446007 TAJ342040622312446007M Ohr and PK KaiserTherapeutic Advances in Chronic Disease
`
`2012
`
`Aflibercept in wet age-related macular
`degeneration: a perspective review
`
`Matthew Ohr and Peter K. Kaiser
`
`Ther Adv Chronic Dis
`
`(2012) 3(4) 153 –161
`
`DOI: 10.1177/
`2040622312446007
`
`© The Author(s), 2012.
`Reprints and permissions:
`http://www.sagepub.co.uk/
`journalsPermissions.nav
`
`Abstract: In the treatment of neovascular age-related macular degeneration (AMD), vascular
`endothelial growth factor (VEGF) has emerged as a key target of therapy. Currently, patients
`with neovascular AMD are treated with monthly intravitreal injections of anti-VEGF medications.
`Aflibercept is a novel recombinant fusion protein engineered to bind all isoforms of VEGF-A,
`VEGF-B, and placental growth factor. It is the latest medication to receive US Federal Drug
`Administration (FDA) approval for the treatment of neovascular AMD. Theoretical models
`suggest this molecule may have a longer duration of action compared with current treatments.
`The results of the VEGF Trap-Eye: Investigation of Efficacy and Safety in wet Age-related Macular
`Degeneration studies (VIEW 1 and VIEW 2) support this by demonstrating that aflibercept, dosed
`every 2 months after a monthly loading dose for 3 months, was noninferior in the proportion of
`patients who maintained or improved vision at 52 weeks compared with monthly injections of
`ranibizumab. These results were maintained over the 2 years of the studies. Aflibercept (Eylea;
`Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA and Bayer, Basel, Switzerland) was
`approved by the FDA for the treatment of neovascular AMD on 18 November 2011.
`
`Keywords: aflibercept, neovascular age-related macular degeneration, ranibizumab, vascular
`endothelial growth factor, wet age-related macular degeneration
`
`Introduction
`In the USA, age-related macular degeneration
`(AMD) is the leading cause of vision loss in older
`patients. It is estimated that the prevalence of
`AMD is 6.5% among people aged 40 years and
`older [Klein et al. 2011]. AMD also remains a
`leading cause of vision loss among older adults in
`other Western countries. Most of this vision loss
`stems from advanced AMD. Advanced AMD can
`be classified into two major forms: the non-neo-
`vascular, atrophic (dry) form or the neovascular
`(wet) form. The majority of people with severe
`vision loss (20/200 or worse) from AMD have the
`neovascular form, which is estimated to occur in
`10–20% of patients [Ferris et al. 1984]. Currently,
`there is no effective treatment for advanced, dry
`AMD [Meleth et al. 2011]. However, neovascular
`AMD has been successfully targeted by a number
`of treatment strategies.
`
`Overview of current therapy
`The hallmark of wet AMD is the formation of
`new, anomalous blood vessels that typically arise
`
`from the choroidal vasculature and can grow into
`the subretinal pigment epithelial or subretinal
`space. Rarely, this process may originate from the
`retina and extend posteriorly into the subretinal
`space, a form of neovascular AMD termed retinal
`angiomatous proliferation. These neovascular
`vessels commonly hemorrhage and leak and can
`compromise vision by distorting the retinal and
`subretinal architecture with fluid, blood, or fibro-
`vascular tissue [Spilsbury et al. 2000]. Untreated,
`choroidal neovascularization (CNV) usually leads
`to permanents loss of central vision.
