Clinical Trial UpdatesPutting Research Into Practice for Retinal Diseases

Jointly provided by The University of Louisville office of Continuing MedicalEducation and MedEdicus LLC

This continuing education activity is supported through an unrestrictededucational grant from Regeneron Pharmaceuticals, Inc.

Distributed with

Original Release Date: June 1, 2014Most Recent Review Date: May 11, 2014

Expiration Date: June 30, 2015

Peter K. Kaiser, MD (Chair and Moderator)

Jay S. Duker, MDAllen C. Ho, MD

Daniel F. Martin, MD

CME MONOGRAPH

Instant CME Certificate Available With Online Testing and Course Evaluation

Proceedings From an Expert Roundtable Discussion

Purpose and Target AudienceThe clinical management of retinal diseases such as age-related maculardegeneration (AMD), diabetic macular edema (DME), and retinal vein occlusion(RVO) continues to evolve rapidly as novel therapies and new clinical trialoutcomes expand and refine our practice patterns. In this educational activity,our primary goal is to clarify optimal management of these common retinaldiseases in the context of data from recent clinical trials.

This educational activity is designed for retina specialists and otherophthalmologists treating patients with AMD, DME, and RVO.

Designation StatementThe University of Louisville Continuing Medical Education & ProfessionalDevelopment designates this enduring material for a maximum of 2.0 AMA PRACategory 1 Credits™. Physicians should claim only the credit commensuratewith the extent of their participation in the activity.

AccreditationThis activity has been planned and implemented in accordance with the EssentialAreas and Policies of the Accreditation Council for Continuing Medical Education(ACCME) through the joint providership of the University of Louisville andMedEdicus LLC. The University of Louisville School of Medicine is accredited bythe ACCME to provide continuing medical education for physicians.

Instructions & RegistrationThis course takes approximately 2 hours. Please read the monograph, consultany additional references if needed. Once the materials have been reviewed,you will go to http://bit.ly/retinal2014 to take a post test followed by courseevaluations, after which you will be able to generate your CME certificate. Ifyou prefer, you can also complete the post test and evaluation found at the endof this monograph and fax it to 908-462-6555.

Learning ObjectivesUpon completing this educational activity, participants should be able to:• Discuss clinical data pertaining to the management of AMD, DME, and RVO• Evaluate the relative efficacy and safety (ocular and systemic) of anti-VEGFagents, steroids, and laser in the treatment of AMD, DME, and RVO

• Apply evidence-based approaches to individualize treatment for patients withAMD, DME, and RVO

Hardware & Software RequirementsHigh speed Internet connection (Broadband, Cable or DSL)Windows 2000 or higher256 MBs or more of RAMInternet Explorer 6.0 higherWindows Media Player 10.0 or higherAdobe Acrobat 7.0 or higherCourse content compatible with Mac OS

DisclosureAs a sponsor accredited by the ACCME, the University of Louisville School ofMedicine must ensure balance, independence, objectivity, and scientific rigor inall its sponsored educational activities. All faculty participating in this CMEactivity were asked to disclose the following:1. Names of proprietary entities producing health care goods or services—

with the exemption of nonprofit or government organizations and non–health-related companies—with which they or their spouse/partnerhave, or have had, a relevant financial relationship within the past 12months. For this purpose, we consider the relevant financial relationships ofa spouse/partner of which they are aware to be their financial relationships.

2. Describe what they or their spouse/partner received (eg, salary, honorarium).

3. Describe their role.4. No relevant financial relationships.

DisclosuresCME Reviewers: John Sorenson, MD, has no relevant financial relationshipswith any commercial interests.

Faculty: Dr Jay S. Duker is a consultant to: Alcon/Novartis PharmaceuticalsCorporation; Allergan, Inc; EMD Serono, Inc; Optos; and ThromboGenics NV.He is a contracted researcher for Carl Zeiss Meditec, Inc; and Optovue, Inc. Heis a stockholder in EyeNetra; Hemera Biosciences Inc; OphthotechCorporation; and Paloma Pharmaceuticals, Inc.

Dr Allen C. Ho is a consultant to, a scientific advisory board member of, and acontracted researcher for: Alcon, Inc; Allergan, Inc; Genentech, Inc; JanssenPharmaceuticals, Inc/Johnson & Johnson; Ophthotech Corporation; OrayaTherapeutics, Inc; Physician Recommended Nutriceuticals; RegeneronPharmaceuticals, Inc; Second Sight; and ThromboGenics NV. He is a consultantto, and a scientific advisory board member of: DigiSight Technologies Inc;Endo Optiks; Merck & Co, Inc; and ONL Therapeutics, LLC. He is a contractedresearcher for NEI/NIH.

Dr Peter K. Kaiser is a consultant for: Alcon, Inc; Allegro Ophthalmics, LLC;ArticDx Inc; Bayer; Chengdu Kanghong Biotechnology Co, Ltd; Genentech, Inc;Novartis; Ophthotech Corporation; Oraya Therapeutics, Inc; RegeneronPharmaceuticals, Inc; and ThromboGenics NV.

Dr Daniel F. Martin has no relevant financial relationships with any commercialinterests.

Planning Committee: Dr Peter Kaiser (see above); Cynthia Tornallyay, RD,MBA, CCMEP; and Robert M. Geist IV, MD, MA, have no relevant financialrelationships with any commercial interests.

University of Louisville CME & PD: The CME & PD staff and Advisory Boardhave nothing to disclose with the exception of Dr Douglas Coldwell: Sirtex, Inc(Speaker) and DFine, Inc (Consultant).

Medium or Combination of Media Used: Online Enduring Material ActivityMethod of Physician Participation: Printed and Online/Digital MonographEstimated Time to Complete the Educational Activity: 2.0 hours

Commercial SupportThis activity is supported through an unrestricted educational grant fromRegeneron Pharmaceuticals, Inc.

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Privacy PolicyAll information provided by course participants is confidential and will not beshared with any other parties for any reason without permission.

Copyright©2014 MedEdicus LLC

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FacultyPeter K. Kaiser, MD (Chair and Moderator)Chaney Family Endowed Chair in Ophthalmology ResearchProfessor of OphthalmologyCleveland Clinic Lerner College of MedicineCole Eye InstituteCleveland, Ohio

Jay S. Duker, MDDirectorNew England Eye CenterProfessor and ChairDepartment of OphthalmologyTufts University School of MedicineBoston, Massachusetts

Allen C. Ho, MDProfessor of Ophthalmology Thomas Jefferson University School of MedicineDirector of Retina ResearchWills Eye HospitalPhiladelphia, Pennsylvania

Daniel F. Martin, MDChairmanCole Eye InstituteBarbara and A. Malachi Mixon III Institute Chair in Ophthalmology

Cleveland ClinicCleveland, Ohio

IntroductionThe clinical management of retinal diseases such as age-related macular degeneration (AMD), diabetic macular edema(DME), and retinal vein occlusion (RVO) continues to evolverapidly as novel therapies and new clinical trial outcomesexpand and refine our practice patterns. In this educationalactivity, our primary goal is to clarify optimal management ofthese common retinal diseases in the context of data fromrecent clinical trials. We will be emphasizing salient pointsand take-home messages for our readers.

—Peter K. Kaiser, MD

Age-related Macular DegenerationDr Kaiser: Dr Martin, you designed CATT*1 and haveextensive knowledge of the other key AMD treatmentcomparison studies. Please give us an overview of the resultsof these trials.

Dr Martin: There have been 6 randomized clinical studiescomparing bevacizumab and ranibizumab for the treatment ofAMD: CATT, IVAN, MANTA, GEFAL, BRAMD, and LUCAS.1-6 All6 have reported their results, with 4 studies published1-4 and2 studies presented.5,6 The data from these studies show nodifferences with respect to visual acuity outcomes betweenbevacizumab and ranibizumab. There are, however, smalldifferences with respect to anatomic outcomes, such asamount of residual fluid and retinal thickness. Although both agents are remarkably effective in decreasing fluid,ranibizumab was shown to decrease fluid more. The absolutedifferences were small and there did not appear to be avisual acuity correlate.

There are no differentiating safety signals that emerge whencomparing bevacizumab and ranibizumab, and when youconsider the major events—death, myocardial infarction,stroke—the 6 trials do not show any statistically significantdifferences. In CATT, there was some concern about thedifference in total serious adverse events, with a higher rate among bevacizumab users than among those usingranibizumab (34.5% vs 28.4%, P=.02)7; however, thesefindings were not reproduced in the other 5 trials.

Dr Kaiser: A key finding of the comparison studies was the conclusion concerning treatment regimens, namelydiscontinuous, or as-needed, protocols vs monthly/fixedtreatment. Some of the studies reported that discontinuous,or as-needed, treatment was “not non-inferior” to monthlytreatment; and clinicians have interpreted the findings relatedto these terms differently or inconsistently. What is yourassessment of these results?

