wet AMD,can and should they continue to monitor themselvesat home? Right now, based on our treatment regimens,I think that the money is in educating our patients athighest risk of developing wet AMD, because we haveeffective interventions.

DR. HO: While patient screening with at-home

technology is still evolving, it makes great sense that

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these technologies will likely mature to provide ourincreasingly sophisticated senior patients with the abilityto monitor disease progression outside of the officesetting with improving reliability and ease.

InItIAL evALuAtIon of tHe Amd PAtIent

DR. HO: A 75-year-old woman is sent to you withnew blurred vision in her right eye. Lets have eachfaculty member discuss his initial evaluation of thispatient.

DR. PRENNER: Ill typically perform a comprehensiveophthalmologic examination and pay careful attentionto ophthalmoscopy, often times utilizing a contactlens exam, to get a good first time look at the macularanatomy. Then, pending those results, Ill typicallyobtain an optical coherence tomography (OCT) andcolor fundus photograph to document the baselinefeatures. If we assume that the patient in this scenario

has only dry AMD, I may initiate the use of AREDSvitamins and exogenous omega 3s, depending on theseverity of their disease, and ask the patient to check an

Amsler grid daily. I would schedule a follow-up visit in6-12 months.9

DR. RICHARD KAISER: I agree with the paradigmDr. Prenner laid out. The exam findings may push youto deviate a bit. If your exam reveals hemorrhage or

new clinical changes, Id consider ordering a fluoresceinangiogram (FA), which is still the backbone test forevaluating the pathologic activity of this disease.

DR. PETER KAISER: In addition to an OCT, FA is vitalin the diagnosis of this disease. There are masqueradesyndromes, so I always obtain a FA at baseline. Ifyou live in a part of the country where you see morepigmented races, the risk of polypoidal choroidalvasculopathy (PCV) is higher and you may also getan indocyanine green (ICG) angiogram at baseline. Ipractice in a part of the country where most of my

patients are Caucasian, and I generally do not obtainan ICG at baseline except in the patients for whom Imconcerned about PCV.

Table 1. anTi VeGF Therapies used For The TreaTmenT oF weT amd11-14

Agent Generic/Brand Name)

Molecular Mechanism/Structure

Specific Binding FDA Approvalfor Wet AMD?

Comments

Pegaptanib

(Macugen; Eyetech

Pharma, NY, NY, USA)

RNA aptamer Only the VEGF165

isoform of VEGF-A

Yes Not as effective as pan-VEGF

blockers12

Bevacizumab

(Avastin, Genentech,South San Francisco,

CA, USA)

Humanized antibody All isoforms of

VEGF-A

No FDA approved in oncology

indications Used off-label in AMD

Requires compounding for

intravitreal injection

Ranibizumab

(Lucentis, Genentech,

South San Francisco,

CA, USA)

Humanized, antibody

fragment

All isoforms of

VEGF-A

Yes Developed specifically for

AMD13

Developed as antibody

fragment rather than

antibody for better

intravitreal penetration14

Higher affinity than

bevacizumab

Intravitreal

aflibercept injection

(VEGF Trap-Eye,

EYLEA, Regeneron

Pharmaceuticals,

Tarrytown, NY

and Bayer, Basel,

Switzerland)

Recombinant fusion

protein: Human VEGF

receptor 1 and 2

extracellular domains fused

to Fc portion of IgG1

All isoforms of

VEGF-A and PLGF

Yes Acts as a soluble decoy

receptor

Longer-half life in the eye

and higher binding affinity

to VEGF-A vs ranibizumab

or bevacizumab

Formulated as iso-osmotic

solution (formulation

used in oncology is hyper-

osmotic, therefore, cannot

be used for ophthalmologic

indications)

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DR. PRENNER: When I am seeing a new patient withchoroidal neovascularization (CNV), I typically use bothfluorescein and ICG angiography to confirm the presenceand location of the CNV and to rule out the presenceof PCV or atypical central serous chorioretinopathy.10It is critical that a retina specialist become involved

with exudative AMD cases. While this may seem like astraightforward diagnosis to make, the nuances of thedisease make maximizing patient outcomes a continuingchallenge. Making the diagnosis correctly the first timeis critical to optimizing patient outcomes. For example,PCV doesnt necessarily respond well to anti-VEGFtherapy, but photodynamic therapy (PDT) works verywell. If subtleties are missed on the initial examination,one might mismanage the patient going forward.

DR. HO: So it appears that our panelists still utilizeangiography as an important diagnostic tool in the

evaluation of AMD, particularly at the time of initialassessment when neovascular AMD is of concern or whenthere are clinical changes or unexplained or incongruousclinical signs or symptoms. OCT is an essential diagnostictool in the initial evaluation and follow-up examinationof a patient with AMD, particularly a patient withneovascular AMD.

current mAnAgement of

neovAScuLAr Amd

The Differences in VEGF TherapiesDR. HO: In the past year, weve had major

randomized controlled clinical trials present level 1evidence for various anti-VEGF agents in the treatmentof neovascular AMD. Dr. Peter Kaiser, can you tell usabout the differences between these therapies?

DR. PETER KAISER: The nice thing about practicingmedicine currently is that we have several commerciallyavailable anti-VEGF agents with which to treat ourpatients. Some of the key differences between theseagents are summarized in Table 1. What we see in thechronologic development of these agents is expansionof relevant targets. For example, pegaptanib, the earliestcommercially available anti-VEGF agent for use in AMD,

only binds to the VEGF165 isoform of VEGF-A, whilebevacizumab and ranibizumab bind all isoforms ofVEGF-A. These panVEGF agents are associated with higherefficacy than pegaptanib. The latest developed agent,aflibercept, not only binds all isoforms of VEGF-A, it alsobinds placental growth factor (PLGF) and VEGF-B, whichthe others dont inhibit. With the more advanced agents,we also see a progression in improved pharmacologiccharacteristics (increased affinity for relevant targets and/or penetration into the eye). For example, ranibizumabhas a higher binding affinity than bevacizumab, andaflibercept has an even higher affinity, as well as a longer

half-life in the eye.11

DR. HO: Is there any relevance about the role ofPLGF in neovascular AMD? Or is this unproven?