`
`The pathogenesis of CNV is not completely
`understood. However, the overexpression of vas-
`cular endothelial grown factor (VEGF), a pro-
`angiogenic cytokine, has been shown to play a
`crucial role [Spilsbury et al. 2000]. Previous stud-
`ies have demonstrated increased levels of VEGF in
`the presence of inflammatory cytokines, suggest-
`ing that inflammation is a key component of AMD
`[Nagineni et al. 2012]. Others have suggested that
`ischemia, also associated with increased VEGF
`[Witmer et al. 2003], may play a role in AMD
`
`Correspondence to:
`Peter K. Kaiser, MD
`Cleveland Clinic – Cole
`Eye Institute, 9500
`Euclid Avenue, Desk i3,
`Cleveland, OH 44122, USA
`pkkaiser@mac.com
`Matthew Ohr, MD
`Cleveland Clinic – Cole
`Eye Institute, Cleveland,
`OH, USA
`
`http://taj.sagepub.com
`
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`[Feigl, 2009]. All of these reports clearly indicate
`that VEGF is vital to the pathogenesis of CNV in
`AMD.
`
`Early treatment strategies focused on destruction
`of choroidal neovascular membranes using laser
`photocoagulation. The Macular Photocoagulation
`Study (MPS) established guidelines for treatment
`of these lesions [Macular Photocoagulation Study
`Group, 1982, 1986, 1991]. Although this treat-
`ment reduced the likelihood of severe vision loss
`compared with the natural course of the disease,
`there were many limitations, especially when
`treating lesions in the fovea. The primary down-
`sides were related to the fact that the laser induced
`a permanent scotoma, and recurrence of the CNV
`occurred in over 50% of treated eyes [Macular
`Photocoagulation Study Group, 1991].
`
`Until 1999, laser photocoagulation was the only
`treatment for neovascular AMD that had been
`shown to reduce the risk of vision loss. At that
`time, the Treatment of Age-Related Macular
`Degeneration with Photodynamic Therapy (TAP)
`Study reported that photodynamic therapy (PDT)
`with verteporfin (Visudyne; Novartis Pharma AG,
`Basel, Switzerland) reduced the risk of moderate
`to severe vision loss for at least 5 years in patients
`who presented with subfoveal lesions classified as
`predominantly classic [TAP Study Group, 1999;
`Azab et al. 2004; Blumenkranz et al. 2002; Bressler
`and TAP Study Group, 2001; Bressler et al. 2002;
`Kaiser et al. 2006]. PDT is a two-step process
`that involves the intravenous injection of verte-
`porfin, a photosensitizing molecule, which is
`taken up by dividing cells within CNV. The drug
`is activated by local application of energy from a
`diode laser source at a wavelength that corre-
`sponds to an absorption peak of the molecule. A
`photochemical reaction occurs and activated free
`radicals are generated that can lead to capillary
`endothelial cell damage and vessel thrombosis. At
`2 years, 59% of verteporfin treated eyes versus
`31% of placebo eyes avoided at least moderate
`vision loss [Bressler and TAP Study Group, 2001].
`While PDT improved the results seen with laser
`photocoagulation, there remained a pressing need
`for better treatment modalities.
`
`The first VEGF inhibitor to obtain US Federal
`Drug Administration (FDA) approval for CNV
`in AMD was pegaptanib (Macugen; OSI/
`Eyetech Pharmaceuticals, New York, NY, USA)
`in 2004. Pegaptanib is an RNA aptamer that
`binds human VEGF165 with high affinity and
`
`specificity [Gragoudas et al. 2004]. The drug,
`however, did not bind other active VEGF isoforms
`such as VEGF121. Pegaptanib is administered as
`an intravitreal injection every 6 weeks. The VEGF
`Inhibition Study in Ocular Neovascularization
`(VISION) trial was a prospective, randomized,
`double-masked, controlled, dose-ranging phase
`III clinical trial in which 1186 patients with
`AMD and subfoveal CNV received one of three
`doses of pegaptanib or sham injections every
`6 weeks for 48 weeks [Gragoudas et al. 2004].
`The results of this study were promising, with
`70% of patients losing less than three lines of
`vision compared with 55% of controls (p < 0.001).
`Unfortunately, similar to the results with PDT,
`a minority of patients gained vision with this
`therapy.