Dr Martin: CATT and IVAN were the only trials from thegroup of 6 major trials to compare monthly treatment with as-needed, or discontinuous, treatment. In analyzing the 2-year data from CATT,7 and examining all 15 pair-wisecomparisons, we find no statistically significant difference inany of the treatment arms. We took advantage of the powerthat we had and collapsed the data with respect to drug and

dosing regimen. This revealed a difference of 2.4 fewerletters gained with the as-needed regimen than with themonthly treatment regimen after 2 years (P=.046). This maylead people to conclude that we should not use an as-neededregimen; however, this is where the particular differences ofapplying population statistics to an individual level arise. I stillusually begin with a less-than-monthly regimen because thedata from CATT showed that 10% to 20% of patients neededonly 3 injections, and although this need for low treatmentfrequency occurs in a minority of patients, the monthlytreatment approach does not allow for identification of thesepatients. With the CATT data, the treatment curves do notbegin to diverge until 9 months of therapy (Figure 1).7 Applyingthis information to my clinical practice, I will usually start withas-needed or, sometimes, treat-and-extend. If I find that thepatient is losing ground or having multiple relapses, I will not hesitate to change to more frequent therapy. I amtrying to balance the treatment burden and the risk thatcomes with every injection against a very small difference inoutcomes with a less- than-monthly injection regimen.

Dr Ho: I find it interesting that you have redirected yourtreatment paradigm to begin with a less-than-monthlyapproach. In my opinion, individualizing treatment isimportant, but I am not willing to “let the reins out” right awaywith an as-needed regimen when I am starting treatment for apatient with newly diagnosed wet AMD. I will do 3 or 4monthly injections and then begin to consider a treat-and-extend regimen, because my bias in AMD, based on thetotality of all the trials, is that more treatment is better for mypatient. Although the treatment burden is greater, I start offwith several monthly injections.

Dr Duker: I think that true as-needed protocols arediminishing in popularity. In the 2013 American Society ofRetina Specialists Preferred Practice Patterns Survey, 16.4%of US respondents reported that they would use the wet AMDtreatment strategy of seeing the patient monthly and treatingonly if there were signs of neovascular activity.8 To do an

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*Abbreviations for all studies defined at end of monograph.

Figure 1: CATT 2-Year Data: Mean changes in visual acuity from enrollment overtime.7 Reprinted with permission from Elsevier.

as-needed regimen properly, you still need to see the patientmonthly, at least at the beginning, and that is still a burden tothe patient. Treat-and-extend has really emerged as the waythe majority of us handle patients with wet AMD.8

Dr Kaiser: I think it is important to clarify exactly what “as-needed” means. Most physicians who use the term “as-needed” (or “prn”) to describe their treatment plan are notactually doing a true monthly as-needed regimen like the onesperformed in the comparison studies they are relying on forguidance; instead, they are doing a treat-and-extend type ofas-needed regimen that extends the time between visits, butstill results in as-needed injections. Neither CATT nor IVANevaluated that type of regimen. The CATT and IVAN as-needed regimens still necessitated assessment withoptical coherence tomography (OCT) every 28 days, withtreatment based on signs of active neovascularization.1,2

Dr Duker, Dr Martin brought up an interesting point earlierwhen he mentioned that patients in CATT and IVAN receivingranibizumab had less residual fluid than those treated withbevacizumab.1,2,7,9 Then the VIEW studies came along andindicated that patients receiving aflibercept had less fluid thanthose treated with ranibizumab.10 What is the relevance ofthese facts to you as a clinician?

Dr Duker: I think that there may be a real difference amongthe anti-vascular endothelial growth factor (VEGF) agents withrespect to the “drying effect”, which may reflect possibledifferences in anti-VEGF activity for each medication. Sometheoretical studies with pharmacokinetic modeling havelooked at concept, but it has not been established in clinicalstudies.11 We all see patients with AMD who have smallamounts of persistent subretinal fluid that does not resolvewith monthly treatment, and yet their vision does not suffer.Unlike in DME, in which signs of anatomic improvementcontinue to be seen many months into treatment, such apattern is not the case with most patients who have AMD, inwhich condition anatomic stability typically is achieved in thefirst 3 to 6 months of treatment.

For patients with good vision and a small amount ofsubretinal fluid, I will regard their small amount of fluid as anew baseline, and employ a treat-and-extend protocol relativeto that baseline. When the fluid increases or the visual acuitydrops, I shorten the interval between treatments. I think thatintraretinal fluid is a better indicator of disease activity than issubretinal fluid.

Dr Martin: I agree with Dr Duker–in the CATT macularmorphology paper, subretinal and subretinal pigmentepithelium fluid did not have any adverse effects on visualacuity outcomes; in fact, the mean visual acuity at 1 year wasactually 3 letters better for patients with subretinal fluid.12The story with intraretinal fluid was quite different; patientswho had small amounts of intraretinal fluid in the center of thefovea had a mean visual acuity that was 9 letters worse.12

Dr Duker: I think that we tend to overlook this structure/function relationship in neovascular AMD because we useOCT as a gauge of disease activity. We have this mantra thatwe need to dry up all fluid, even though some eyes just willnot respond no matter how much treatment we give them.

Dr Martin: Knowing this information regarding which fluidcategories tend to be more problematic with respect to visualconsequences, and knowing the concerns about retinalthinning with monthly treatment and geographic atrophy seenin CATT and IVAN,9,13 I wonder about our drive toward thegoal of a completely dry OCT. Is that the best goal for ourpatients? It is certainly a simpler approach, but I continue toencounter data that make it a little easier to tolerate tinyamounts of residual fluid that will not go away over time.

Dr Ho: I think that a binary approach of “dry” or “not dry”may be limiting. In the HARBOR study—the only study to haveall spectral-domain (SD)-OCT, the reading center had analgorithm graded on a binary approach,14 whereby many ofthe variables such as cysts in the retina and fluid under theretina could be evaluated on a continuum. Ultimately, I stillthink that in AMD we want to dry the macula as much aspossible. Practically, when I begin to see atrophy in mypatients with AMD who are receiving continuous anti-VEGFtherapy, I begin to back off a bit because I fear the potentialfor exacerbation of retinal pigment epithelial atrophy andchoroidal atrophy.15

Dr Duker: Much of what we are discussing here pertains tothe “maintenance” phase of treatment, during which we aretrying to maintain visual gains and when a little bit of fluidmay be tolerable. What about initial treatment? One of theanalyses that came out of the VIEW study looked at patientswho were still wet after 3 monthly injections of anti-VEGFtherapy. They were either switched to injections every 2months or maintained on monthly therapy: those who weretreated with anti-VEGF therapy every 2 months had worsevisual outcomes than those who were maintained on monthlytherapy.16 What should our initial approach be? Should wetreat monthly to start? Should we monitor patients monthly?

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Most physicians who use the term “as-needed” (or “prn”) to describe their treatment plan are notactually doing a true monthly as-needed regimenlike the ones performed in the comparison studiesthey are relying on for guidance; instead, they aredoing a treat-and-extend type of as-neededregimen that extends the time between visits, butstill results in as-needed injections. Neither CATTnor IVAN evaluated that type of regimen.

—Peter K. Kaiser, MD

I wonder about our drive toward the goal of acompletely dry OCT. Is that the best goal for ourpatients? It is certainly a simpler approach, but Icontinue to encounter data that make it a littleeasier to tolerate tiny amounts of residual fluid thatwill not go away over time. —Daniel F. Martin, MD

Dr Martin: I suspect that virtually all clinicians begintreatment on a monthly basis with their drug of choice untilthey have achieved a desired end point. For most of us, thatwill be a dry OCT with as much normalization of the fovealanatomy as possible. That goal will never be achieved in somepatients, and they may wind up with monthly injections. Inother patients, normal foveal anatomy may be restored with asingle injection. And this is where the debate begins. Are 3monthly injections at the beginning of treatment necessary inevery case if you intend to do as-needed or treat-and-extend?Specifically, if you achieve normal foveal anatomy after thesecond injection, is the third injection necessary? Manyphysicians give it because it has become part of clinicalpractice. But where are the data that shows it is necessary—those data do not exist. If the purpose is to add extrainsurance that the lesion will remain dry after the third injectionwhen you do switch to as-needed or treat-and-extend, again,there are no data to support that. In CATT, 12 monthlyinjections did not add any insurance to lesion stability whenpatients switched to as-needed in the second year of thestudy (Figure 2).7 So why do we think that 1 more monthlyinjection would? It is perfectly fine to give that third injectionwith normal foveal anatomy. You just have to understand it isnot a data-driven decision. It is the vestige of an old protocolthat has been perpetuated in the absence of data.

Dr Kaiser: I think all of us here use a treat-and-extendregimen, which ultimately necessitates more injections thandoes as-needed, but certainly less than monthly treatment.Given that, what are your thoughts on the capacity of treat-and-extend protocols to individualize therapy? We have theresults of the LUCAS study,6 which used an “inject andextend” protocol that provided treatment at every visit,extending treatment intervals when disease activity was notevident, and shortening intervals when there were signs ofrecurrent activity. This protocol is a little bit different from theapproach most of us employ in treat-and-extend, but stillgives us Level 1 evidence supporting such an approach,especially with respect to visual outcomes.