DR. PETER KAISER: At this point, its clinicallyunproven, but there are some good animal datasuggesting that PLGF plays a role in neovascularizationas well as in CNV. So PLGF plays a role, but its probably

a minor one. We are still learning about the role of PLGFin AMD.15

DR. PRENNER: We have 3 outstanding drugscertaineyes and certain lesions may respond preferentially toaflibercept, bevacizumab, or ranibizumab. We haveall been excited by some of the early responses inaflibercept-treated patients who did not respond tobevacizumab or ranibizumab. I wonder if this preferentialresponse is partially due to PLGF binding. However, theseresponses may reflect the increased binding affinity ofaflibercept to VEGF.

DR. RICHARD KAISER: We have no way of actuallymeasuring a patients intrinsic PLGF levels to determinewhich isoform of VEGF is more active in their particularcase, etc. Having multiple therapeutic options gives usmore opportunity to tailor our therapy for each patient.Ideally we would like to have a biomarker to guide ourtreatment approach.

DR. HO: How much attention do we pay to thissequence of sciencefrom affinity in a petri dish,to activity in an animal model, to efficacy in our

patients with neovascular AMD? Are there meaningfuldifferences among our current treatment options?

DR. PETER KAISER: Its difficult to translate biologicactivity from a mathematical model, say, MichaelStewarts model that reported that biologic activity isgreatest for aflibercept, then ranibizumab, and finallylowest with bevacizumab.16 However, we do see someclues from the population-based studies. For instance,if you look at the early aflibercept studies in which theyfollowed patients with as-needed treatment, they wereable to go a very long time between treatments.17 Ifyou look at the ranibizumab as-needed studies over the

long term, the visual acuity does not remain a straightline, like it did in the aflibercept phase 2 studies withas-needed treatment, but instead trails off over time.18

But, what matters is what happens in an individualpatient. And the biologic activity in the individualpatient is going to be based on a lot of things. Forinstance, in vitrectomized patients, biologic activityis going to be very different. In my mind, there is adifference in biologic activity in terms of the length oftime these products last. Whether it will translate intoa much longer time between injections with afliberceptor not remains to be seen. Some patients will respond

better to certain agents.

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DR. RICHARD KAISER: There is always a gap betweenanimal studies, clinical trials, and clinical reality. Clinicaltrials test a homogeneous population with fresh, activeCNV lesions with few complicating clinical features suchas significant pigmental epithelial detachments (PEDs),hemorrhage, and early fibrosis. Clinical trials are designed totest the drug on substrate that will best respond to therapy.In clinical practice, we need to treat all lesions and in realitysome respond to therapy better than others. Thus, visionoutcomes and treatment regimens can vary and may notexactly follow the FDA label in clinical practice.

DR. PRENNER: In a clinical trial, efficacy is judged by thechange in ETDRS letters read. For better or for worse, thisis not the efficacy metric that we use daily in our clinicalpractices. In large part, we use surrogate markers ratherthan ETDRS vision to judge pharmacologic effect in dailypatient care. These surrogate markers include anatomicchanges on ophthalmoscopy, OCT, and angiography.When one carefully reviews anatomic data from recentprospective AMD trials, aflibercept may demonstrateanatomic advantages in terms of OCT thickness and CNVquiescence on OCT and angiography compared withranibizumab or bevacizumab.19,20 We may be seeing the

scientific advantages of aflibercept at the bench (in termsof durability and efficacy) translate to an improvement ofthe anatomic biomarkers that we use to judge efficacy asclinicians. These anatomic markers are clinically important,but did not translate into a major difference in ETDRSletters read in a relatively short-term clinical trial.

Reviewing the Evidence from Clinical TrialsThe HARBOR Trial-Safety but No Increased Efficacy withHigher-Dose Ranibizumab

DR. HO: The HARBOR trial enrolled approximately1200 patients and was a comparison of standard-dose

ranibizumab (0.5 mg) vs higher-dose ranibizumab (2.0

mg) on a monthly basis as well as those2 dosages on a PRN basis (after 3 loadingdoses). All 4 groups showed substantialimprovement in mean visual acuity at 1year (0.5 mg PRN: 8.2 letters, 2.0 mg PRN:8.6 letters, 0.5 mg monthly: 10.1 letters, 2.0

mg monthly: 9.2 letters), similar to whatwe saw in the original ranibizumab trials(Figure 1).21 The PRN groups, however, didnot meet the strict noninferiority margin(4 letters) of monthly ranibizumab.

The other significant information aboutHARBOR is related to safety. With theANCHOR and MARINA trials, there wassome suggestion of a safety disadvantagewith the higher dose of ranibizumab (0.5mg vs 0.3 mg). This was highlighted inthe preliminary analysis of the SAILOR

data, which culminated in the DearHealthcare Provider letter citing numerical difference incerebrovascular accidents with the higher dose22 in thefirst 6 months of the study. However, this subsequentlydid not pan out upon further follow-up. But theHARBOR study showed that there were no significantsafety differences between the 2 mg and 0.5 mg dosagesof ranibizumab. At least to my thinking, this gives a lotof relief from any safety concerns in a dose response.The disappointment of the HARBOR trial was that wedid not raise the bar for efficacy (mean improvementin visual acuity or 3-line gainers) with the higher dose.