`
`One of the most exciting advances in the treat-
`ment of CNV in AMD came with the introduc-
`tion of ranibizumab (Lucentis; Genentech, South
`San Francisco, CA, USA) in 2006. Ranibizumab
`is a recombinantly produced, humanized, anti-
`body (Fab) fragment that binds VEGF [Rosenfeld
`et al. 2006]. Unlike pegaptanib, ranibizumab
`binds to and inhibits the biological activity of
`all active forms of VEGF-A. The Minimally
`Classic/Occult Trial of the Anti-VEGF Antibody
`Ranibizumab in the Treatment of Neovascular
`AMD (MARINA) study was a randomized, dou-
`ble-masked, sham-controlled clinical trial of 716
`patients with minimally classic or occult CNV
`secondary to AMD treated with one of two dif-
`ferent doses of intravitreal ranibizumab or sham
`injections given every 4 weeks for 2 years
`[Rosenfeld et al. 2006]. The results of this study
`were revolutionary with 94.5% of patients treated
`with ranibizumab 0.3 mg and 94.6% of patients
`treated with ranibizumab 0.5 mg experiencing
`vision stabilization or improvement compared
`with 62.2% of patients receiving sham injections
`(p < 0.001). In fact, visual acuity improved by
`15 letters or more in 24.8% of patients receiving
`0.3 mg and 33.8% of patients receiving 0.5 mg
`ranibizumab compared with 5.0% of the sham
`injection group (p < 0.001). These results were
`further supported by the Anti-VEGF Antibody
`for the Treatment of Predominantly Classic
`Choroidal Neovascularization in AMD (ANCHOR)
`study, which was a randomized, controlled, dou-
`ble-masked phase III clinical trial of 423 patients
`that compared patients treated with ranibizumab
`with patients treated with PDT with verteporfin
`treatment [Brown et al. 2006, 2009]. These results
`showed that 94.3% of patients treated with
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`0.3 mg ranibizumab and 96.4% of patients treated
`with 0.5 mg ranibizumab lost less than 15 letters
`of vision compared with 64.3% of patients treated
`with PDT at 1 year (p < 0.001). Patients receiving
`ranibizumab again showed increased vision in
`35.7% of patients treated with 0.3 mg ranibi-
`zumab and 40.3% of patients treated with 0.5 mg
`ranibizumab compared with only 5.6% of patients
`treated with PDT (p < 0.001). The results of these
`trials resulted in anti-VEGF therapies largely
`replacing previous treatment modalities.
`
`Bevacizumab (Avastin; Genentech) is a full-
`length monoclonal antibody that binds all isoforms
`of VEGF-A. The FDA originally approved it in
`February 2004 for the treatment of metastatic
`colorectal cancer. Soon thereafter, physicians
`started to use it off label as an intravenous or
`intravitreal treatment for neovascular AMD.
`Despite the lack of clinical research to support its
`safety or efficacy, anecdotal evidence led to its
`widespread popularity prior to the approval of
`ranibizumab in 2006. To deliver an intravitreal
`injection, a physician or pharmacy takes a vial of
`bevacizumab and makes numerous unit doses.
`This dramatically lowers the cost of the drug. The
`approximate cost differential between ranibizumab
`(US$2000) and bevacizumab (US$S50) was
`prohibitive for some patients, and bevacizumab
`continued to be utilized, despite not being FDA
`approved for intravitreal use. In fact, in a review
`of Medicare claims for neovascular AMD in 2008,
`it was noted that 58% of all intravitreal injections
`given were bevacizumab and 41% were ranibi-
`zumab [Brechner et al. 2011].