Dr Ho: The whole point of individualized therapy wasbrought out elegantly in the second year of the HARBORstudy,17 when patients were treated on an as-needed basis.During the second year, there was a surprisingly flatdistribution of the number of injections needed to maintain

the visual gains achieved in the first year. Treat-and-extendallows you to individualize AMD therapy.

Dr Kaiser: According to the visual acuity outcomes from theVIEW extension study,18 in which patients were required tocontinue a modified as-needed regimen (treatment at leastevery 3 months at the beginning and every 2 months afteraflibercept approval), the mean change in the visual acuitycurve was almost a straight line. This stands in contrast toother long-term extension studies such as HORIZON andSECURE,19,20 in which patients were switched to as-neededprotocols from monthly treatments, or to the as-neededtreatments according to predefined retreatment criteria. InHORIZON and SECURE, there was a drop-off in visual acuityover time in the extension phase. From my perspective, thatvalidates the use of a treat-and-extend protocol to preservethe early visual gains.

After considering these data pertaining to frequency oftreatment, what might be an initial agent of choice fortreatment of AMD, and for what period of time mighttreatment intervals be extended ?

Dr Ho: I think we have 3 excellent treatments for neovascularAMD. I prefer to use on-label therapy, such as aflibercept orranibizumab. If a patient has an associated retinal pigmentepithelial detachment, I lean toward the use of aflibercept. Forpatients who are refractory or who develop tachyphylaxis to 1of those 2 anti-VEGF agents, I will switch to the other agent.21I also have used bevacizumab in situations in which availableresources were insufficient to meet the financial demands ofthe first 2 options. My outer treatment extension boundary forpatients with wet AMD is approximately 12 weeks, although Itend to get nervous after 8 weeks.

Dr Duker: I, too, prefer to use an on-label drug, and Iusually begin treatment with aflibercept, on the basis of theresults of the phase 3 VIEW 1 and VIEW 2 studies.10 I will tryto get patients out to 3 months, and I rarely will go longer. If I do extend the time between treatments to longer than 3months, I still want to see the patient regularly, and not allow4 or 5 months to elapse between visits. When the visits getthat far apart, then the regimen approach becomes as-needed, rather than treat-and-extend.

Dr Kaiser: I also prefer to use on-label therapy if thepatient’s financial considerations do not limit treatmentoptions. In my practice, we are leaning toward usingaflibercept. For patients who have insurance limitations orwho are concerned about the co-payment amount, I will startwith bevacizumab. If they do well with bevacizumab, then Icontinue that therapy. If they do not, I will then considerswitching to a different agent.

Dr Martin: I discuss all 3 anti-VEGF agents with my patients.If the choice is left entirely to me, I begin with bevacizumab. I may start with an as-needed or treat-and-extend regimen,again after discussing the options thoroughly with the patient.In terms of how far I would extend treatment intervals, I agreewith my colleagues, that beyond 8 or 10 weeks, I start to getnervous, at least in the first year of treatment.

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Figure 2. Mean change in visual acuity from enrollment, over time, by dosingregimen within drug group.7 Reprinted with permission from Elsevier.

Dr Kaiser: Dr Ho, do you use different treat-and-extendregimens according to which anti-VEGF agent you choose?

Dr Ho: I do not; I get very cautious with any of the 3 anti-VEGF agents that we have been discussing when it gets tothe 3-month point. My experience thus far is that afliberceptmay last a little longer for some patients, but I have seen theopposite as well. Each patient may respond differently toaflibercept, to bevacizumab, or to ranibizumab.

Dr Duker: I also think that AMD has different activity levels at different times. Some patients who have had theirtreatment intervals extended out to 3 months may experiencean increase in disease activity and suddenly require a greaterfrequency of injections. I also think that it is appropriate toperiodically, say every 6 to 12 months, attempt to extendtreatment intervals for patients who have been receiving monthlyinjections, to see if the disease activity level has changed and ifit is possible to space out the treatment intervals.

Dr Kaiser: In how many of your patients with AMD have you been able to stop anti-VEGF therapy? Even when I havestopped therapy in a patient, it seems that I have to restart it6 months later.

Dr Duker: Only in a very few patients have I been able tostop anti-VEGF therapy. Once I am able to get a patient out to 3 months and he or she is doing well, I still want toevaluate the patient on a regular basis, effectively adopting amonthly as-needed approach. My patients will frequentlychoose the additional time afforded by getting an injectionevery 3 months over spending the time to come into Bostonevery month.

Dr Kaiser: My experience has been similar. I rarely can stopmy treat-and-extend regimens. For patients with AMD who dowell for several months without treatment, I am alwaysconcerned about the possibility of hemorrhage, which can bedevastating, so I continue to treat even when they are dry,and extend the time intervals.

Let us now discuss safety comparisons for the different anti-VEGF agents for a moment. Several randomized, publishedcomparison studies have shown similar safety profiles formost known anti-VEGF adverse events for bevacizumab andranibizumab as well as for ranibizumab and aflibercept.2-6,9,10We do not, however, have any head-to-head safety analysesbetween aflibercept and bevacziumab. Regarding afliberceptand ranibizumab, the bottom line from the phase 3 VIEWstudies was that the 2 drugs were equal in safety.10 AEuropean Public Assessment Report (EPAR), however, issuedby the European Medicines Agency, contained a safetyanalysis that some have used to suggest that there may be adifference between aflibercept and ranibizumab.22 What areyour thoughts on this information?

Dr Duker: To me, there really is no safety difference, if youlook at the totality of the EPAR data, as well as the datapresented in the VIEW studies.10,22 Most retina specialists feelthat aflibercept, bevacizumab, and ranibizumab have similarsystemic safety profiles.8 There are naturally going to bedifferences if we examine a subgroup of a subgroup, and

thus are looking at small numbers. In the case of the EPARdataset, it showed a higher rate of cerebrovascular eventsfor older patients (≥85 years) with the use of aflibercept(20/283 [7.1%]) than with the use of ranibizumab (1/87[1.1%]) after the first year of treatment.22 In the second yearof treatment, the rate of cerebrovascular events amongpatients aged 85 years and older was 9.5% (27/283) in theaflibercept-treated group and 3.4% (3/87) in the ranibizumab-treated group.22 If you look at that same subset of elderlypatients, they reported a higher rate of cardiovascular eventswith the use of ranibizumab than with aflibercept at year 1(8/87 [9.2%] vs 8/283 [2.8%]) and at year 2 (9/87 (10.3%)vs 21/283 [7.4%]). With this subgroup of a subgroupanalysis, I do not believe that aflibercept is more likely tocause a cerebrovascular accident than is ranibizumab, or thatranibizumab is more likely to cause myocardial infarction (MI)than is aflibercept.

Dr Kaiser: We recently conducted a safety assessment ofaflibercept across all the phase 2 and phase 3 trials in AMD,DME, and central retinal vein occlusion (CRVO). The data havebeen presented, but not published. There were no statisticallysignificant differences with respect to systemic safety eventssuch as death and Antiplatelet Trialists’ Collaboration-adjudicated arterial thromboembolic events amongaflibercept-treated groups and their comparators in the 8 trialsthat we assessed (CLEAR-IT 2, VIEW 1, VIEW 2, COPERNICUS,GALILEO, DA VINCI, VIVID-DME and VISTA-DME).23

Dr Martin, on the basis of the large patient numbers in thissafety assessment study, what is your opinion regarding how we are affecting the stroke rate of our patients by usingthese drugs? If there is an increased risk associated with the use of anti-VEGF therapy, what is the magnitude of that increase?

Dr Martin: I think that it is fair to say that any potentialincrease in stroke rate with the use of anti-VEGF therapy islow. I do not think we can ever say that there is no increasedrisk at all, because we are never going to do a randomizedtrial that is large enough to really capture that data. And sowe are left with reviewing administrative databases. There are analyses, such as the one conducted by Campbell andcolleagues,24 that showed no changes in the rate ofhospitalization for stroke among patients in Canada treatedwith bevacizumab or ranibizumab for AMD. There always willbe some degree of uncertainty, but from my perspective,there are no differences in safety among these 3 drugs,according to the evidence presented in major trials. Withrespect to the use of anti-VEGF therapies as a class, I think itunlikely that there is a doubling of risk of major events suchas MI and stroke. If there is any increase in risk, it must bevery, very small.

