Aflibercept in the Treatment of Neovascular Age-RelatedMacular Degeneration in Previously Treated Patients

Laura B. Hall, Nazlee Zebardast, John J. Huang, and Ron A. Adelman

Abstract

Purpose: To study the visual outcomes and change in central macular thickness (CMT) in patients withneovascular age-related macular degeneration (AMD) who were previously treated with ranibizumab (Lucentis)and/or bevacizumab (Avastin) and were subsequently switched to aflibercept (VEGF Trap-Eye; Eylea).Methods: Retrospective study of patients who received intravitreal aflibercept from December 2011 to De-cember 2012 and had previous anti-vascular endothelial growth factor treatment for AMD. The main outcomemeasures were best-corrected visual acuity (BCVA) and CMT as measured by optical coherence tomography.Results: The study population included 30 patients aged 80.4 – 1.45 (mean – SEM) who received 6.27 – 0.37(range 4–11) aflibercept injections. Eighteen patients had previously received only bevacizumab (12.4 – 2.18injections), 2 had received only ranibizumab (19 – 6 injections), and 10 had received both ranibizumab andbevacizumab (mean 19.3 injections). BCVA logMAR at the initial visit (aflibercept initiation) was0.506 – 0.054 (mean VA 20/64), and then, follow ups at 1-month 0.504 – 0.055 (20/64) P = 0.903, 3-months0.458 – 0.061 (20/57) P = 0.112, 6-months 0.413 – 0.071 (20/52) P = 0.036, and 12-months 0.521 – 0.076 (20/66)P = 0.836. CMT at the initial visit was 261 – 10.9, and then, at 1-month 238 – 12.4 P = 0.021, 3-months245 – 10.6 P = 0.102, 6-months 245 – 10.4 P = 0.099, and 12-months 237 – 10.2 P = 0.012. Results were similarin a subset of patients (n = 15) with central macular edema or submacular fluid at aflibercept initiation. While onaflibercept, 2 patients developed intraocular pressure increases that required treatment.Conclusions: These findings demonstrate a significant decrease in CMT but no statistically significant im-provement in BCVA through the 12-month follow up in patients previously treated who were switched toaflibercept for AMD. Patients may develop ocular hypertension after multiple aflibercept injections.

Introduction

Age-related macular degeneration (AMD) is theleading cause of central vision loss in the U. S. elderly

population.1,2 Over the past 8 years, there has been wide-spread acceptance of agents that directly inhibit the action ofvascular endothelial growth factor (VEGF) in the retina.3,4

In 2005, bevacizumab was first used off-label and in 2006,ranibizumab came to the market, both of which were used totreat wet (exudative or neovascular) AMD. Until recently,these were the mainstay management for wet AMD.

On November 18, 2011, the Food and Drug Administra-tion (FDA) granted regulatory approval to a new agentnamed aflibercept and within the past 2 years, it has gainedpopularity.

The effect of aflibercept is nested in its molecular struc-ture. While bevacizumab and ranibizumab use an antibody-based binding strategy, aflibercept is a recombinant decoy

fusion protein with 2 binding domains for VEGF receptors 1and 2, as well as a placental growth factor (another proposedpro-angiogenic factor present in the retina).4 The fusing ofthese extracellular components enables aflibercept to have amuch higher binding capacity than the others, and it is hy-pothesized to enable a more persistent, longer-lasting VEGFblockade.4–6

Based on clinical trial results [VEGF Trap-Eye: In-vestigation of Efficacy and Safety in Wet AMD (VIEW1and VIEW2)], the FDA approved aflibercept for the treat-ment of wet AMD.7 For the purpose of this current researchstudy, these clinical trials included 2 interesting details.First, the dosing regimen for aflibercept is 2 mg every 2months after 3 initial monthly doses. As a result, patientscan potentially avoid monthly clinic visits8 and instead goevery 2 months, which, respectively, the VIEW 1 and 27 andthe CLEAR-IT29 trials showed to be as effective at main-taining vision. Second, the VIEW trials excluded patients

Department of Ophthalmology and Visual Science, Yale School of Medicine, Yale Eye Center, New Haven, Connecticut.

JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICSVolume 30, Number 4, 2014ª Mary Ann Liebert, Inc.DOI: 10.1089/jop.2013.0188

346

previously treated with any anti-VEGF modality, specifi-cally bevacizumab or ranibizumab.10 As a result, the utilityof aflibercept in patients previously treated with anti-VEGFagents rather than in the treatment of naı̈ve patients remainsunclear.

Methods

The Yale School of Medicine Institutional Review Board(IRB) approved this single institution retrospective studythat adhered to the Declaration of Helsinki. Yale Eye Centerbilling data identified 64 patients from December 2011 toDecember 2012 as having received aflibercept (VEGF Trap-eye; Eylea�, Regeneron, Tarrytown, NY). Efforts weremade to have similar inclusion and exclusion criteria setforth in the VIEW trials10 with 3 notable inclusion criteriaexceptions. First, for the treatment of wet AMD, patientsshould have received at least 2 previous intravitreal anti-VEGF injections in the study eye, either 1.25 mg of bev-acizumab (Avastin�; Genentech, Inc., South San Francisco,CA) and/or 0.5 mg of ranibizumab (Lucentis�; Genentech,Inc.) before being transitioned to 2.0 mg intravitreal afli-bercept. Second, patients were included despite having best-corrected visual acuity (BCVA) vision better than 20/40.Third, all patients had to be followed at the Yale Eye CenterRetina Clinic for a minimum of 6 months after their firstaflibercept injection. This ensured the same team using thesame optical coherence tomography (OCT)-guided retreat-ment strategy managed the patients and that the time be-tween each treatment was not influenced by the use of othertherapeutic techniques or other physician opinions. Chor-oidal neovascularization from wet AMD was diagnosedusing both fluorescein angiography (FA) and OCT (Cirrus-OCT; Zeiss, Jens, Germany). Thirty patients met criteria andwere treated with aflibercept in at least 1 eye. If both eyes ofa patient matched the inclusion criteria, the right eye wasincluded in the study.

Both patients who responded well to previous anti-VEGFtherapy and those who were refractory were included in thisstudy. A subgroup analysis identified patients qualitativelyand quantitatively by a retina specialist as having centralmacular edema or submacular fluid on initial OCT definedas intraretinal fluid, or accumulation of fluid under themacula. Two patients with noncentral edema were excludedfrom this analysis.

Data were collected from December 2012 to February2013. Once aflibercept treatment began, patients did notreceive any concurrent AMD treatment such as photody-namic therapy or other anti-VEGF injections. Retina phy-sicians performed all aflibercept injections using a standard,sterile technique.

The option to switch was discussed with all active wetAMD patients. Risks, benefits, alternatives, and coveragewere discussed with each patient. The general guideline wasthat since aflibercept’s dosing regimen7 was preferred, allpatients with active disease and the desire to change wouldbe transitioned.

Since patients were not treatment naı̈ve, physicians used amodified treat and extend11,12 model to determine if andwhen treatment with aflibercept was needed, unless patientsdesired not to switch the treatment or there was a contrain-dication. Specifically, if patients exhibited subretinal fluid onOCT at the time of the switch, they then began aflibercept

monthly for the first 3 months and then, the treat and extendmodel was instituted. If OCT exhibited no subretinal fluid atthe time of the switch, then the treat and extend model wasinstituted at the time of the first aflibercept injection.7

At each visit, patients underwent Snellen visual acuitymeasurements with attempts to obtain Snellen BCVA aswell as slit-lamp and biomicroscopic fundus examinations.Snellen BCVA and central macular thickness (CMT) (mm)data were collected at multiple time points: initial visit,defined as the day of the first aflibercept injection, and then,at all subsequent visits between the retina specialist and thepatient regardless of whether an injection was administered.Demographic information, the length of time between eachvisit, the number and timing of each intravitreal injection,and adverse events were also collected. Pretreatment andsubsequent FA results were collected but were limited,precluding adequate analysis. FA was not routinely donebefore the switch. For the purpose of statistical analysis,Snellen visual acuity data was converted to BCVA loga-rithm of the minimal angle of resolution (logMAR).