`
`To address the safety and therapeutic concerns of
`the widespread, off-label use of bevacizumab in
`the treatment of wet AMD, the National Eye
`Institute commissioned the Comparison of Age-
`Related Macular Degeneration Treatment Trial
`(CATT) [CATT Research Group et al. 2011]. In
`this multicenter, single-blind, noninferiority trial,
`1208 patients with neovascular AMD were rand-
`omized into four groups. After the first mandatory
`intravitreal injection, patients received ranibi-
`zumab every 28 days (ranibizumab monthly), bev-
`acizumab every 28 days (bevacizumab monthly),
`ranibizumab only when signs of active neovascu-
`larization were present (ranibizumab as needed),
`and bevacizumab only when signs of active
`neovascularization were present (bevacizumab as
`needed). The 1-year results of this study demon-
`strated that monthly bevacizumab was equivalent
`to monthly ranibizumab with 8.0 and 8.5 letters
`
`gained, respectively. Bevacizumab as needed was
`found to be equivalent to ranibizumab as needed
`with 5.9 and 6.8 letters gained, respectively. While
`ranibizumab as needed was found to be equivalent
`to ranibizumab monthly, the equivalence of beva-
`cizumab as needed compared with bevacizumab
`monthly was found to be inconclusive.
`
`Aflibercept
`Aflibercept (Eylea; Regeneron, Tarrytown, NY,
`USA and Bayer, Basel, Switzerland) is a fully
`human, recombinant fusion protein composed of
`the second immunoglobulin (Ig) binding domain
`of VEGF receptor 1 and the third Ig binding
`domain of VEGF receptor 2, fused to the Fc
`region of human IgG1. It binds to all VEGF-A
`isoforms, VEGF-B, and placental growth factor
`(PlGF) [Papadopoulos et al. 2012]. Aflibercept
`is a member of Regeneron’s proprietary family
`of ‘Trap’ products that catch, hold, and block
`(i.e. trap) certain cytokines [Adis R&D Profile,
`2008]. Aflibercept is being developed for the
`treatment of cancer (Zaltrap; Regeneron and
`Sanofi, Bridgewater, NJ, USA) and eye disorders.
`The eye formulation, also referred to in the liter-
`ature as VEGF Trap-Eye, is identical in structure
`to the intravenous cancer treatment, with further
`purification steps and buffer modification to
`allow for comfortable, nonirritating intravitreal
`injection [Dixon et al. 2009].
`
`Unlike currently available anti-VEGF therapies,
`aflibercept binds PlGF in addition to all iso-
`forms of VEGF-A and VEGF-B. Like VEGF,
`PlGF is present in human CNV membranes, and
`animal studies have shown that PlGF contrib-
`utes to the development of experimental CNV
`[Rakic et al. 2003]. Another differentiating
`feature of aflibercept is that the binding affinity
`for VEGF is 0.5 pM Kd, which is considerably
`stronger than ranibizumab, bevacizumab, or native
`VEGF receptors. This allows for effective block-
`ing of VEGF, even at low concentrations, which
`may translate into a longer duration of action and
`extended dosing intervals [Stewart and Rosenfeld,
`2008].
`
`The results of preclinical studies were promising.
`In Matrigel-induced models of CNV in rats,
`aflibercept was shown to arrest the growth of CNV
`and led to the regression of recently established
`lesions [Cao et al. 2010]. Primate studies of laser-
`induced CNV also showed promise for the drug.
`When aflibercept was given prior to and following
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`attempted laser induction of CNV, minimal neo-
`vascularization was noted compared with placebo.
`In drug-naïve eyes with previously established
`CNV, aflibercept was successful in causing regres-
`sion of the CNV and resolving vascular leakage
`[Nork et al. 2011]. These encouraging results cou-
`pled with the apparent safety of the drug, fueled
`the demand for human clinical trials.
`
`Phase I
`A phase I, randomized, multicenter, masked,
`placebo-controlled clinical trial of intravenous
`aflibercept in patients with subfoveal CNV from
`AMD showed a dose-dependent decrease in
`retinal thickness [Nguyen et al. 2006]. However,
`at systemic doses of 3 mg/kg, hypertension and
`proteinuria were observed, and the study was
`halted for safety concerns. This led to investiga-
`tion of alternative delivery methods.