Diabetic Macular EdemaDr Kaiser: Diabetic macular edema has had someinteresting developments as well. A lower dose ofranibizumab (0.3 mg) has been approved by the US Food and Drug Administration (FDA) for treatment of DME,accompanied by the 3-year results of the RISE and RIDE

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studies.25 We now also have phase 3 results of VIVID-DMEand VISTA-DME pertaining to the use of standard-doseaflibercept in the treatment of DME26; this medication iscurrently being evaluated by the FDA for potential approvalfor DME. Bevacizumab and even pegaptanib continue todemonstrate efficacy in the treatment of DME in follow-upassessment studies.27,28

One of the interesting things that many clinicians may notrealize is that the 0.3-mg dose, not the 0.5-mg dose, ofranibizumab was approved for the treatment of DME. Whatare your thoughts regarding the selection of that particularstrength for approval?

Dr Ho: The basic concept was to achieve the lowest dosethat was still safe and efficacious. There were somenumerical differences when the investigators used a BenefitRisk Action Team framework assessment of the differentranibizumab doses in this vasculopathic population oftypically younger patients who may require longer courses ofanti-VEGF therapy to preserve vision in the setting ofpersistent diabetes mellitus.25

Dr Duker: In the pooled 3-year data for RISE and RIDE, theefficacy results were equivalent for the 0.3- and the 0.5-mgdoses.25 Given that patients with diabetes have an elevatedrisk for vascular complications, including stroke and MI, itwas thought that the lower dose would reduce any riskspotentially associated with systemic VEGF suppression.Interestingly, the 0.5-mg dose is the one approved in Europefor the treatment of DME.29

Dr Kaiser: The data in RISE and RIDE also showed thatpatients who initially received sham treatments and crossedover to receive ranibizumab therapy were not able to matchthe visual acuity gains seen in those patients who wereinitially started on ranibizumab.25

Unlike the situation in AMD, there are no direct comparisontrials that have reported their results among the different anti-VEGF agents for DME. RISE and RIDE compared ranibizumabwith sham injection,25 and the DRCR.net (Diabetic RetinopathyClinical Research Network) Protocol I compared ranibizumabin varying combinations with triamcinolone, laser therapy, andsham injection.30 There have been no major comparison trialspertaining to the use of bevacizumab in DME, and the VIVID-DME and VISTA-DME studies compared aflibercept withlaser.26 DRCR.net is conducting a CATT-like treatmentcomparison trial, Protocol T, in which all the drugs exceptpegaptanib are being tested head-to-head, and those studyresults will soon be available.31 In current clinical practice,pegaptanib, bevacizumab, and ranibizumab are available. Dr Ho, do you find that there are any differences among theseoptions for your patients with DME? Which one do you beginwith, and is the treatment paradigm the same as it is for AMD?

Dr Ho: Because bevacizumab and ranibizumab are morecommonly used, I will focus my comments on thosetreatments. Although bevacizumab and ranibizumab havesimilar efficacy in the treatment of AMD, I believe thatranibizumab has greater efficacy in the treatment of DME,according to my personal experience. I am looking forward to

the results of the aforementioned DRCRnet Protocol T study,expected later this year, comparing bevacizumab,ranibizumab, and aflibercept for the treatment of DME.31Ultimately, DRCR.net, RISE/RIDE, VIVID-DME, VISTA-DME,RESTORE, and RESOLVE all point toward a major paradigmshift to first-line anti-VEGF therapy for DME.25,26,30,32,33

Regarding the issue of visual acuity and response totreatment, I want to draw your attention to an important pointpertaining to anti-VEGF treatment gleaned from comparingthe visual acuity curves between AMD and DME. The slope ofthe curves is usually quite steep over the first 4 months in theAMD trials, such as MARINA, ANCHOR (Figure 3), and VIEW3436;the slope is much more gradual for the DME studies,including RISE/RIDE (Figure 4), DRCRnet Protocol I, and VIVID-DME/VISTA-DME.25,26,30 This difference in curve slopeshighlights the point that with DME, one frequently needs to bepersistent and consistent with therapy over many months inorder to gauge the true level of functional response to anti-VEGF treatment. I believe that this persistent approachapplies to RVO, as well.

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Figure 3. BCVA curves for ANCHOR.35 Reprinted with permission from The NewEngland Journal of Medicine.

Figure 4. BCVA curves for RISE and RIDE.25 Reprinted with permission from Elsevier.

[The difference in visual acuity curve slopesbetween AMD and DME] highlights the point thatwith DME, one frequently needs to be persistentand consistent with therapy over many months inorder to gauge the true level of functional responseto anti-VEGF treatment. I believe that this persistentapproach applies to RVO, as well. —Allen C. Ho, MD

Dr Duker: There are major differences between the treatmentof AMD and DME. First, with DME, a little bit of fluid on thepatient’s OCT does not necessarily equate with an elevated risk for adverse visual outcomes. Second, patients with DMErequire multiple injections in order to dry the macula, and itmay take several injections to predict response to therapy. In patients with AMD, you can often predict response after 1 or 2 injections.

There are many good treatment alternatives for DME,including laser, steroids, and surgery. I do not have a setapproach to the treatment of DME because of these otheroptions.

Dr Kaiser: Dr Duker, has your sequence of treatmentprogression changed? We used to begin treatment forclinically significant macular edema with laser therapy. Has your DME treatment paradigm shifted at all?

Dr Duker: Yes. First of all, I am not treating non-foveal-involved macular edema with anti-VEGF. I am treating withfocal laser photocoagulation; most retina specialists regardthis as an effective, initial treatment modality for clinicallysignificant macular edema that does not have fovealinvolvement.8 For all other patients, unless they have amechanical issue such as an epiretinal membrane or tautposterior hyaloid, I start with an anti-VEGF agent likeranibizumab. For my patients who have a circinate or otherleakage pattern that I believe is amenable to laser therapy, I will add laser.

I have an up-front discussion with patients about the need for multiple treatments, which may necessitate the use ofdifferent agents. If a patient is pseudophakic and does notrespond to an initial course of anti-VEGF therapy, I will addsteroid therapy. For patients who require monthly anti-VEGFinjections, in whom I am not able to extend the treatmentinterval, I will use an off-label dexamethasone implant. Thisapproach has allowed me to provide some of my patients 3 and 4 months between intravitreal injections. Singer andcolleagues have examined the combination of anti-VEGFtherapy and a dexamethasone implant in the treatment ofrecalcitrant edema secondary to RVO, and noted a reducedneed for subsequent anti-VEGF therapy.37 This same strategyhas worked well in my patients with DME.

Dr Kaiser: Let us explore the idea of combination treatmentwith anti-VEGF and laser therapy. Several studies, such asREAD-2 and RESTORE, have looked at the combination oflaser and anti-VEGF therapy for DME in which no additional

improvement in visual outcomes was demonstrated in thecombination groups relative to the outcomes in the anti-VEGFmonotherapy groups.32,38 In these studies, the combinationapproach may have decreased the number of injections, butthere was no additional improvement in visual acuity. How doyou respond to these results?

Dr Duker: In terms of an overall population, I agree with theresults, but I think there are individual eyes with individualpatterns of leakage that still benefit from laser and so I offerit. For example, I have patients with 15-year follow-up after asingle focal laser to circinate exudate who have required nofurther therapy.

Dr Kaiser: Let us continue exploring other combinationapproaches; Dr Martin, what are your thoughts on theincorporation of steroids into the treatment for DME?

Dr Martin: Corticosteroids are particularly effective ateliminating fluid.39 I begin with an anti-VEGF agent, keeping inmind that it takes multiple anti-VEGF injections to determinetherapeutic effect. If I am unable to eliminate the fluid and if I think that fluid is clinically important, I will probably selectsteroid therapy for a patient who is pseudophakic. If thepatient is phakic, I will probably switch anti-VEGF agentsbefore moving to a steroid.

Dr Ho: For pseudophakic patients, I view corticosteroids asa way to reboot the system. DME is a complex, multifactorialdisease, involving VEGF, cytokines, and other inflammatorycomponents. The steroids can provide a different mechanismto dry the macula, and a corticosteroid trial may lead to anentirely different pattern of requirements for anti-VEGFinjections.

Dr Kaiser: The steroid studies demonstrated the greatesteffect with the initial injection. Subsequent injections have aprogressively diminished effect, so intermittent use of thistherapy may be helpful in improving outcomes.40

Dr Ho: A corticosteroid approved for DME would helppatients. Some new phase 3 safety and efficacy data havebeen released, but are as yet unpublished, pertaining to theuse of a dexamethasone implant for the treatment of DME.41

Dr Kaiser: How does surgery fit into the treatmentparadigm, particularly for patients who do not have signs oftraction or epiretinal membrane?

Dr Duker: Surgery is a fourth-line option for patients who do not respond to the other therapies that we have beendiscussing. The data indicate that anatomical outcomes arebetter than functional outcomes with surgical intervention,and I have found that to be true in my clinical experience.Although you can achieve a dry macula at least 50% of thetime after removing the posterior hyaloid and/or epiretinalmembrane, the visual results do not necessarily mirror theseanatomic results.42

But many of these patients have been treated for yearswithout improvement in their macular edema. Had the surgerybeen done earlier, perhaps the macular edema would have

8

There are major differences between the treatmentof AMD and DME. First, with DME, a little bit of fluidon the patient’s OCT does not necessarily equatewith an elevated risk for adverse visual outcomes.Second, patients with DME require multipleinjections in order to dry the macula, and it maytake several injections to predict response totherapy. —Jay S. Duker, MD

been resolved earlier and the visual results would be better. I still reserve surgery as fourth-line therapy at this point in my practice.

