Hindawi Publishing Corporation
`Journal of Ophthalmology
`Volume 2012, Article ID 637316, 7 pages
`doi:10.1155/2012/637316
`
`Review Article
`New Approach of Anti-VEGF Agents for Age-Related
`Macular Degeneration
`
`Young Gun Park, Hyun Wook Rhu, Seungbum Kang, and Young Jung Roh
`
`Department of Ophthalmology, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea,
`No. 62 Yeouido-dong, Yeongdeungpo-gu, Seoul 150-713, Republic of Korea
`
`Correspondence should be addressed to Young Jung Roh, youngjungroh@hanmail.net
`
`Received 30 July 2011; Accepted 3 November 2011
`
`Academic Editor: Yoshiaki Kiuchi
`
`Copyright © 2012 Young Gun Park et al. This is an open access article distributed under the Creative Commons Attribution
`License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
`cited.
`
`Age-related macular degeneration (AMD) is the leading cause of visual loss in older population. Angiogenesis is an important fac-
`tor associated with the development of CNV due to AMD. Treatment of CNV with intravitreal anti-VEGF monotherapy is curren-
`tly the standard of care. However, not all patients respond to monotherapy, and modified anti-VEGF treatment regimen and com-
`bination therapy may target reducing treatment frequency or improving visual outcome. This paper reviews the many clinical trials
`that have been performed utilizing several treatment regimens. While many trials have shown that this variable therapy is justifi-
`able, further study is required to determine correct regimens and dosage.
`
`1. Introduction
`
`Age-related macular degeneration (AMD) is one of the lead-
`ing causes of substantial and irreversible vision loss. The
`prevalence of AMD can be expected to increase along with
`life expectancy, which has risen steadily [1, 2]. Without treat-
`ment, the neovascular form of AMD leads to severe quality-
`of-life loss within a short time period and considerable eco-
`nomic burden.
`VEGF is a key mediator involved in the control of angio-
`genesis and vascular permeability and has been shown to be
`induced by hypoxia in cultured human RPE [3]. Vascular
`endothelial growth factor A (VEGF-A) is the most potent
`promoter of angiogenesis and vascular permeability within
`the VEGF family and its role in the pathogenesis of neovascu-
`lar AMD is well recognized [4, 5]. The advent of intravitreous
`VEGF inhibitors has revolutionized the management of neo-
`vascular AMD. Yet, frequently, indefinite injections of VEGF
`blocking agents introduce a significant treatment burden for
`patients with neovascular AMD. Many studies on modified
`treatment regimens have been performed in an attempt to
`mitigate this burden without compromise to visual acuity
`outcomes. Meanwhile, various randomized clinical trials on
`
`combination therapies and efforts to develop new pharma-
`cologic agents are ongoing.
`
`2. Material and Methods
`
`A MEDLINE search of the English language literature from
`1990 to present was conducted. The search strategy was
`based on combinations of medical subject headings (MeSH)
`and keywords and was not restricted to specific journals
`or years of publication. The searches were supplemented by
`handsearching the bibliographies of included studies and re-
`views.
`
`3. Results
`
`3.1. Three Antivascular Endothelial Growth Factor (VEGF)
`Therapies. Three antivascular endothelial growth factor
`(VEGF) therapies are currently used for the treatment of pa-
`tients with wet age-related macular degeneration (AMD):
`pegaptanib (Macugen, Pfizer, UK), ranibizumab (Lucentis,
`Novartis, UK), and bevacizumab (Avastin, Roche, UK).
`Petaganib is an oligonucleotide aptamer and was the first
`VEGF antagonist to be approved by the US Food and Drug
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`Administration for use in wet AMD. However, wet AMD
`patients treated with petaganib still experience visual decline
`[2, 6]. For this reason, petaganib was seldom used now.
`Ranibizumab (Lucentis) is also a humanized antibody
`fragment against VEGF which was specifically designed for
`intraocular use as a smaller antibody fragment to penetrate
`through the retina better. The Food and Drug Administra-
`tion (FDA) approved ranibizumab for treatment of subfoveal
`neovascular AMD in June, 2006. It was the first treatment for
`AMD shown to improve visual acuity in a substantial per-
`centage of patients.
`Bevacizumab (Avastin) is a recombinant humanized mo-
`noclonal immunoglobulin antibody that inhibits the activity
`of VEGF. It has a similar action and is related to the rani-
`bizumab compound with respect to its structure. Bevacizu-
`mab was approved by the FDA for the treatment of metastatic
`colorectal cancer in 2004, but it has not been licensed for
`the treatment of wet AMD or any other ocular conditions.
`However, it is recently used off-label worldwide not only for
`wet AMD but also for other ocular disease entities associated
`with macular edema and abnormal vessel growth.