The primary outcomes collected for this study included(1) visual acuity change from initial (day of afliberceptinitiation) to 1-, 3-, 6-, 9-, and 12-month follow ups: im-provement in visual acuity (decrease ‡ 0.3 logMAR), de-cline in visual acuity (increase ‡ 0.3 logMAR) or stability ofvisual acuity (any change £ 0.3 logMAR), (2) change inCMT (mm) from initial to 1-, 3-, 6-, 9-, and 12-month followups, and (3) the number and timing of aflibercept injections.

While patients without initial BCVA or CMT measure-ments or at least 6 months follow up were excluded from allanalyses of mean change, other missing data were imputedby the last-observation-carried-forward (LOCF) method.The LOCF was never used as a final observation (the 6-, 9-,or 12-month follow ups) and was never carried forward formore than 1 time point.

Visual acuities and CMT were statistically comparedbetween the aflibercept initiation visit and follow ups usingP values from paired Student’s t-tests. Statistical signifi-cance was defined as P < 0.05. Unless otherwise noted, alldata are presented as mean – SEM. Statistical analyses wereperformed using Microsoft Excel (Microsoft Corporation,Redmond, WA), and paired Student’s t-tests were calculatedusing GraphPad QuickCalcs Website www.graphpad.com/quickcalcs/ttest1.cfm (accessed April 2013).

Results

Billing records indicated 64 patients had received afli-bercept at the Yale Eye Center during the study period.Thirty of these patients received at least 2 previous bev-acizumab and/or ranibizumab injections, had at least 6months of follow up, and fit the inclusion criteria mentionedearlier. A single patient chart was unable to be locatedduring the data collection period. The LOCF was used for 5patients without a 1-month follow up (BCVA and CMT), for1 patient without a 1-month CMT, and for 1 patient withouta 9-month follow up (BCVA and CMT).

Demographics and clinical characteristics

The study population included 8 men (27%) and 22 wo-men (73%) aged 80.4 – 1.45 years with 9 right eyes, 12left eyes, and 9 with both eyes. Eighteen patients previously

AFLIBERCEPT IN PREVIOUSLY TREATED PATIENTS 347

received only bevacizumab (12.4 – 2.18 injections), 2 re-ceived only ranibizumab (19 – 6 injections), and 10 receivedboth anti-VEGF agents (mean 19.3 total injections). Overall,the patients received a total of 14.9 – 2.01 (range 2–53) pre-vious injections in the study eye. Patients received 6.27 – 0.37(range 4–11) aflibercept injections during the study period.

Visual acuity in all patients

While there was a modest trend toward improvementwithin the first 6 months, by 12 months there was no overallchange in BCVA (P = 0.84) (Table 1 and Fig. 1).

To evaluate the change in the BCVA, we defined 3 ca-tegories relative to the initial visit: improvement in visualacuity (decrease ‡ 0.3 logMAR), decline in visual acuity(increase ‡ 0.3 logMAR), and stable (any change £ 0.3logMAR). In addition, gross changes in vision were definedas follows: any improvement (any decrease in logMAR),any decline (any increase in logMAR), and stayed the same(no change in logMAR). The vast majority (73%–96% of

patients) fit into the stable category at all follow ups, simi-lar to clinical studies involving aflibercept (Table 2).7 Itshould be noted that LOCF was not applied to this analysis,because change is assessed.

CMT in all patients

There was a significant initial decrease in CMT after thefirst month of aflibercept treatment that remained significantat the 12-month follow up for all patients, with initial CMT264 – 12.5 mm compared with 237 – 10.2 at 12 months(P = 0.012) (Table 1 and Fig. 2).