Dr Ho: If there is a patient with a mechanical issue, I thinkthat surgery is a reasonable option. I think that “the jury is stillout” on the optimal timing of surgical intervention.

Retinal Vein OcclusionDr Kaiser: Let us discuss treatment options for CRVO. Dr Martin, what is your initial approach for these patients?

Dr Martin: I usually start with bevacizumab for the treatmentof CRVO, as I have generally had excellent results with thisoption in my clinical experience. For those patients who arephakic and do not respond adequately, I will consider changingto a different anti-VEGF agent. If a patient is pseudophakic anddoes not respond adequately, I may still switch to a differentanti-VEGF agent, but I will certainly give more seriousconsideration to the use of an intravitreal steroid.

Dr Ho: I tend to start with either ranibizumab or aflibercept,both of which are on-label for the treatment of CRVO. I thinkthat there is an advantage in overall safety relative tobevacizumab, because the processes that are necessary foran on-label medication to be developed and commerciallysold are more tightly regulated. We have limited prospectivecomparative data on these 3 agents in the treatment ofretinal venous occlusive disease, but in my clinicalexperience, all can be highly effective. Although bevacizumabis widely used, there may be safety concerns related to theuse of this compounded product because it is not subjectedto the same level of scrutiny in the preparation process as isan on-label agent; and, there has been documentednoncompliance with face-mask use hypothesized to be thesource of contamination of compounded intravitrealbevacizumab resulting in several cases of endophthalmitis.43

Dr Duker: Although there are no direct head-to-headcomparisons among the 3 principal anti-VEGF agents—aflibercept, bevacizumab, and ranibizumab (pegaptanib, thefourth anti-VEGF agent, is available though not widely used)—I usually start with aflibercept therapy, which is on-label, formy patients with CRVO. In the absence of a direct studycomparison, my evaluation of results among clinical trialslooking at the anti-VEGF agents suggest to me that afliberceptis superior to ranibizumab for the treatment of CRVO.44-46

Dr Ho: There may be an element of “apples to oranges”when you do cross-trial comparisons, though. For example,

in the CRUISE study, which examined the safety and efficacyof ranibizumab,44 the patients may have received priortreatment, and therefore had a longer duration of disease (4 months on average) at the beginning of the study thanpatients enrolled in COPERNICUS and GALILEO (whichexamined the safety and efficacy of aflibercept), in which theaverage disease duration was 2 months.45,46 It is a subtledifference, but it might have an effect on data application toclinical practice.

Dr Duker: I agree that there may be differences, but when I look at cross-trial comparisons, there are some intriguingdata. In CRUISE, 16.9% of patients treated with shaminjection experienced ≥15 letters of improvement after 6 months, and 46.2% and 47.7% of those treated withranibizumab, 0.3 mg and 0.5 mg, respectively, experiencedthat level of improvement.44 In COPERNICUS, 12.3% ofpatients treated with sham injection experienced ≥15 lettersof improvement after 6 months, and 56.1% of patientstreated with aflibercept experienced that level ofimprovement.45 In GALILEO, 22.1% of patients treated withsham injection had gained ≥15 letters after 6 months,compared with 60.2% in the aflibercept-treated group (Table 1).46 If aflibercept and ranibizumab were equal in termsof efficacy, then the magnitude of improvement relative tosham treatment should have been similar. Again, this is cross-trial comparison, but I would rather rely on the use of cross-trial comparison to help shape my treatment approach forpatients with CRVO than on my own clinical experience,because of the greater number of patients encompassed by clinical trials.

Dr Kaiser: In your clinical practice with ranibizumab, do you follow the protocol used in CRUISE, that is, the use of 6 injections before considering any change in therapy?

Dr Duker: I treat with the same therapy until the macula isdry or until there are 2 consecutive visits with no furtherimprovement. At that point I have a discussion with mypatient, in which we talk about subsequent treatment options,such as continuing monthly dosing, beginning a period ofobservation, or starting a treat-and-extend protocol.

Dr Kaiser: Dr Martin, you mentioned earlier that you beginwith bevacizumab. What would prompt you to switch therapy?What are your criteria for making a switch?

Dr Martin: I will consider switching therapy if I do not achievethe degree of drying or visual acuity results that I want.

Dr Kaiser: When do you switch or add steroids?

9

Sham Injections Anti-VEGF Injections Magnitude of Improvement Relative to Sham

CRUISE (ranibizumab) 16.9% ~46.9% ~2.7 times

COPERNICUS (aflibercept) 12.3% 56.1% ~4.5 times

GALILEO (aflibercept) 22.1% 60.2% ~2.7 times

Table 1. Percent of CRVO Patients Experiencing ≥15 Letters Improvement After 6 Months46

Dr Martin: I will switch after an average of 4 to 6 injections,according to the visual acuity response curves seen in phase3 trials such as CRUISE, COPERNICUS, and GALILEO.44-46Changes in visual acuity tend to be slow and to evolve over the course of the first year; I am not too quick to changetherapy. I tend to switch or change treatment options moreoften for patients who require every-4-weeks injections forthis predominantly VEGF-driven disease. As seen in SCOREand GENEVA, corticosteroid injection or the use of adexamethasone implant can be quite effective in drying out the macula and resetting the responsiveness topharmacologic treatment, and use of these procedures has allowed me to extend my treatment intervals.47,48

What are the panel’s thoughts on the utility of widefieldimaging and peripheral photocoagulation therapy in situationsin which you have difficulty completely drying out the maculaor extending treatment intervals?

Dr Duker: I do not object to the concept of widefieldimaging and peripheral photocoagulation, but there are not alot of data out there to support its use. One small prospectivestudy conducted by Spaide and colleagues failed to show anyinfluence of peripheral panretinal photocoagulation (PRP) oninjection frequency or improved visual acuity in patients withCRVO who had been treated with ranibizumab.49 We have allbeen in situations in which we have “thrown the kitchen sinkat” recalcitrant edema, and still do not achieve resolution. Inthat situation, using targeted peripheral PRP would be low-riskand possibly worth trying.

Dr Kaiser: At the Cleveland Clinic Cole Eye Institute, wehave done quite a bit of targeted peripheral PRP based on widefield angiography images, and I have beenunderwhelmed by the results. I have looked at fluoresceinangiograms and seen massive amounts of peripheralnonperfusion, which I treated with PRP. Despite the use oflaser, my number of anti-VEGF injections in these patients has not dropped appreciably. Even in situations in which there is early, peripheral neovascularization, in my personalexperience, the results have been underwhelming.

Dr Martin: My experience with patients who havenonperfusion on fluorescein imaging has been similar. I havenot been able to reduce the anti-VEGF injection frequency.

Dr Duker: I think there is a reason for this lack of efficacy.Patients may have areas of peripheral nonperfusion onfluorescein angiography, but I think that VEGF is being

released diffusely through the retina. Even though you aretargeting areas that are nonperfused, those may not be the areas from which all the VEGF is coming. I am moreimpressed with steroids than with targeted peripheral PRP.

Dr Ho: I do not use targeted PRP because we do not havethe widefield imaging technology; the empiric results havebeen underwhelming for me, and steroids can be veryeffective in treating patients with macular edema due toCRVO who do not respond to anti-VEGF therapy.50

Dr Kaiser: Lastly, let us discuss branch retinal vein occlusion(BRVO). Is your treatment approach for BRVO the same as itis for CRVO? Does anyone here follow the Branch VeinOcclusion Study recommendations and begin with anobservation period,51 or do you tend to start anti-VEGFtherapy right away?

Dr Duker: If the patient has macular edema and decreasedvisual acuity, I begin anti-VEGF therapy; a recent study by Tan and colleagues showed that, compared with standard-of-care grid laser, anti-VEGF therapy provides sustainedimprovements in visual gain and anatomic outcomes.52I also consider adding laser therapy once any existenthemorrhages resolve; there have been some prospectivestudies that have looked at the combination of laser and anti-VEGF therapy for the treatment of BRVO, in which patientswho received this combination had a lower number of repeatanti-VEGF injections in follow-up.53,54 Targeted laser therapyfor BRVO can be quite effective.

Dr Martin: I agree with Dr Duker’s approach.

Dr Ho: I also tend to start therapy right away for patientswho have macular edema and decreased visual acuity.

Dr Kaiser: I believe that we all can concur on this matter.The treatment paradigm for BRVO continues to evolve, andresults of the recently presented VIBRANT study, comparingthe use of laser therapy and monthly aflibercept for thetreatment of macular edema following BRVO,55 may furthershape our treatment approaches. All the retinal diseases thatwe have discussed herein are topics of active, ongoinginvestigation, and we must be vigilant as new evidencecomes to light, in order to create optimal treatment protocolsfor our patients. Fortunately, we do have an increasingarmamentarium to aid in the management of patients withAMD, DME, and RVO, as evidenced by findings of some of therecent clinical investigations pertaining to retinal diseases,summarized in Table 2 following.