Therefore, the standard dose of ranibizumab (0.5 mg)remains the benchmark for that drug.21

The VIEW1 and VIEW2 Trials: Aflibercept Efficacy with q8Week Dosing

DR. PETER KAISER: The VIEW1 and VIEW2 trialsenrolled approximately 2400 patients, making VIEW,collectively, the largest AMD trial to date.11,19,20 TheVIEW trials were noninferiority studies, which havesome specific caveats: (1) The comparator group mustbe the gold standard therapy (monthly ranibizumab);(2) They must enroll patients similar to those enrolled

in the original trials as the gold-standard therapy (ie,patients who were treatment nave with wet AMDand any type of lesion composition like the MARINAand ANCHOR studies); and (3) They must use aprespecified endpoint for noninferiority. In this case, itwas maintenance of vision at 52 weeks (

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and 2 mg given with a loading dose of 3 monthlyinjections and then every 2 mos (q8 wk) up to 52weeks. From wks 52 to 96, patients were dosed atleast quarterly, with more frequent dosing based onpredetermined retreatment criteria.11,19,20

Overall, all the groups prevented moderate vision lossin almost equal amounts. At 52 weeks, all the groupswere well within the 5% non-inferiority margin, so all

the treatment regimens were clinically equivalent.19

These trends held up at the 96-wk endpoint. Forexample, the proportion of patients maintaining visualacuity (loss of

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activity but the intervals between treatments areextended as long as disease remains quiescent.

In the CATT trial, patients were randomized toranibizumab and bevacizumab, both monthly and PRN.This trial employed a treat-and-observe regimen, inwhich the investigator had carte blanche to retreat a

patient in the PRN arms based on strict OCT or visualcriteria as well as the clinical exam. At 1 year, the CATTresults showed that PRN therapy is not as effective asstrict monthly on-label therapy. There was actuallya decrease of 2.4 letters between PRN and monthlyregimens.28

DR. HO: This shows that persistent monthly anti-VEGFinhibition is superior to the tested PRN intermittentanti-VEGF suppression treatment regimens in CATT.

DR. RICHARD KAISER: This brings up a point about

the use of OCT in a treat-and-observe manner. We haveelevated the OCT to be the gold standard for detectingactive disease. But in actuality, the OCT is highly effectiveat detecting early anatomic change, but the OCTcannot detect biologic activity. Perhaps we put toomuch emphasis on the OCT to determine if and when apatient should be treated.

DR. PRENNER: We believe that with a treat-and-extend treatment strategy, we can employ the art ofretinal care, taking advantage of our clinical intuition,multifaceted imaging modalities, and interpretation of

patients symptoms, to both maximize patient outcomesand decrease treatment burden. Unfortunately, treat-and-extend is not a treatment regimen thats easy to testin a clinical trial.

DR. RICHARD KAISER: To add onto that, if we had adifferent imaging modality, maybe one that was moreeffective at OCT, or we had an assay to detect biologicactivity, say VEGF or PLGF levels, then our PRN dosingregimens would be much different and we would betreating more frequently. Perhaps we would have betteroutcomes in the PRN dosing regimens.

DR. HO: With the exception of the q8-weekaflibercept regimen (after 3 monthly inductioninjections) as studied in the VIEW trial, monthly therapyaffords the greatest improvement in mean visual acuityin the HARBOR, CATT, and VIEW trials.

I think then we have to translate the data to reality,and it is generally not practical or possible to treatpatients every month. It may be possible but thetreatment burden often outweighs the benefit. I thinkthe take-home message from this discussion in generalis more anti-VEGF therapy is better than less anti-

VEGF therapy. If you are going to adopt a treatment

regimen that deviates from monthly ranibizumab orbevacizumab, you really have to be cognizant of thePRN data. The aflibercept 2 mg q8-week results are theonly less than monthly regimen that is equivalent over 2years to monthly ranibizumab. Certainly, not all patientsrequire aggressive anti-VEGF inhibition but many do to

achieve their best visual potential.

DR. PRENNER: I think we all have patients who clearlydont need to be treated on a monthly basis and who dovery well, and we wouldnt want to be heavy-handed inour approachand take on the liabilities of safety, costand treatment burden for those particular patients. Thatgroup is not a small subset. There are many patients whodo quite well with less frequent dosing. We wouldntwant to miss those patients by treating everybody on amonthly basis.

Two-year Update to CATTDR. HO: If we look at the 2-year CATT, over time,

what you saw was that monthly ranibizumab andbevacizumab were very similar. But there are certainpotential advantages to receiving monthly ranibizumab.For example, a higher percentage of patients had no OCTfluid at the end of 1 year with monthly ranibizumab vsbevacizumab. If you compare the molecules over 2 years within the same treatment regimen they performsimilarly with respect to mean visual acuity. However, thePRN-treatment arms failed to meet the gold standard ofranibizumab monthly (ranibizumab monthly 8.5 letters

gained, bevacizumab monthly 8.0 letters, ranibizumabPRN 6.8 letters, bevacizumab PRN 5.9 letters, Figure2).29 We saw this right before the end of year 1 andagain at year 2 the slope of the PRN curves for bothranibizumab and bevacizumab began to fall off anddiverge when compared with monthly curves. Althoughocular safety comparisons between ranibizumab andbevacizumab are equivalent, bevacizumab use wasassociated with a higher systemic serious adverse eventrate that was observed at 1 and 2 years.

The current discussion of equivalence in my viewmight apply to an unrealistic monthly comparison

of bevacizumab vs ranibizumab. But if youre goingto use bevacizumab PRN, at least by the CATT studymethodology, youre going to have patients lose visioncompared to a monthly treatment.