Visual acuity and CMT in those with initialmacular edema

In a subgroup analysis, there were 15 patients (50%) whoat the time of aflibercept initiation had central macu-lar edema or submacular fluid; essentially, these were pa-tients who had suboptimal response to previous treatment

Table 1. Best-Corrected Visual Acuity logMAR with (Mean Visual Acuity)

and Central Macular Thickness (mm)

Time point Initial BCVA Follow-up BCVA P-value Initial CMT Follow-up CMT P-value

1-month (n = 30) LOCF = 5 0.506 – 0.054 (20/64) 0.504 – 0.055 (20/64) 0.903 261 – 10.9 238 – 12.4 0.0213-month (n = 30) 0.506 – 0.054 (20/64) 0.458 – 0.061 (20/57) 0.112 261 – 10.9 245 – 10.6 0.1026-month (n = 30) 0.506 – 0.054 (20/64) 0.413 – 0.071 (20/52) 0.036 261 – 10.9 245 – 10.4 0.0999-month (n = 27)LOCF = 1 0.518 – 0.059 (20/66) 0.465 – 0.065 (20/58) 0.210 262 – 10.7 242 – 9.66 0.01512-month (n = 22) 0.533 – 0.072 (20/68) 0.521 – 0.076 (20/66) 0.836 264 – 12.5 237 – 10.2 0.012

Values reported are mean – SEM. P-values compare initial values for the patients with data at each respective follow-up time point.BCVA, best-corrected visual acuity; CMT, central macular thickness; LOCF, last-observation-carried-forward.

FIG. 1. Mean change duringstudy period in best-corrected vi-sual acuity (BCVA) logMAR. Val-ues compare mean logMARBCVA from the follow-up timepoint to the initial mean BCVAlogMAR in each patient subset,where a positive change in log-MAR BCVA correlates to a decline(worsening) in vision.

348 HALL ET AL.

regimens. These patients received 19.1 – 0.06 (range 3–53)previous anti-VEGF injections in the study eye. The sub-group analysis results for BCVA were similar to the all-patients results and did not show a significant improvementafter aflibercept initiation (Table 3 and Figure 1). The sub-group analysis results for CMT demonstrated a similar de-crease in CMT over most of the 12-month period (Table 3and Fig. 2).

Clinic visit and treatment frequency

Data used for the follow-up time points (1, 3-months,etc.) were obtained from visits as close to these time pointsas possible. We had clinic visit dates for all 30 patientsfor their initial visit. Follow-up data were collected for 25patients at 1 month (45.2 – 2.28 days), 30 patients for 3months (99.1 – 3.02) and 6 months (175 – 4.87), 26 patientsfor 9 months (265 – 4.98), and 22 patients for 12 months

(341 – 6.30). Six months from the first aflibercept injection,all 30 patients returned to the clinic with an average of4.50 – 0.11 injections; 9 months from the first injection, 26patients returned to the clinic with an average of 6.00 – 0.23injections and 12 months from the first injection, 22 patientsreturned to the clinic with an average of 7.17 – 0.38 injec-tions. It should be noted that LOCF was not applied to thisanalysis, because the time between visits and the number ofinjections within a designated time frame were assessed.

Intraocular pressure

There were 2 instances in which injections were held dueto intraocular pressures (IOP) > 25 mmHg. Patients weregiven IOP-lowering agents and had glaucoma evaluations.In this study, both patients were noted to have elevated IOPat their last follow up study. The injections were held at thisvisit, but the BCVA and CMT data were still collected.

Table 2. Change in Vision Relative to Initial Visit, with Number of Patients (%) Experiencing

the Column Category of Visual Change at Each Subsequent Time Point (Rows)

Time pointImprovement in

visual acuity Any improvementDecline in

visual acuity Any decline Stable Same

1-month (n = 25) 0 8 (32%) 1 (4%) 5 (20%) 24 (96%) 12 (48%)3-month (n = 30) 3 (10%) 14 (47%) 1 (3%) 4 (13%) 26 (87%) 12 (40%)6-month (n = 30) 4 (13%) 19 (63%) 1 (3%) 5 (17%) 25 (83%) 6 (20%)9-month (n = 26) 3 (11%) 13 (50%) 2 (8%) 7 (27%) 21 (81%) 6 (23%)12-month (n = 22) 2 (9%) 10 (45%) 4 (18%) 8 (36%) 16 (73%) 4 (18%)

Improvement is a decrease ‡ 0.3 logMAR, any improvement is any decrease in logMAR, decline is an increase ‡ 0.3 logMAR, anydecline is any increase in logMAR, stable is any change £ 0.3 logMAR and same is no change in logMAR.