10

11

Study Comparison Top-Line Results

Age-related Macular Degeneration

LUCAS6 Multicenter randomized trial comparingbevacizumab vs ranibizumab for treatmentof wet AMD, using inject-and-extendprotocol

• 1-year outcomes showed that mean number of treatments was 8.8 forbevacizumab, 8.0 for ranibizumab (P=.002), with equivalent effects on visual acuity• 6 patients (2.8%) in ranibizumab group had nonfatal MI vs 0 in bevacizumab group• Nonfatal strokes occurred in 1.4% of patients receiving ranibizumab vs 0.9% ofpatients receiving bevacizumab• 1 vascular-related death in bevacizumab group

SECURE20 Multicenter open-label phase IV extensionstudy to assess long-term safety of 0.5-mgranibizumab in treatment of wet AMD

• Ranibizumab given according to flexible, visual acuity-guided protocol, was welltolerated over 2 years• On average, patients lost BCVA relative to baseline

VIEW ExtensionStudy18

Analysis of effect of different medicationdosing regimens on persistent macularfluid in patients with wet AMD

• Patients who had persistent fluid following 3 monthly loading doses had bettervisual acuity (P<.05) with aflibercept dosed every 4 weeks than with afliberceptdosed every 8 weeks or ranibizumab dosed every 4 weeks

Diabetic Macular Edema

RISE/RIDE 3 year results25

Multicenter randomized, double-masked,sham injection-controlled (for 2 years)studies comparing monthly 0.3-mg to 0.5-mg ranibizumab for treatment of DME

• VA outcomes seen at 2 years with ranibizumab-treated groups were maintainedthrough year 3• Patients who made transition from sham treatment to 0.5-mg ranibizumab in third year did not see same amount of improvement as patients who were initiallytreated with ranibizumab• Incidence of SAEs potentially related to systemic VEGF suppression was 19.7% in0.5-mg group, 16.8% in 0.3-mg group

VIVID-DME and VISTA-DME26

Multicenter randomized double-maskedstudies comparing monthly aflibercept vsbimonthly aflibercept (after 5 monthlytreatments) vs laser for treatment of DMEwith central involvement

• 31.1% to 41.6% of aflibercept-treated eyes gained ≥15 letters at 1 year vs 7.8%to 9.1% of laser-treated eyes• Overall incidence of ocular, nonocular, and serious adverse events was similar forboth laser- and aflibercept-treated groups

Dexamethasone implant study41

3-year multicenter masked randomizedcontrolled trial to assess safety and efficacyof dexamethasone in treatment of DME

• Significantly more patients treated with dexamethasone had ≥15 lettersimprovement than those treated with sham• Mean number of treatments over 3 years: 4.1 for 0.7 mg, 4.4 for 0.35 mg, and 3.3for sham• Rates of cataract-related AEs: 67.9%, 64.1%, and 20.4% for 0.7 mg, 0.35 mg, andsham, respectively• IOP increases generally controlled with medication or no therapy

Retinal Vein Occlusion

VIBRANT55 Multicenter double-masked trial tocompare monthly aflibercept (2 mg) vs laser for macular edema secondary to BRVO

• 53% of patients receiving monthly aflibercept gained ≥15 letters from baseline atweek 24 vs 27% who received laser• Mean BCVA improvement was 17.0 letters in aflibercept group vs 6.9 letters inlaser group (P<.0001)• SAE incidence was 9.9% in aflibercept group vs 9.8% in laser group• 1 death and 1 APTC-defined event occurred, both in laser group

AEs=adverse events; AMD=age-related macular degeneration; APTC=Antiplatelet Trialists’ Collaboration; BCVA=best corrected visual acuity; BRVO=branch retinal veinocclusion; DME=diabetic macular edema; IOP=intraocular pressure; SAEs=serious adverse events; VA=visual acuity; VEGF=vascular endothelial growth factor.

Table 2. 2013 Studies in the Management of Patients With AMD, DME, and RVO and Corresponding Top-Line Results

12

ANCHOR Anti-VEGF Antibody for the Treatment of PredominantlyClassic Choroidal Neovascularization in Age-Related MacularDegeneration

BRAMD Netherlands study to compare the effectiveness and costs ofbevacizumab and ranibizumab in patients with exudative age-related macular degeneration.

CATT Comparison of Age-related Macular Degeneration TreatmentsTrials

CLEAR-IT CLinical Evaluation of Anti-angiogenesis in the RetinaIntravitreal Trial

COPERNICUS and GALILEO

Vascular Endothelial Growth Factor [VEGF] Trap-Eye:Investigation of Efficacy and Safety in Central Retinal VeinOcclusion [CRVO]

CRUISE Ranibizumab for the Treatment of Macular Edema afterCentral Retinal Vein OcclUsIon Study: Evaluation of Efficacyand Safety

DA VINCI DME And VEGF Trap-Eye: INvestigation of Clinical Impact

GEFAL French Evaluation Group Avastin Versus Lucentis

GENEVA Global Evaluation of Implantable Dexamethasone in RetinalVein Occlusion With Macular Edema

HARBOR pHase III, double-masked, multicenter, randomized, Activetreatment-controlled study of the efficacy and safety of 0.5 mgand 2.0 mg Ranibizumab administered monthly or on an as-needed Basis (PRN) in patients with subfoveal neOvasculaRage-related macular degeneration

HORIZON Extension study to evaluate the safety and tolerability ofranibizumab in subjects with choroidal neovascularizationsecondary to AMD or macular edema secondary to RVO

IVAN Inhibit VEGF in Age-related Choroidal Neovascularization

LUCAS Lucentis Compared to Avastin Study

MANTA Multicenter Anti-VEGF Trial in Austria

MARINA Minimally Classic/Occult Trial of the Anti-VEGF AntibodyRanibizumab in the Treatment of Neovascular Age-RelatedMacular Degeneration

READ-2 Ranibizumab for Edema of the mAcula in Diabetes

RESOLVE Phase 2 study evaluating safety and efficacy of ranibizumabin diabetic macular edema

RESTORE Phase 3 study evaluating ranibizumab monotherapy orcombined with laser vs laser monotherapy for diabeticmacular edema

RISE and RIDE Phase 3 studies evaluating efficacy and safety of intravitrealranibizumab in diabetic macular edema

SCORE Standard Care vs. Corticosteroid for Retinal Vein Occlusion

SECURE Long-Term Safety of Ranibizumab 0.5 mg in NeovascularAge-related Macular Degeneration

VIBRANT Phase 3 study of aflibercept in treating macular edema due to branch retinal vein occlusion

VIEW 1 and 2 VEGF Trap-Eye Investigation of Efficacy and Safety in WetAMD

VISTA-DME andVIVID-DME

Double-masked, randomized, active-controlled, phase 3studies of the efficacy and safety of intravitreal administrationof VEGF Trap-Eye in patients with diabetic macular edema

Trial Abbreviations Used

1. CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ.Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897-1908.

2. IVAN Study Investigators, Chakravarthy U, Harding SP, Rogers CA, et al. Ranibizumabversus bevacizumab to treat neovascular age-related macular degeneration: one-yearfindings from the IVAN randomized trial. Ophthalmology. 2012;119(7):1399-1411.

3. Krebs I, Schmetterer L, Boltz A, et al; MANTA Research Group. A randomised double-masked trial comparing the visual outcome after treatment with ranibizumab orbevacizumab in patients with neovascular age-related macular degeneration. Br JOphthalmol. 2013;97(3):266-271.

4. Kodjikian L, Souied EH, Mimoun G, et al; GEFAL Study Group. Ranibizumab versusbevacizumab for neovascular age-related macular degeneration: Results from the GEFALnoninferiority randomized trial. Ophthalmology. 2013;120(11):2300-2309.

5. Schauwvlieghe AME, Dijkman G, Hooymans JM, et al; The BRAMD Study Group.Ranibizumab versus bevacizumab in the Netherlands: Comparing the efficacy ofbevacizumab to ranibizumab in patients with exudative age-related macular degeneration–The BRAMD Study. Ophthalmologica. 2013;230(suppl 1):2-3.

6. Berg K. Lucentis Compared to Avastin Study (LUCAS). Presented at: Retina SubpecialtyDay, American Academy of Ophthalmology 2013 Annual Meeting; November 15-19,2013; New Orleans, LA.

7. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) ResearchGroup, Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and bevacizumab fortreatment of neovascular age-related macular degeneration: two-year results.Ophthalmology. 2012;119(7):1388-1398.