I think the safety from an ocular standpoint was likelysimilar between the 2 products. However, in terms ofsystemic safety, the CATT trial showed a difficult-to-explain disadvantage to bevacizumab compared toranibizumab (Table 2).29 The disconnect there was thatit occurred more frequently in the PRN group, andtherefore, people began to think that this underminedthe idea that bevacizumab was less safe systemically

because it occurred more frequently in the as-needed

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treatment group.However, not everything is dose response-related in

terms of safety effects. In addition, the other systemicsafety events were not typically thought related toan anti-VEGF mechanism that we currently hold (eg,higher rates of hospitalizations for pneumonia). Mythinking after year 1 was that this was simply a numericaldifference that would likely equalize over time. However,

at the end of 2 years, as recently presented, thosesystemic safety differences persisted.

Now, none of the trials we do in ophthalmology arepowered to detect significant difference between lowadverse event rates. But that numerical persistenceof a safety disadvantage with bevacizumab concernsme because we dont have a good explanation for it. Iexpected it to go away, but it did not.29I feel obligedin my practice to discuss that with my patients. Thatposes some dilemma for me when I am proposingoff-label bevacizumab. Comments?

DR. PRENNER: CATT demonstrated a statisticallysignificant safety issue that needs to be addressed andlooked at going forward.

One should keep in mind that the bevacizumab usedin clinical practice is not the same bevacizumab thatwe had in the clinical trial. As a CATT investigator, Ifelt very confident giving patients a product that wasaliquoted in a safe and uniform manner. The CATTbevacizumab was aliquoted into 2-mL borosilicateglass vials and was delivered to the investigators in amonitored and uniform manner. That is a differentprocess and product than what I am able to obtain

from my local compounding pharmacy. There are a

number of studies that show thatthe bioavailability of compoundedbevacizumab differs depending onhow it is aliquoted, so I wonderabout drug efficacy. I also worrywhen I hear the seemingly annual

background noise concerningan outbreak of bevacizumab-associated endophthalmitis thatcauses significant visual loss.30

ImAgIng In neovAScuLAr

Amd foLLoW-uP

DR. HO: How frequently do youuse FA for follow-up in a patientwith neovascular AMD?

DR. RICHARD KAISER: Its easyto fall into the trap of continuing

to monitor patients with examsand OCTs. I think its imperative toperiodically perform an angiogram,especially if youre going to alter

your treatment regimen and move off label in terms ofmonthly treatment with ranibizumab or bevacizumab.Many retina specialists dont stick exactly to the label, soI think its very important to do angiograms periodically,especially as you start to extend the time between yourvisits. I have seen many cases where the OCT is dry, butthe lesion is growing at a rapid rate, and the angiogram isgoing to reveal that.

DR. PRENNER: We have evidence-based datademonstrating the superiority of frequent, persistent anti-VEGF therapy compared to PRN dosing strategies utilizedin recent clinical trials. We balance that data against theburden of treatment involved with monthly injections andthe fact that we think that with a very careful treat-and-extend paradigm, which has not been formally tested, wecan get very close to the outcomes achieved with persistentanti-VEGF inhibition. Treat-and-extend management is avery nuanced process. It has to be managed very carefully bya retina specialist, and it has to incorporate all the tools at

our disposal.I think we tread on somewhat thin ice when we start

treating patients in a manner other than with monthlyinjections. And so, I try to be extremely careful with mytreat-and-extend management, and make sure that beforeI change a dosing interval, that I reimage with OCT andfluorescein angiography, to confirm that there is not agrowing CNV component that I cant identify by OCT.

DR. PETER KAISER: I would also add that forpatients who dont respond to therapy, then Im morelikely to get ICG in addition to fluorescein to rule out

masquerade syndromes and guide future management.

Figure 2. Visual acuity across the 2-year CATT study. Reprinted from Martin et al.

2012,29 with permission from Elsevier.

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neXt StePS In Amd WHAtS In tHe future?

DR. HO: Weve laid out some of the evidence. We dohave a lot of evidence for choices now for our patients.And yet, even with those choices and a game-changingkind of treatment, we, for example, still have manypatients that dont improve visual acuity. We have

maximized the limits on the metric of maintaining orpreventing vision loss, but in terms of 3-line gainers,were still at an opportunity for 60-70% of patients toimprove vision with therapies.

Combination therapy has been held to have greathope, but today, my assessment is its fallen flat interms of raising the bar and improving visual acuity.That may be changing, however, as we evaluate theinformation from Ophthotech on their positive phase 2study combining anti-platelet-derived growth factor(anti-PDGF) and ranibizumab.

DR. RICHARD KAISER: Clearly VEGF is not the onlypathway that is driving this disease. As a clinician, I lookforward to therapies that block other pathways that maybe as important or even more important in treating thisdisease.

DR. HO: We look forward to the hope that rests on theshoulders of combining anti-VEGF therapy with perhapsnoninvasive radiation therapy and other strategies suchas anti-PDGF factor treatment.31 We are watching somepotentially significant trials of new combination treatmentoptions that have yet to be presented in a peer-reviewed

setting. Once we learn more about these combinations,we will have a better sense of the incremental benefit aswell as the safety and convenience implications of thesemore complex approaches.

IndIvIduALIZIng tHerAPy of neovAScuLAr

Amd PAtIentS

DR. HO: When treating individual patients with wetAMD, the art is in interpreting and processing theinformation from our trials and then tailoring it forthat patient. We have choices in 2012 going forwardthat may benefit 1 patient more than another. The

discussion below and the video case discussionseyetube.net/portals/New-Evidence-in-the-Treatment-of-Neovascular-AMD illustrate some of the factors weconsider in individualizing therapy.