`
`The safety, tolerability, maximum tolerated dose,
`and bioactivity of intravitreal injection of afliber-
`cept were evaluated in a phase I, multicenter,
`dose-escalation study [Nguyen et al. 2009]. In the
`study, 21 patients received a single dose of afliber-
`cept. Patients were monitored for 12 weeks after
`injection. There were no serious ocular or sys-
`temic events noted. With any dose of aflibercept,
`stable or improved vision was seen in 95% of
`patients at 6 weeks. The mean decrease in foveal
`thickness was −105.5 µm, and the mean increase
`in visual acuity was +4.43 letters. Half of the
`patients receiving 2 or 4 mg doses showed no reti-
`nal leakage and maintained vision gains at 12
`weeks after a single injection. These positive
`results paved the way for further development of
`an intravitreal formulation of aflibercept.
`
`Phase II
`The clinical evaluation of anti-angiogenesis in the
`retina study (CLEAR-IT) 2 trial was a phase II
`multicenter, prospective, randomized, double-
`masked clinical trial designed to study the effect
`of intravitreal aflibercept in patients with neovas-
`cular AMD [Brown et al. 2011; Heier et al. 2011].
`This trial was divided into two parts. In the first
`part, patients were treated with a fixed dosing
`interval up to 12 weeks. The second part of the
`study was designed to be as needed (PRN) dosing
`and took place from week 16 to 52. The primary
`endpoint of the study was the change in central
`retinal thickness. The mean change in best cor-
`rected visual acuity (BCVA) was evaluated as a
`
`secondary outcome. The study included 159
`patients who were randomized into five treatment
`groups. The first two groups received treatment
`every 4 weeks and were dosed at 0.5 mg (group 1)
`or 2 mg (group 2). The last three groups were
`treated every 12 weeks and were dosed at 0.5 mg
`(group 3), 2 mg (group 4), or 4 mg (group 5). The
`primary outcome was at 12 weeks, following the
`fixed dosing period. The mean decrease in central
`retinal thickness from baseline to 12 weeks in all
`groups was −119 µm. Monthly dosing with either
`0.5 or 2 mg (groups 1 and 2) provided a more
`profound and consistent effect than any of the
`groups treated every 12 weeks. Overall, there was
`a mean increase in BCVA of +5.7 Early Treatment
`Diabetic Retinopathy Study (ETDRS) letters in
`all groups. The greatest mean increase in BCVA,
`more than +8 letters, was seen in the monthly
`dosing groups compared with the patients receiv-
`ing only one injection [Brown et al. 2011].
`
`For the PRN dosing arm of the study, patients
`were evaluated every 4 weeks to determine the
`need for continued treatment. Patients received an
`injection of the baseline dose at week 12. At week
`16 and thereafter, eyes were reinjected with afliber-
`cept if any of the following conditions were noted:
`increase in central retinal thickness of at least
`100 µm by optical coherence tomography (OCT);
`loss of at least 5 ETDRS letters with recurrent
`fluid on OCT; persistent fluid on OCT; new-onset
`of classic CNV; new or persistent leak on fluores-
`cein angiography; or new macular hemorrhage on
`clinical examination. Using these criteria, the
`mean decrease in central retinal thickness in all
`groups from baseline to 52 weeks was −130 µm.
`The mean increase in BCVA was +5.3 ETDRS
`letters in all groups. The greatest increase in BCVA
`occurred in the group initially treated with 2 mg
`every 4 weeks for 12 weeks before PRN dosing
`with a mean increase of +9.0 letters at 1 year. To
`achieve these excellent visual gains, an average of
`two additional injections was administered after
`the 12-week fixed-dosing phase across all groups.
`The mean time to the first reinjection was 129
`days, with 19% of patients receiving no injections
`and 45% receiving one or two additional injec-
`tions [Heier et al. 2011].
`
`Phase III
`Two parallel, phase III, double-masked, rand-
`omized studies were initiated in August 2007. The
`VEGF Trap-Eye: Investigation of Efficacy and
`Safety in wet Age-Related Macular Degeneration
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`Table 1. Summary of the 1-year results of VIEW 1 and VIEW 2 studies compared with MARINA and CATT trials.