FIG. 2. Mean change duringstudy period in central macularthickness (CMT) (mm). Values com-paremean follow-up timepoint CMTto mean initial CMT in each indi-cated patient subset.

AFLIBERCEPT IN PREVIOUSLY TREATED PATIENTS 349

Holding the medication at the 12-month follow up (laststudy visit) did not affect macular edema or visual outcomesduring the study period. After adequate pressure control by aglaucoma specialist, anti-VEGF treatment resumed.

Adverse events

No significant sight-threatening complications developedin the study patients during the specified period. There wereno other drug- or injection-related adverse events except formild subconjunctival hemorrhage.

Discussion

Aflibercept was approved in 2011 for the treatment ofwet AMD based on clinical trial data in the treatment ofnaı̈ve patients.7 PubMed and Medline searches performedon August 14, 2013 with the search criteria ‘‘aflibercept’’and ‘‘macular degeneration’’ revealed a handful of papersevaluatingafliberceptinpreviouslytreatedpatients.13–18Kumaret al. assessed patients with persistent subfoveal fluid re-sistant to ranibizumab with 6-months’ follow up and foundsignificant improvements in visual acuities and pigmentepithelial height and diameter.13 The most comprehensiverecent studies by Cho et al.,15 Bakall et al.,16 and Yonekawaet al.17 also only have 6-months’ follow up. All of themreported anatomical improvement in subretinal thickness butno significant change in BCVA by 6 months. This articleextends the conclusions to 12 months. Further, only thepaper by Yonekawa et al.17 analyzed all patients and not justthose who were refractory (defined as persistent exudationdespite monthly injections) to treatment. Including thesearch terms ‘‘switch,’’ ‘‘resistant,’’ and ‘‘previous treat-ment’’ yielded no further relevant papers. There is not en-ough generalizable and long-term information in theliterature on whether aflibercept is effective in previouslytreated uncomplicated wet AMD patients.

Visual acuity and CMT

This study followed patients with and without initialmacular edema for approximately 12 months. Overall, after12 months of follow up, there was no statistically significantimprovement in BCVA and the subgroup analysis of thosewith initial central macular edema or submacular fluidshowed a worsening from baseline. In the literature, therehave only been reports with approximately 6 months of afli-bercept follow up in previously treated patients.13–18 Similarto those reports, in this study, BCVA showed a trend towardimprovement by 6 months of follow up. However, by 12months, the BCVA was close to or worse than initial values.

Notably, initial BCVA for 9 of the 30 patients (30%) was20/40 or better. While the VIEW and CLEAR-IT2 trialsshowed noninferiority in BCVA at all time points, it ex-cluded patients with initial vision better than 20/40.7,9 Thepresent study included patients with any visual acuity. Thus,our patients have a smaller margin for improvement.

The CMT in all patients as well as in the subgroup withinitial central macular edema or submacular fluid showed adecline throughout the study period, as it also did in the6-month studies.13–18 The subgroup showed the largest nu-merical improvement ( - 35 mm) at 12 months, but the smallsample size (n = 11) made it difficult to reach statisticalsignificance.

Given that aflibercept was introduced later in the treat-ment course for patients in all of the studies mentionedearlier (particularly in this study after they had received arange of 2 to 53 anti-VEGF injections), some irreversiblevisual loss and retinal damage may have occurred. Thesedata are representative of the previously treated patients whowere switched to aflibercept.