Initial Therapy for Wet AMD (Case presented by Dr. Allen Ho)DR. HO: We have a 77-year-old woman, with new-

onset vision loss, fluid and hemorrhage in the macula,and visual acuity at 20/100 attributable to neovascularAMD. How would you proceed?

DR. PRENNER: I would treat her on the same day thatshe presents. I would use an approved therapy, either

aflibercept or ranibizumab, rather than bevacizumab

because of safety concerns with the compoundeddrug that I can obtain in my clinical practice. Untilrecently, I most frequently used ranibizumab becauseof its availability and our extensive experience with thedrug. Lately, Ive begun using aflibercept as well, morefrequently as the drug becomes more readily available to

our patients and reimbursement issues are addressed.

DR. RICHARD KAISER: We are restricted byreimbursement issues. Insurance coverage is an issue,so we do not always get to use our first-choice drugs.At this point, we are waiting for a J-code for aflibercept,so that affects our choices. As time goes on andreimbursement issues are resolved, I believe we will beable to offer patients the drugs we want.

DR. PETER KAISER: I agree with everything that hasbeen said. I also prefer aflibercept or ranibizumab as first

line in a patient with new onset, treatment-nave, wetAMD because of their established safety and efficacy,and the fact that fractionation is not required. However,its important to note that bevacizumab is the mostcommonly used drug for wet AMD in the United Statesand all the recent comparison studies show minimalefficacy differences.32 When talking with patients, Ipresent clinical trial data for all 3 drugs, I highlight thedifferences, and then I let them choose. In general, mypatients choose ranibizumab or aflibercept. I use themom testin other words, what would I use to treatmy mother? That would be aflibercept or ranibizumab.

DR. HO: We make treatment decisions based onsafety and efficacy. Are there any safety differencesthat we should be aware of among these agents?

DR. PRENNER: The FDA-approved therapies appearto have similar efficacy and safety. There are some safetyconcerns with bevacizumab that came out of the 1-yearand 2-year CATT data.28,29 While that is an evolving story,it is a concern that I discuss with my patients now thatthe data are available.

DR. RICHARD KAISER: I share those concerns. There

are potential ocular issues with bevacizumab relatedto the formulation (ie, the source of bevacizumab). Inthe CATT trial, serious adverse events occurred in 32%of patients receiving ranibizumab vs 39% of patientsreceiving bevacizumab.29 This was statistically significant.We may not have a rational explanation at this point, butwe need to investigate it further, and it is something weshould discuss with our patients.

DR. PETER KAISER: There are 2 different safetyissues associated with use of an off-label molecule likebevacizumab. Rick outlined the safety issues from the

molecule itself that arose in CATT and other comparison

A

B

C

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studies. However, the significant differences in adverseevents seen in these studies are not the ones we usuallyassociate with anti-VEGF agents. So we really do notknow what to do with these data. It is important tonote that the CATT trial was not powered to measuresafety events, such as myocardial infarction and stroke.However, larger retrospective case series using theMedicare database have shown a possible increasedrisk.33 So the jury is still out in terms of the safety ofthe molecule. The clinical trials for the approved drugs,aflibercept and ranibizumab, suggest that they are safe.

To me, the main safety issue regarding bevacizumab is

related to risk introduced with compounding of themolecule. In CATT, the molecule was supplied in asterile single-use vial like we receive ranibizumab andaflibercept that was produced in a sterile fashion bya pharmaceutical company. This is not how we getbevacizumab when we use it. In practice, we have to

trust that the bevacizumab that our compoundingpharmacy gives us is free of microbiologic contaminantsand contains the appropriate amount of the drug. Weknow that this can be an issue, given the case reports ofclusters of bevacizumab-associated endophthalmitis dueto compounding pharmacy errors.30

DR. HO. Lets say it is your mother, and there are nopayer issues, how would you treat her?

DR. PRENNER: I have extensive experience withranibizumab, but I am very encouraged by my earlyexperience with aflibercept. Right now, I would be

comfortable giving either aflibercept or ranibizumab.That answer may change in a few months, as I gain moreexperience with aflibercept.

DR. RICHARD KAISER: I agree. I am comfortable usingranibizumab or aflibercept as a primary therapy. We arefortunate to have multiple excellent drugs.

DR. PETER KAISER: I would give my mom thebest medication possible. In my opinion, I wouldchoose aflibercept. While I agree that aflibercept andranibizumab are similar in efficacy, aflibercept has a small

safety advantage, in that I can give her fewer injections.That lowers the risk of an adverse event simply becauseof the reduced numbers of injections.

DR. HO: For my mother, I would be comfortable withafliberceptI do have a lot of experience with thatagent, since we were involved in the trials. I do like thepotential advantage of fewer injections. However, wedont know whether ranibizumab would be effectivein a similar dosage regimen, since its never really beenstudied in a less than monthly fashion and comparedwith aflibercept. Certainly, I am very comfortable with

ranibizumab as well.

When is it too Late to Treat Wet AMD? (Case presentationby Dr. Richard Kaiser)

DR. RICHARD KAISER: Lets discuss the case of an89-year-old gentlemen, status post stroke 10 years ago,who was left in a somewhat debilitated state. He wasfollowed by another retina specialist. Left eye had adisciform scar. His right eye was treated from 2005 to2007 with regular ranibizumab injections. The right eyetreatment was halted in 2007 when it was deemed notworth continuing (he had counting-finger vision in both

eyes). The patient was observed only until November

Figure 3. imaging result, right eye, in an 89-year-old man

previously treated with ranibizumab in 2007. a. November,

2011, prior to initiation of ranibizumab. b. 1 week post

ranibizumab injection. c. 5 weeks post ranibizumab injection.