`
`MARINA
`
`CATT
`
`VIEW 1 (12 months)
`
`VIEW 2 (12 months)
`
`Ran
`0.5 mg
`
`Sham Ran
`0.5 mg
`
`Bev
`0.5 mg
`
`Afl
`0.5 mg
`
`Afl
`2 mg
`
`Afl
`2 mg Q*
`
`Ran
`0.5 mg
`
`Afl
`0.5 mg
`
`Afl
`2 mg
`
`Afl
`2 mg Q*
`
`Ran
`0.5 mg
`
`
`
`
`
`≥15 letter gain (%)
`Stable vision (%)
`Mean gain in VA from
`baseline at 12 months
`Number of injections
`
`33
`90
`+7.2
`
`12
`
`4
`53
`–10.4
`
`34
`94
`+8.5
`
`31
`94
`+8.0
`
`12
`
`12
`
`96
`+8.1
`
`95
`95
`+10.9 +7.9
`
`94
`+8.1
`
`96
`+9.7
`
`96
`+7.6
`
`96
`+8.9
`
`
`94
`+9.4
`
`
`
`*Dosed every 8 weeks after treatment initiation with 3 monthly doses.
`Afl, aflibercept; Bev, bevacizumab; CATT, Comparison of Age-Related Macular Degeneration Treatment Trial; MARINA, Minimally Classic/Occult
`Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD; Ran, ranibizumab; VA, visual acuity; VIEW, VEGF Trap-Eye:
`Investigation of Efficacy and Safety in Wet Age-related Macular Degeneration.
`
`(VIEW 1) study was performed in North America.
`The VIEW 2 study was an international study
`including Europe, Asia Pacific, Japan, and Latin
`America. The studies were designed as noninferi-
`ority studies comparing intravitreal aflibercept
`with ranibizumab. Patients with subfoveal CNV
`due to AMD were randomized into four groups.
`The first two groups received intravitreal injections
`of aflibercept at doses of 0.5 and 2 mg adminis-
`tered at 4-week intervals. The third group received
`2 mg of aflibercept at 8-week intervals following
`three loading doses given every 4 weeks. These
`were compared with the fourth group, the control,
`receiving 0.5 mg of ranibizumab administered
`every 4 weeks. The primary endpoint was statisti-
`cal noninferiority in the proportion of patients
`who maintained or improved vision over 52 weeks
`compared with ranibizumab.
`
`The 1-year results of the VIEW 1 study showed
`that vision was maintained, defined as losing
`fewer than 15 ETDRS letters, in 96% of patients
`receiving aflibercept 0.5 mg monthly, 95% of
`patients receiving 2 mg monthly, and 95% of
`patients receiving 2 mg every 2 months. These
`results compared favorably with the 94% of
`patients maintaining vision in the group receiving
`ranibizumab 0.5 mg monthly [Regeneron, 2010;
`Heier, 2011]. The patients receiving aflibercept
`2 mg monthly on average gained 10.9 letters
`compared with a mean 8.1 letter gain with ranibi-
`zumab 0.5 mg dosed every month (p < 0.01). The
`VIEW 2 study showed similar results, with
`maintenance of vision in 96% of patients receiv-
`ing 0.5 mg monthly, 96% of patients receiving
`2 mg monthly, and 96% of patients receiving 2 mg
`every 2 months. These results also compared
`
`favorably with the 94% of patients maintaining
`vision in the group treated with ranibizumab 0.5
`mg monthly [Schmidt-Erfurth, 2011]. They are
`similar to results found in the MARINA and
`CATT trial (Table 1). The safety of both VIEW 1
`and VIEW 2 studies was excellent with no differ-
`ence seen between any aflibercept group and the
`ranibizumab group. The fact that 2 mg aflibercept
`dosed every 8 weeks after three loading doses was
`noninferior to ranibizumab dosed every 4 weeks
`in terms of safety and efficacy is exciting, as it
`offers the hope of similar visual gains with less
`treatment burden.