Persistent IOP rise after aflibercept

There are reports in the literature on persistent ocularhypertension (OHT) after bevacizumab and ranibizu-mab19,20 but not with aflibercept treatment in wet AMD. APubmed and Medline search on August 14, 2013 with thesearch terms ‘‘aflibercept’’ and either ‘‘ocular hyperten-sion’’ or ‘‘intraocular pressure’’ revealed studies that reporta rise in IOP immediately after aflibercept injection in pa-tients with AMD or diabetic macular edema but not as aspecific long-term consequence.7,21,22 In this retrospectivestudy, 2 patients had persistent IOP rises after afliberceptuse. The first patient received 14 bevacizumab and 5 rani-bizumab and had no history of OHT. Previous pressureswere stable in the mid teens and 11 months after switchingto aflibercept (9 injections), the IOP increased to 35. Thesecond patient received 13 previous ranibizumab injectionsand was stable on 1 IOP-lowering agent. Despite being onthe same IOP-lowering medication with pressures stable inthe mid teens, 11 months after switching to aflibercept(5 injections) the IOP increased to 38. Retina and glaucomaspecialists examined both patients and prescribed an IOP-lowering regimen.

Clinic visit and treatment frequency

Rather than following with monthly injection for 3 timesfollowed by bimonthly treatment regimen for aflibercept,7

since the patients were not treatment naı̈ve, a modified

Table 3. Best-Corrected Visual Acuity logMAR with (Mean Visual Acuity)

and Central Macular Thickness (mm) in Those with Central Macular Edema

or Submacular Fluid at the Time of Aflibercept Initiation

Time point Initial BCVA Follow-up BCVA P-value Initial CMT Follow-up CMT P-value

1-month (n = 15) 0.464 – 0.061 (20/58) 0.469 – 0.059 (20/59) 0.866 274 – 15.9 242 – 17.7 0.0303-month (n = 15) 0.464 – 0.061 (20/58) 0.423 – 0.067 (20/53) 0.261 274 – 15.9 255 – 15.8 0.2076-month (n = 15) 0.464 – 0.061 (20/58) 0.374 – 0.058 (20/47) 0.014 274 – 15.9 241 – 10.2 0.0309-month (n = 13) 0.458 – 0.070 (20/57) 0.472 – 0.092 (20/59) 0.800 268 – 17.9 239 – 12.5 0.04112-month (n = 11) 0.443 – 0.082 (20/55) 0.508 – 0.100 (20/64) 0.360 275 – 20.7 240 – 13.4 0.078

Values reported are mean – SEM. P-values compare initial values for the patients with data at each respective follow-up time point.

350 HALL ET AL.

‘‘treat and extend’’ model was used.11,12 In this study, pa-tients required fewer clinic visits and received fewer injec-tions over time. These findings suggest that the treat andextend model may be effective with aflibercept treatment.During the study, some macular edema and submacular fluidcompletely resolved and in these patients, the treatmentinterval was gradually extended to every 3–4 months. Sincemost physicians use a treat and extend model when treatingwet AMD, this current study is relevant to a large number ofpractitioners.

Other considerations

This study has several limitations. Primarily, it is retro-spective and nonrandomized. It included a small sample sizeof patients with a relatively short follow-up time of 12 months.

However, this study still adds to the growing body ofliterature on aflibercept’s effectiveness in wet AMD, espe-cially after previous treatments. A larger and longer pro-spective randomized study is needed to better understand theutility of aflibercept in previously treated AMD patients.

Acknowledgments

This research was supported in part by the Richard K.Gershon M.D. Student Research Fellowship (New Haven,CT), Leir Foundation (New York City, NY), Newman’sOwn Foundation (Westport, CT), and Research to PreventBlindness (New York, NY). The sponsors or funding orga-nizations had no role in the design or conduct of this re-search. The authors would like to thank Victoria Donaldsonfor technical support.

Author Disclosure Statement

The authors have no proprietary interests to disclose.

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22. Ford, J.A., Lois, N., Royle, P., Clar, C., Shyangdan, D., andWaugh, N. Current treatments in diabetic macular oedema:systematic review and meta-analysis. BMJ Open. 3:1–58,2013.

Received: September 5, 2013Accepted: December 10, 2013

Address correspondence to:Dr. Ron A. Adelman

Department of Ophthalmology and Visual ScienceYale School of Medicine

Yale Eye Center40 Temple Street

Suite 3DNew Haven, CT 06510

E-mail: ron.adelman@yale.edu

352 HALL ET AL.