Ph

otographcourtesyofRichardKaiser,MD

.

A

B

C

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2011, when his daughter brought him into our clinicfor a second opinion. I was unable to get an angiogrambecause he had a known history of fluorescein dyeallergy, but the OCT and the red-free image showscarring in the central macular, atrophy, somefibrovascular change, a lot of edema, and subretinal fluid(Figure 3a). As poor as his vision was, I didnt get a sensethat this was an end-stage eye.

We opted to proceed with treatment with

ranibizumab. After 1 injection, he did not notice anychange in vision, but the OCT shows some improvement(Figure 3b). Fast forward, after 5 injections withranibizumab, his OCT is greatly improved, althoughobviously his scarring is still there (Figure 3c). At thatpoint his vision was 20/200, and his quality of life wasgreatly improved.

This raises an important pointhow do we knowwhen it is too late to treat wet AMD? We dont haveclinical trials or guidelines to inform us on this issue.

DR. HO: The status in the fellow eye helps me to

determine how aggressive Ill be with an eye with a

fibrotic lesion. Ricks rightthere is no clear guidance.When a patient is down with 2 eyes with wet AMD, Illtalk with the patient, asking them what his/her preferredeye is. Ill suggest being more aggressive with that eye andtalk with the patient and the family, since that patientwill need to be brought in on a regular basis. Its the art

of retina care. I will get aggressive if they have 2 bad eyes,trying to figure out which eye has more potential.

DR. PETER KAISER: I agree with Allen. I would get alot of information from the prior retina specialist aboutprevious responses to anti-VEGF. If there was at leastsome response in the past, then its probably worthtrying 1 injection to evaluate the clinical response. Onequestion I have about this case is whether the patientgave up on therapy because of the central atrophy andwasnt getting a visual improvement. When the fluidcame back after treatment was stopped, the visual field

and quality of life were much worse. Obviously, thispatient has had a great outcome with anti-VEGF therapy,but this is not the case in all late AMD cases.

DR. RICHARD KAISER. This patient would neverqualify for a clinical trial, and its tough to measure thebenefit of these therapies in a near-end stage case likethis one. But for this patient, going from counting fingersvision to 20/200 was life-changing.

Management of Suboptimal Responses and Extending theDosing Interval (Cases provided by Dr. Jonathan Prenner)

DR. PRENNER: Id like to discuss some patients withpartial or suboptimal responses. The first is a monocular,75-year-old widow, who is very independent, and hasa visual acuity 20/50. We treated her with monthlyranibizumab for more than 2 years, and despite visualand anatomic improvement over the first year or so,her progress stalled. She had some residual intraretinalfluid, and some subretinal tissue consistent with a CNVmembrane. Despite monthly treatments, she continuedto leak on FA and OCT, and we confirmed the absenceof IPCV on ICG angiography. So I felt that she was apartial responder to ranibizumab. She looked forward

to ongoing developments with aflibercept and thepotential for less frequent injections. When available, wetreated her with aflibercept and evaluated her at her 1week post injection for signs of a biologic response. Shelooked quite good, with functional improvement; shewas a 2-hands up, hugging, kissing kind of patient. Fiveweeks outshe had significant improvement.

I have 2 other cases with a similar responseie,incomplete or partial response to ranibizumab, whoresponded well to aflibercept. Thoughts?

DR. HO. Jon discussed a case of partial or incomplete

responses to the existing therapy ranibizumab. Before

Figure 4. Response to aflibercept after stable response to

ranibizumab dosed q 5 weeks. a. After 27 of 32 ranibizumab

injections doses q5 weeks. b. 5 weeks post a singleaflibercept injection. Courtesy of Jonathan Prenner, MD.

A

B

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the introduction of aflibercept, for such a patientmy strategy would be to go to an every 2-week cycle,alternating between bevacizumab and ranibizumab.We would get a response to that strategy in about30% of cases. With such a regimen, we get more VEGFinhibition. Currently, for such a patient, I would consider

switching to aflibercept, because mechanistically ithas both VEGF and potentially relevant PLGF activity,perhaps such a switch can be effective. Weve had similarresponses as Jon has outlined.

DR. PETER KAISER.Jon presented a type 1 lesion,which is marked by CNV beneath the retinal pigmentalepithelium (RPE).34 Usually, such lesions have relativelygood visual acuity, a persistent RPE detachment, andrequire a lot of injections. I would have taken a similarapproach as Allen (ie, alternating between bevacizumaband ranibizumab prior to the introduction of

aflibercept). These patients generally do well whenswitched to aflibercept, so I do offer that as an option.However, this wasnt studied in the clinical trials, sowe dont have guidance on how or when to do this.I generally bring them back 4 weeks after the changein drugs, then add approximately 2 weeks every timethey come back dry (treat-and-extend) and stable afterthey are reinjected. We dont know the correct wayto extend the interval. But Im cautiously optimistic,because I have seen good responses to afliberceptafter suboptimal response to other therapies in somepatients.

DR. PRENNER: Weve looked carefully at thistreatment grouppatients with partial or incompleteresponse to other therapies who then receiveaflibercept. About a quarter of eyes have completeresolution of their anatomic abnormalities, a quarterhave partially improved anatomy, and 40% remainunchanged. Interestingly about 10% of patients do notdo as well anatomically with aflibercept as they didon ranibizumab or bevacizumab. For example, Figure4 shows results in a monocular woman who had astable response to ranibizumab (Figure 4a). She had

received 32 injections of ranibizumab. But I couldntextend the interval between doses. When dosed at5-week intervals, she was reliably dry and 20/20. Butif I tried to extend the interval, she leaked. So shewas looking forward to the potential benefits of lessfrequent dosing with aflibercept. So I switched her toaflibercept and gave her 1 dose. When I looked at herat 5 weeks post injection, she had some retinal fluidthat she recognized and was 20/25 (Figure 4b). Whenwe switched her back to ranibizumab every 5 weeks,this went away. So I agree with Peter, we are cautiouslyoptimistic about the benefits of aflibercept, but this is

a nuanced process.