`
`The 2-year results of the VIEW 1 and VIEW 2
`studies were recently released [Regeneron, 2011].
`The integrated analysis of these two studies
`(Table 2) shows that patients receiving aflibercept
`2 mg every 8 weeks gained +7.6 letters from base-
`line at week 96 compared with +8.4 letters at
`week 52. The visual acuity gain in from baseline
`in patients receiving monthly ranibizumab was
`+7.9 letters at week 96 compared with +8.7 letters
`at week 52. Patients receiving aflibercept 2 mg
`every 8 weeks received an average of 11.2 injec-
`tions over 2 years while patients treated with
`ranibizumab had an average of 16.5 injections
`over 2 years. Aflibercept (Eylea) was approved by
`the FDA for the treatment of wet AMD on 18
`November 2011.
`
`Conclusions
`The evolution of treatment strategies for neovas-
`cular AMD has resulted in a paradigm shift in
`terms of expectations among patients and physi-
`cians. Prior to these recent advances, patients
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`Table 2. Summary of combined 2-year results of
`VIEW 1 and VIEW 2 studies.
`
`Aflibercept
`
`Ranibizumab
`
`2 mg Q*
`95
`
`0.5 mg
`94
`
`+8.4
`+7.6
`11.2
`
`+8.7
`+7.9
`16.5
`
`Study arm
`Stabilization of
`VA (%)
`Mean gain in VA
`(ETDRS letters)
` Year 1
` Year 2
`Average number
`of injections over
`24 months
`
`*Dosed every 8 weeks after treatment initiation with 3
`monthly doses.
`ETDRS, Early Treatment Diabetic Retinopathy Study;
`VA, visual acuity; VIEW, VEGF Trap-Eye: Investigation
`of Efficacy and Safety in Wet Age-related Macular
`Degeneration.
`
`who developed neovascular changes could antic-
`ipate a progressive and permanent decrease in
`vision. While destruction of the CNV lesion with
`laser photocoagulation was possible, in particu-
`lar when the lesion was located outside of the
`visual axis, it offered only modest hope of main-
`taining vision compared with the natural history
`of the disease, and results were less than satisfac-
`tory. The introduction of PDT with verteporfin
`offered some improvement, especially to patients
`with subfoveal disease. However, many patients
`continued to lose vision, and only minimal visual
`gains were achieved.
`
`The advent of anti-VEGF therapy marked a
`turning point in the treatment of neovascular
`AMD. The first FDA-approved anti-VEGF
`therapy for neovascular AMD was pegaptanib.
`Unfortunately, the specific targeting of VEGF165
`seemed to limit its effectiveness, and as with
`PDT, patients generally continued to slowly lose
`vision. It was the phase III results of ranibizumab
`and the off-label intravitreal use of the cancer
`drug, bevacizumab, that began to change expec-
`tations. Anecdotal evidence of improvements in
`vision and retinal thickness after a single treat-
`ment were reported in patients whose condition
`had failed to respond to pegaptanib therapy
`[Rosenfeld et al. 2005]. With the publication of
`the ANCHOR and MARINA trials, and the sub-
`sequent FDA approval of ranibizumab, vision
`could be expected to stabilize in close to 95% of
`cases, with improvement of BCVA by three or
`more lines in approximately 40% of patients.
`
`While anti-VEGF therapy has changed the efficacy
`of treatment, it is not without drawbacks. Patients
`are subjected to intravitreal injections as often as
`every 4 weeks to maintain vision. Frequent office
`visits, testing, and medication costs represent a
`burden to patients, physicians, and society. Although
`there have been no proven, adverse systemic
`effects from intravitreal injections, every injection
`puts patients at risk for endophthalmitis, intraoc-
`ular inflammation, vitreous hemorrhage, retinal
`tear, retinal detachment, and iatrogenic cataract.