8. American Society of Retina Specialists Preferences and Trends (PAT) MembershipSurvey, 2013. Chicago, IL.

9. Chakravarthy U, Harding SP, Rogers CA, et al; IVAN study investigators. Alternativetreatments to inhibit VEGF in age-related choroidal neovascularization: 2-year findings ofthe IVAN randomised controlled trial. Lancet. 2013;382(9900):1258-1267.

10. Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection forneovascular age-related macular degeneration: ninety-six-week results of the VIEWstudies. Ophthalmology. 2014;121(1):193-201.

11. Stewart MW, Rosenfeld PJ, Penha FM, et al. Pharmacokinetic rationale for dosing every2 weeks versus 4 weeks with intravitreal ranibizumab, bevacizumab, and aflibercept(vascular endothelial growth factor Trap-eye). Retina. 2012;32(3):434-457.

12. Ying GS, Huang J, Maguire MG, et al; Comparison of Age-related Macular DegenerationTreatments Trials Research Group. Baseline predictors for one-year visual outcomes withranibizumab or bevacizumab for neovascular age-related macular degeneration.Ophthalmology. 2013;120(1):122-129.

13. Grunwald JE, Daniel E, Huang J, et al; CATT Research Group. Risk of geographic atrophyin the Comparison of Age-related Macular Degeneration Treatments Trials.Ophthalmology. 2014;121(1):150-161.

14. Busbee BG, Ho AC, Brown DM, et al; HARBOR Study Group. Twelve-month efficacy andsafety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology. 2013;120(5):1046-1056.

15. Young M, Chui L, Fallah N, et al. Exacerbation of choroidal and retinal pigment epithelialatrophy after anti-vascular endothelial growth factor treatment in neovascular age-relatedmacular degeneration. Retina. 2014 Jan 21. [Epub ahead of print]

16. Jaffe GJ. The effect of early, persistent fluid on subsequent visual acuity in the VIEW 1and VIEW 2 studies of neovascular AMD. Presented at: 2013 American Society of RetinaSpecialists 31st Annual Meeting; August 24-28, 2013; Toronto, Ontario, Canada.

17. Busbee B. HARBOR 2-year results support individualized dosing in patients with wet age-related macular degeneration. Presented at: 2013 American Society of RetinaSpecialists 31st Annual Meeting; August 24-28, 2013; Toronto, Ontario, Canada.

18. Kaiser PK. VEGF Trap-eye (VIEW) extension study. Presented at: Retina Subpecialty Day,American Academy of Ophthalmology 2013 Annual Meeting; November 15-19, 2013;New Orleans, LA.

19. Singer MA, Awh CC, Sadda S, et al. HORIZON: an open-label extension trial ofranibizumab for choroidal neovascularization secondary to age-related maculardegeneration. Ophthalmology. 2012;119(6):1175-1183.

20. Silva R, Axer-Siegel R, Eldem B, et al; SECURE Study Group. The SECURE study: long-term safety of ranibizumab 0.5 mg in neovascular age-related macular degeneration.Ophthalmology. 2013;120(1):130-139.

21. Patel KH, Chow CC, Rathod R, et al. Rapid response of retinal pigment epithelialdetachments to intravitreal aflibercept in neovascular age-related macular degenerationrefractory to bevacizumab and ranibizumab. Eye (Lond). 2013;27(5):663-667.

22. European Medicines Agency. Committee for Medicinal Products for Human Use.Assessment report: Eylea (aflibercept), Procedure No. EMEA/H/C/002392/. 20 September 2012.

23. Kaiser P. Systematic review of safety across the phase II and phase III clinical trials ofintravitreal aflibercept injection. Presented at: The Macula Society 37th Annual Meeting;February 19-22, 2014; Key Largo, FL.

24. Campbell RJ, Bell CM, Paterson JM, et al. Stroke rates after introduction of vascularendothelial growth factor inhibitors for macular degeneration: a time series analysis.Ophthalmology. 2012;119(8):1604-1608.

25. Brown DM, Nguyen QD, Marcus DM, et al; RIDE and RISE Research Group. Long-termoutcomes of ranibizumab therapy for diabetic macular edema: the 36-month resultsfrom two phase III trials: RISE and RIDE. Ophthalmology. 2013;120(10):2013-2022.

26. Heier J. Intravitreal aflibercept for diabetic macular edema: 12-month efficacy and safetyresults of phase 3, randomized, controlled VISTA-DME and VIVID-DME studies. Presentedat: The Macula Society 37th Annual Meeting; February 19-22, 2014; Key Largo, FL.

27. Kriechbaum K, Prager S, Mylonas G, et al; Diabetic Retinopathy Research Group.Intravitreal bevacizumab (Avastin) versus triamcinolone (Volon A) for treatment ofdiabetic macular edema: one-year results. Eye (Lond). 2014;28(1):9-15.

28. Pacella E, La Torre G, Impallara D, et al. Efficacy and safety of the intravitreal treatmentof diabetic macular edema with pegaptanib: a 12-month follow-up. Clin Ter.2013;164(2):e121-e126.

30. Diabetic Retinopathy Clinical Research Network, Elman MJ, Qin H, Aiello LP, et al.Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred lasertreatment: three-year randomized trial results. Ophthalmology. 2012;119(11):2312-2318.

31. Clinical Trials.gov. Comparative Effectiveness Study of Intravitreal Aflibercept,Bevacizumab, and Ranibizumab for DME (Protocol T).http://www.clinicaltrials.gov/ct2/show/NCT01627249. Accessed February 7, 2014.

32. Mitchell P, Bandello F, Schmidt-Erfurth U, et al; RESTORE study group. The RESTOREstudy: Ranibizumab monotherapy or combined with laser versus laser monotherapy fordiabetic macular edema. Ophthalmology. 2011;118(4):615-625.

33. Massin P, Bandello F, Garweg JG, et al. Safety and efficacy of ranibizumab in diabeticmacular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked,multicenter phase II study. Diabetes Care. 2010;33(11):2399-2405.

34. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab forneovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431.

35. Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versusverteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444.

36. Heier JS, Brown DM, Chong V, et al; VIEW 1 and VIEW 2 Study Groups. Intravitrealaflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology.2012;119(12):2537-2548.

37. Singer MA, Bell DJ, Woods P, et al. Effect of combination therapy with bevacizumab anddexamethasone intravitreal implant in patients with retinal vein occlusion. Retina. 2012;32(7):1289-1294.

38. Nguyen QD, Shah SM, Khwaja AA, et al; READ-2 Study Group. Two-year outcomes of theranibizumab for edema of the macula in diabetes (READ-2) study. Ophthalmology. 2010;117(11):2146-2151.

39. Martidis A, Duker JS, Greenberg PB, et al. Intravitreal triamcinolone for refractorydiabetic macular edema. Ophthalmology. 2002;109(5):920-927.

40. Rudnisky CJ, Lavergne V, Katz D. Visual acuity after intravitreal triamcinolone fordiabetec macular edema refractory to laser treatment: a meta-analysis. Can JOphthalmol. 2009;44(5):587-593.

41. Sadda S, Boyer D, Yoon YH, et al. Safety and efficacy of dexamethasone intravitrealimplant in patients with diabetic macular edema: phase III, 3-year, randomized, sham-controlled study. Presented at: The Macula Society 37th Annual Meeting; February 19-22, 2014; Key Largo, FL.

42. Hartley KL, Smiddy WE, Flynn HW Jr, Murray TG. Pars plana vitrectomy with internallimiting membrane peeling for diabetic macular edema. Retina. 2008;28(3):410-419.

43. Frost BA, Kainer MA. Safe preparation and administration of intravitreal bevacizumabinjections. N Engl J Med. 2011;365(23):2238.

44. Brown DM, Campochiaro PA, Singh RP, et al; CRUISE Investigators. Ranibizumab formacular edema following central retinal vein occlusion: six-month primary end pointresults of a phase III study. Ophthalmology. 2010;117(6):1124-1133.

45. Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular edemasecondary to central retinal vein occlusion: 1-year results from the phase 3COPERNICUS study. Am J Ophthalmol. 2013;155(3):429-437.

46. Korobelnik JF, Holz FG, Roider J, et al; GALILEO Study Group. Intravitreal afliberceptinjection for macular edema resulting from central retinal vein occlusion: one-year resultsof the phase 3 GALILEO Study. Ophthalmology. 2014;121(1):202-208.

47. Ip MS, Scott IU, VanVeldhuisen PC, et al; SCORE Study Research Group. A randomizedtrial comparing the efficacy and safety of intravitreal triamcinolone with observation totreat vision loss associated with macular edema secondary to central retinal veinocclusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) studyreport 5. Arch Ophthalmol. 2009;127(9):1101-1114.

48. Haller JA, Bandello F, Belfort R Jr, et al; Ozurdex GENEVA Study Group. Dexamethasoneintravitreal implant in patients with macular edema related to branch or central retinalvein occlusion twelve-month study results. Ophthalmology. 2011;118(12):2453-2460.

49. Spaide RF. Prospective study of peripheral panretinal photocoagulation of areas ofnonperfusion in central retinal vein occlusion. Retina. 2013;33(1):56-62.