DR. RICHARD KAISER. We are limited in our abilityto understand the biology. We use OCTs, but they showanatomic but not biologic benefits. As a clinician, itsgreat to have choices, so we can see what works for eachpatient.

DR. HO: Monthly treatment is beneficial. But its usedin only a minority of patients. Many retinal specialists useas needed, PRN treatment.

DR. PRENNER: Persistent anti-VEGF therapy givesyou the best chance of a good visual outcome. It isimportant to consider the status of the fellow eye. Many1-eye patients will choose to have monthly treatment intheir remaining eye. For many binocular patients, I use atreatand-extend approach.

DR. RICHARD KAISER: We have level 1 evidence for

monthly treatment, and level 1 evidence for treat-and-observe approaches. In clinical practice, we try to extendthe interval between treatments-and we dont haveevidence for or against that approach.

DR. HO: How do you extend the interval? Visual andanatomic response?

DR. RICHARD KAISER. I monitor them with OCT,evaluate their vision, and I also use an angiogram toconfirm the disease is quiescent. Once I am convincedthat the disease is stable, then I will extend the intervalsbetween the visits. I will try and keep them quiet with

slightly less frequent visits, and then I will try and extendthe time intervals. I will treat even when there is nodisease. Ill do an angiogram or contact lens exam oncethey enter this stage to look for subtle forms of activity.

DR. PETER KAISER. Most of us dont want to do whatthe level 1 evidence tells us to do. We have the HARBORshowing that monthly therapy did meet the noninferiority endpoint compared to as needed treatment.The IVAN 1-year, CATT 1- and 2-year data show thatas needed treatment was not as good as monthly. So,following level 1 evidence we should all be using monthly

treatment. We dont. While I also use a treat-and-extendapproach, we dont have any level 1 to say whether itworks. The LUCAS study is studying a treat-and-extendregimen using a level 1 paradigm, but not againstmonthly therapy. So, I tell my patients that monthly isbest. Most do not want monthly treatment, so in thosepatients I usually move to treat-and-extend. But I dohave some patients who stay monthly.

concLudIng remArKS

DR. HO. In 2012, our patients with neovascular AMDhave a brighter and more clear future than ever. We

have several excellent treatment options from which to

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choose. Weve raised the bar in neovascular AMDwehave above the line vision improvements and we hopeto have combination approaches that might raise thebar even higher. We still struggle with patient treatmentburden, specifically the need to visit a retina specialistfrequently to assess the need for injection. We look

forward to longer-acting drug delivery platforms to treatneovascular AMD and toward new ways to ward off thedevelopment of choroidal neovascularization in the firstplace. n

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insTrucTions For cme crediT

1. Which of the following is true about the epidemiology ofwet (neovascular) AMD?

A. The at-risk population is growingB. Wet AMD rates are dropping while dry AMD rates

are increasingC. The availability of options for treating wet AMD

probably does not affect the volume of patientsreferred to retinal specialists

D. The disease has a very small impact on quality of life

2. Which of the following is true about screening andmonitoring for AMD?

A. All at-home devices for monitoring AMD have beenfound ineffective

B. The number of patients at risk for wet AMD isdropping with improved management of dry AMD

C. There are specific risk factors for progression fromdry to wet AMD

D. All of the above

1.25 AMA PRA Category 1 Credit Expires August 2013

Supported by an unrestricted educational grant from Regeneron PharmaceuticalsSponsored by the Annenberg Center for Health Sciences

For faster certification go to www.annenberg.net/ce/4961 to complete this form and print your certificate.

This activity has been certified for physicians. It was planned and produced in accordance with the ACCME Essentials and

Standards for enduring materials (Release date: September 2012; expiration date: August 2013). To obtain CME credit, pleasecomplete this form, and return to the Annenberg Center for Health Sciences (ACHS #4961), 39000 Bob Hope Drive, DinahShore Building, Rancho Mirage, CA 92270, or fax to 760-773-4550 or submit online at www.annenberg.net/ce/4961.

YOUR CERTIFICATE FOR CONTINUING EDUCATION CREDIT (if applicable) WILL BE ISSUED FROM THEFOLLOWING INFORMATION. Failure to legibly print, complete and sign this form may jeopardize the creation andforwarding of your certificate.

Name ________________________________________________________________________________________________________First M. Last Degree

Affiliation _____________________________________________________________________________________________________ OHome

Address OWork________________________________________________________________________________________________Street Address

_____________________________________________________________________________________________________________City State/Province Zip/Mail Code Country

Daytime Phone ( ______)_________________________________Email____________________________________________________

Date of Birth___________________________________(used for record keeping purposes only)

What is your professional degree?MDO DOO

Other _________

What is your Specialty?