`Recent studies have also suggested a sustained
`rise in intraocular pressure may occur with serial
`injections of anti-VEGF agents [Tseng et al.
`2011]. Aside from serious complications, patients
`are commonly subject to anxiety, discomfort, and
`the undesirable aesthetics of conjunctival hyperemia
`or hemorrhage.
`
`Current efforts have focused on extending the
`benefits of anti-VEGF treatment with less fre-
`quent dosing. In the phase IIIb, multi-center,
`randomized, double-masked, sham
`injection-
`controlled study of efficacy and safety of ranibi-
`zumab in subjects with subfoveal CNV with or
`without Classic CNV secondary to AMD (PIER)
`study, patients received monthly injections of
`ranibizumab for 3 months followed by quarterly
`dosing. Gains in visual acuity were noted at 3
`months, only to be lost during the quarterly dos-
`ing phase of the trial [Regillo et al. 2008]. In the
`prospective optical coherence tomography OCT
`imaging of patients with neovascular age-related
`macular degeneration treated with intra-ocular
`lucentis (PrONTO) study patients also received
`monthly injections of ranibizumab for 3 months.
`Following the initial dosing, additional treatments
`were given on a PRN basis. After 2 years, 78% of
`patients maintained vision and 43% of patients
`showed improvement in more than three lines of
`vision. An average of 9.9 injections was given over
`the 2-year period [Lalwani et al. 2009].
`
`One of the criticisms of PRN dosing is the fact
`that monthly visits are still required. One approach
`to treatment that aims to reduce the number of
`injections and visits is the ‘inject and extend’
`method [Spaide, 2007]. This strategy involves
`treatment with 3-monthly injections followed by a
`follow up appointment extended to 6 weeks. At
`the follow-up visit OCT and biomicroscopy are
`performed. If edema or any other sign of exuda-
`tion is present, the patient is given an injection
`and told to follow up in 4 weeks. Patients without
`any evidence of exudation are injected and have
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` M Ohr and PK Kaiser
`
`their follow-up visit extended to 8 weeks. The same
`evaluation occurs at the 8-week visit. However,
`patients with signs of exudation are injected and
`scheduled to follow up at 6 weeks. Patients with-
`out evidence of exudation are further extended to
`follow up at 10 weeks. In this way, an optimal,
`individualized treatment strategy can be obtained.
`While a few small studies have reported positive
`results with this method, there have been no large,
`prospective studies to support its effectiveness
`[Engelbert et al. 2009; Oubraham et al. 2011].
`
`Twelve-month results from the VIEW 1 and
`VIEW 2 studies appear promising for afliber-
`cept. Although the data will have to be analyzed
`further, the apparent noninferiority of the vari-
`ous aflibercept dosing regimens compared with
`ranibizumab represents a new milestone in the
`treatment of CNV due to AMD. Of particular
`interest is the 2 mg every 8 weeks dosing interval
`studied in the trials. The recent results of the
`2-year data for the VIEW 1 and VIEW 2 studies
`have further demonstrated the ability of afliber-
`cept to maintain the visual gains attained in the
`first year of the study with a significantly smaller
`number of injections compared with ranibi-
`zumab. Aflibercept was recently approved by
`the FDA for the treatment of CNV in AMD.
`The wholesale price of aflibercept (US$1850)
`is slightly below that of ranibizumab. However,
`the reduced treatment requirements of every
`8-week dosing versus monthly dosing of ranibi-
`zumab may represent a substantial savings in
`cost and treatment burden to patients.
`
`Funding
`This research received no specific grant from
`any funding agency in the public, commercial, or
`not-for-profit sectors.
`
`Conflict of interest statement
`Dr Kaiser is a consultant for Regeneron and Bayer
`that has been disclosed and approved by the
`Cleveland Clinic Conflict of Interest Committee.
`In addition, the Cole Eye Institute, the employer of
`Drs Ohr and Kaiser has received research grant
`support from Regeneron.
`
`References
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