50. Sharareh B, Gallemore R, Taban M, Onishi S, Wallsh J. Recalcitrant macular edema afterintravitreal bevacizumab is responsive to an intravitreal dexamethasone implant in retinalvein occlusion. Retina. 2013;33(6):1227-1231.

51. Argon laser photocoagulation for macular edema in branch vein occlusion. The BranchVein Occlusion Study Group. Am J Ophthalmol. 1984;98(3):271-282.

52. Tan MH, McAllister IL, Gillies ME, et al. Randomized controlled trial of intravitrealranibizumab versus standard grid laser for macular edema following branch retinal veinocclusion. Am J Ophthalmol. 2014;157(1):237-247.

53. Azad R, Vivek K, Sharma Y, Chandra P, Sain S, Venkataraman A. Ranibizumab as adjunctto laser for macular edema secondary to branch retinal vein occlusion. Indian JOphthalmol. 2012;60(4):263-266.

54. Donati S, Barosi P, Bianchi M, Al Oum M, Azzolini C. Combined intravitreal bevacizumaband grid laser photocoagulation for macular edema secondary to branch retinal veinocclusion. Eur J Ophthalmol. 2012;22(4):607-614.

55. Haller J. Intravitreal aflibercept injection (IAI) for macular edema secondary to branchretinal vein occlusion (BRVO):24-week results of the VIBRANT study. Presented at: The Macula Society 37th Annual Meeting; February 19-22, 2014; Key Largo, FL.

13

References

1. Which of the following categories of fluid has been shown tocorrespond with the poorest visual acuity in patients withneovascular AMD?

A. Subretinal B. IntraretinalC. Subretinal pigment epitheliumD. There is no relationship between fluid location and

visual acuity

2. Which of the following statements accurately characterizes a keydifference in anti-VEGF treatment approaches for AMD and thosefor DME?

A. Patients with AMD generally require more injections to drythe macula than do patients with DME

B. Patients with DME lose ground more quickly than patientswith AMD if fluid accumulation is not addressed

C. It generally takes more anti-VEGF injections to determineresponse to therapy for patients who have DME than forpatients who have AMD

D. The anti-VEGF treatment approaches for AMD and DME are identical

3. From the 6 studies (CATT, IVAN, MANTA, GEFAL, BRAMD, LUCAS)that have been conducted comparing bevacizumab andranibizumab for the treatment of AMD, it has been established that:

A. There are substantial differences in visual acuity outcomesbetween the 2 medications

B. Ranibizumab has more statistically significant safetyconcerns than does bevacizumab

C. Bevacizumab is more effective in reducing fluid than isranibizumab

D. There are no statistically different rates of myocardialinfarction or stroke between the 2 medications

4. Findings from the RISE and RIDE studies (year 3) pertaining to the treatment of DME with ranibizumab included all the following,except:

A. Comparable efficacy between the 0.3-mg and 0.5-mgdoses of ranibizumab

B. The capacity for patients receiving delayed therapy tomatch the visual acuity gains seen in patients initiallystarted with ranibizumab

C. Equivalent safety profiles for the 0.3-mg and 0.5-mg dosesof ranibizumab

D. Sustained maintenance of visual gains seen in the first 2 years with the use of ranibizumab

5. The use of intravitreal steroids in the treatment of DME:A. Includes the use of corticosteroid implants that are FDA

approved for DMEB. May alter the injection pattern requirements for anti-VEGF

therapyC. Is more appropriate for patients who are phakic than for

those who are pseudophakicD. Has been shown to be ineffective in drying the macula

6. Which of the following statements is true regarding the treatmentof RVO?

A. There are no head-to-head studies comparing differenttreatments for macular edema following RVO

B. Anti-VEGF therapy is appropriate for the treatment of CRVO,but not BRVO

C. Targeted PRP is frequently effective in reducing the numberof anti-VEGF injections in patients with CRVO who haveperipheral nonperfusion on widefield imaging

D. Intravitreal steroid therapy can be effective for patients with CRVO who are pseudophakic and do not respond toanti-VEGF therapy

7. Examination of visual acuity response curves from recent trialslooking at the use of anti-VEGF therapy for the treatment of DMEhave shown that:

A. The slope of the curves is more gradual over the first 4months than it is for corresponding curves in AMD trials

B. Patient response to therapy to DME can frequently bedetermined after 1 to 2 injections

C. Patients reach maximal gains in visual acuity before 1 yearof therapy

D. Clinicians should have a low threshold for changing therapyif the patient does not respond after a few months

8. Recent long-term extension studies looking at the use of anti-VEGFtherapy for the treatment of AMD have shown:

A. The emergence of new safety signals with prolongedtherapy

B. Universal failure to preserve visual gains seen in initialstudies

C. The likely benefit of using a treat-and-extend protocol topreserve the early visual gains

D. Poor tolerance with prolonged therapy

9. According to the CATT study, visual acuity curves for monthly andas-needed ranibizumab and bevacizumab treatment protocolsbegin to diverge at:

A. 6 monthsB. 9 monthsC. 12 monthsD. 2 years

10. Tan and colleagues demonstrated that in patients with BRVO:A. Observation was as likely to improve vision as was

anti-VEGF therapy in 1 yearB. Anti-VEGF therapy produced sustained visual gains and

anatomic improvements over laser C. Anti-VEGF therapy and laser were both similarly effective

in providing sustained visual gainsD. Standard-of-care laser was more effective in achieving

long-term visual improvements than was anti-VEGF therapy

14

Post Test

To obtain AMA PRA Category 1 Credit™ for this activity, complete the CME Post Test online at http://bit.ly/retinal2014 andreceive an instant certificate of credit upon successful completion of the post test and evaluation. Or, write the best answer toeach question in the Answer Box located on the Activity Evaluation/Credit Request form following the questions and fax youranswer key and evaluation to 908-462-6555.

To receive AMA PRA Category 1 Credit™, complete this Post Test and Evaluation form. Record your answers to the Post Test in the AnswerBox located below. Please provide all the requested information below. This ensures that your certificate is filled out correctly and is sent tothe proper address. Please print clearly or type. Illegible submissions cannot be processed.

PARTICIPANT INFORMATION (Please Print)

Prefix____________ First Name__________________________________ M.I._______ Last Name______________________________________

Street Address__________________________________________________________________________________________________________

City_____________________________________ State/Province_____________ ZIP/Postal Code _____________Country__________________

Phone_________________________ Fax__________________________ Email _____________________________________________________

Organization_______________________________________________________Job Title______________________________________________

Profession (i.e. Ophthalmologist)_____________________________Primary Specialty (i.e. Ophthalmology)______________________________

Secondary Specialty___________________________________Degree________________________ Secondary Degree ____________________

15

Activity Evaluation/Credit Request

1 2 3 4 5 6 7 8 9 10

POST TEST ANSWER BOX

EDUCATIONAL GAPS EVALUATION—This activity was created to address the professional practice gaps listed below:• Treating AMD, DME, and RVO with data from key clinical trials pertaining to the treatment of complex patients with these retinal diseases• Utilizing the sequencing and combination of different treatment options for patients with AMD, DME, and RVO with disparate practicetrends in the absence of therapeutic guidelines

Please respond regarding how much you agree or disagree that the gaps listed above were addressed: 1=Disagree 5=Agree

Participating in this educational activity changed your KNOWLEDGE in the professional 1 2 3 4 5practice gaps listed above.

Participating in this educational activity changed your COMPETENCE in the professional 1 2 3 4 5practice gaps listed above.

Do you feel participating in this educational activity will change your PERFORMANCE 1 2 3 4 5in the professional practice gaps listed above?

Please elaborate on your previous answers___________________________________________________________________________________

ACTIVITY EVALUATIONThis evaluation is confidential and no individual will be identified by this office (Continuing Medical Education and Professional Development). It will only be used for quality improvement.

Please identify a change that you will implement into practice as a result of participating in this educational activity (new protocols, different medications, etc). __________________________________________________________________________________

How certain are you that you will implement this change? � Very certain � Certain � Maybe � Not certain � Will not implement � N/A

What topics do you want to hear more about, and what issues(s) in your practice will they address?

_______________________________________________________________________________________________________________________

_______________________________________________________________________________________________________________________

Were the patient recommendations based on acceptable practices in medicine? � Yes � No

If you answered No on the question above, please explain which recommendation(s) were not based on acceptable practices in medicine?

_______________________________________________________________________________________________________________________

Do you think the activity was without commercial bias? � Yes � No

If you answered No on the above question, please list the topics that were biased. __________________________________________________

_______________________________________________________________________________________________________________________

Please provide any additional comments you may have about this educational activity._______________________________________________

_______________________________________________________________________________________________________________________

Clinical Trial Updates: Putting Research Into Practice for Retinal DiseasesFax Completed Form to MedEdicus: 908.462.6555

Clinical Trial UpdatesPutting Research Into Practice for Retinal Diseases