Ophthalmology O Other ____________________________________________________________

My practice is primarily based in (please check 1):

Academics O Private Practice O Other___________________________________

Hospitals O Managed care O Research O

I hereby certify that I have spent ______ hour(s) in this educational activity.Signature ________________________________ Date _____________

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Sponsored by the Annenberg Center for Health Sciences

insTrucTions For cme crediT

3. Which of the following is true about imaging modalitiesfor AMD?

A. OCT is the best tool to measure the biologicbehavior of lesions

B. For patients who have a high risk of polypoidalchoroidal vasculopathy (PCV), indocyanine green(ICG) testing should be considered

C. Fluorescein angiograms are not helpful for ongoingmonitoring of AMD

D. Most general ophthalmologists can effectivelydiagnose AMDreferral to a retinal specialist isusually unnecessary

4. Retina specialist Y starts the patient on an anti-VEGFtherapy every 4-5 weeks. When the patient has a stable

response, he then decreases the dose frequency to every6 weeks, while monitoring carefully using angiograms andother imaging modalities to make sure there is no diseaseprogression. Which is true about this method?

A. Its treat-and-extendB. Its been studied extensively in the CATT trialC. Its been proven to be less effective than monthly

injectionsD. Its likely to provide greater VEGF inhibition than

monthly injections

5. Which of the following is true about the safety ofbevacizumab for neovascular AMD?

A. It provides numerically fewer adverse events thanranibizumab

B. It has been studied extensively in clinical trialsthat reflect clinical practice (ie, supplied from localcompounding pharmacies)

C. May be associated with an increased risk ofcardiovascular events

D. Has not been associated with any infectiouscomplications

6. AfliberceptA. Has similar targets as bevacizumabB. Is formulated as a hypertonic solution for ocular useC. Has a low binding affinity compared with ranibizumabD. Is active against all isoforms of VEGF as well as PLGF

7. Which of the following is true about the HARBOR trial?A. It established that higher doses of ranibizumab are

definitely not as safe as the standard doseB. It showed increased efficacy with a dose of

ranibizumab above the standard doseC. It established the superiority of ranibizumab to

afliberceptD. It further defined the value of standard-dose

ranibizumab

8. The CATT trial found thatA. PRN bevacizumab is as effective as ranibizumab

monthlyB. The safety of ranibizumab and bevacizumab are similarC. Overall, monthly therapy with ranibizumab provided

the best outcomes over 2 years vs PRN ranibizumabor bevacizumab PRN or monthly

D. Bevacizumab has no systemic side effects whendelivered in the PRN dosing, the side effects are onlyseen upon monthly dosing

9. Which of the following is a finding of the VIEW studies?A. The safety of ranibizumab and aflibercept are similarB. Ranibizumab monthly provides better visual acuity

than aflibercept dosed monthly for 3 months thanevery 8 weeks thereafter

C. Aflibercept and ranibizumab both prevent additionalloss of vision from AMD but are not associated withany improvements in vision

D. Aflibercept has substantial systemic safety sideeffects

10. Patient N has had a partial response to ranibizumabmonthly. Which of the following is true?

A. Increasing the amount of VEGF inhibition deliveredmay benefit this patient

B. Some patients will benefit from a switch to aflibercept

C. This patient may benefit from a switch tobevacizumab dosed every 2 weeks

D. All of the above are true

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acTiViTy eValuaTion

Fill in the appropriate circle on each line:

Low Below Avg Avg Above Avg High

Please evaluate the degree to which you thought the format was appro-

priate for this subject

O O O O O

Upon completion of this activity, the degree to which I can better:

Choose therapeutic options for patients with AMD based on new

clinical evidence

O O O O O

Establish and utilize new ways to reduce the treatment burden for

patients with neovascular AMD and their caregivers

O O O O O

Discriminate effectively among all therapies available for neovascu-

lar AMD today

O O O O O

Individualize treatment of neovascular AMD according to patients

needs

O O O O O

Improve the follow-up care of patients with neovascular AMD O O O O O

Please rate the degree to which the following enhanced your learning

experience:

Allen C. Ho, MD O O O O O

Peter K. Kaiser, MD O O O O O

Richard S. Kaiser, MD O O O O O

Jonathan L. Prenner, MD O O O O O

Program materials O O O O O

Please rate your level of agreement with the following statements Strongly

Disagree

Disagree Neutral Agree Strongly

Agree

This activity met my educational needs, expectations, and objectives O O O O O

This activity was relevant to my practice O O O O O

I feel confident treating patients in my practice based on this activity O O O O O

This activity rates highly in comparison with other CME activities in

which I have participated in the last 12 months

O O O O O

There is a continuing need for education on this topic O O O O O

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acTiViTy eValuaTion

If you thought the presentations were commercially biased, please explain: ___________________________________

____________________________________________________________________________________________

For you, was the educational level of this activity:Too advanced Appropriate Too basic

If disease management was discussed in this activity, what is the approximate percentage of your patients that you man-age for the disease/s addressed by this activity?

0-10

11-20

21-30

31-40

41-50

51-60

61-70

71-80

81-90

91-100

PRACTICAL IMPLICATIONS:Based upon your participation in this activity, choose the statement that applies: I gained new strategies/skills/information that I can apply to my area of practice. I plan to implement new strategies/skills/information in my practice. I need more information before I can implement new strategies/skills/information into my practice behavior. This activity will not change my practice, as my current practice is consistent with the information presented. This activity will not change my practice, as I do not agree with the information presented. This is not within the scope of my practice.

What, if any, strategies/changes do you plan to implement in your practice?

__________________________________________________________________________________________

My confidence level in being able to implement these changes is:Very confidentSomewhat confidentUncertain

Little confidenceNo confidenceNot applicable

If you consider a change in practice, please check any barriers to overcome before initiating that change:

Cost issues

Organizational constraints

Formulary issues

Patient reluctance to change

Patient adherence

Insufficient time

Do not know enough about the recommendations tochange yet

What, if anything, remains?_____________________________________________________________________

__________________________________________________________________________________________

Additional comments: ________________________________________________________________________

__________________________________________________________________________________________

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