`Since 2009, there have been increasing number of studies
`that have compared the properties of ranibizumab and beva-
`cizumab and investigated their efficacy on AMD. The pivotal
`phase III Minimally Classic/Occult Trial of the Anti-VEGF
`Antibody Ranibizumab in the Treatment of Neovascular
`AMD (MARINA) [7] and the Anti-VEGF Antibody for
`the Treatment of Predominantly Classic CNV in AMD
`(ANCHOR) trial [8, 9] demonstrated best-corrected visual
`acuity (BCVA) outcomes far superior to any previously
`published study in the treatment of this disease. At the
`end of 24 months in the MARINA trial, significantly more
`ranibizumab-treated patients had maintained (lost <15 Early
`Treatment Diabetic Retinopathy Study (ETDRS) letters) or
`improved vision than sham-injected patients. Indeed, 90–
`95% of patients treated with 0.3 and 0.5 mg ranibizumab
`maintained vision compared with 53–64% of control pa-
`tients. Over the same period, vision improved in 25–34% of
`treated eyes, compared with 4-5% of sham-injected patients.
`In the ANCHOR trial, ranibizumab was compared with
`verteporfin photodynamic therapy (PDT) and demonstrated
`similar findings: 90–96% of the ranibizumab-treated versus
`64–66% of the PDT-treated patients maintained vision,
`whereas 34–41% versus 6% of each group, respectively,
`gained more than 15 letters. These outcomes were signifi-
`cantly better (P < 0.001) than those achieved by the control
`groups.
`Patient-reported outcomes were also assessed in the
`ANCHOR and MARINA trials to measure the influence of
`the ranibizumab-mediated improvement in VA on quality of
`life. The data demonstrated that patients treated with rani-
`bizumab were more likely to report improvements in near
`activities, distance activities, and vision-specific dependency
`which were maintained over the 2-year duration of the trial
`[10, 11]. These data demonstrate that the clinical impro-
`vements seen with ranibizumab treatment translate into
`meaningful benefits for the patient.
`Bevacizumab, the predecessor of ranibizumab, is a full-
`length monoclonal antibody that binds to and blocks the
`
`action of all VEGF isoforms. Numerous retrospective [12–
`15] and prospective studies [16–18] of intravitreal bevaci-
`zumab have reported its efficacy for neovascular AMD and
`low rates of treatment-related complications [19]. Although
`a number of these studies were uncontrolled, relatively small
`in sample size, of limited followup, and varied with regard
`to outcome measures and retreatment criteria, the reported
`efficacy of bevacizumab coupled with its low cost when utili-
`zed as an intraocular agent has propelled its adoption world-
`wide.
`In clinical practice, many retinal physicians have extrap-
`olated the data and continued using bevacizumab. A formal
`head-to-head comparison of bevacizumab and ranibizumab
`is being conducted by the National Eye Institute of the
`National Institute of Health in the Comparisons of Age-Re-
`lated Macular Degeneration Treatment Trials (CATTs) [20,
`21]. The CATT study design includes four treatment arms:
`either bevacizumab or ranibizumab on a variable schedule
`and either bevacizumab or ranibizumab on a fixed monthly
`schedule for 1 year followed by random assignment to either
`continued monthly injections or a variable schedule based
`on the treatment response. The primary outcome measure is
`mean change in BCVA; secondary outcome measures include
`number of treatments, anatomical changes in the retina, ad-
`verse events, and cost. Preliminary results are reported in
`2011 and will provide insight into how ranibizumab and be-
`vacizumab compare with each other within the context of
`either a fixed monthly or traditional pro re nata (PRN) ap-
`proach. At 1 year, bevacizumab and ranibizumab had equiv-
`alent effects on visual acuity when administered according
`to the same schedule. Bevacizumab administered monthly
`was equivalent to ranibizumab administered monthly, with
`8.0 and 8.5 letters gained, respectively. Bevacizumab admin-
`istered as needed was equivalent to ranibizumab as needed,
`with 5.9 and 6.8 letters gained, respectively. Ranibizumab
`given as needed with monthly evaluation had effects on
`vision that were equivalent to those of ranibizumab admin-
`istered monthly, although the comparison between beva-
`cizumab as needed and monthly bevacizumab was inclusive.
`Differences in rated of serious adverse events require further
`study.
`
`3.2. Modified Treatment Regimens. The prospect of indef-
`initely adhering to the monthly treatment schedules of
`MARINA and ANCHOR has raised ocular and systemic
`safety concerns as well as convenience and cost issues for
`patient and physician alike. The identification of alternative
`dosing strategies capable of reducing the number of required
`anti-VEGF injections while still achieving visual acuity out-
`comes similar to those reached in the pivotal trials has since
`been a subject of great interest.
`The observed biphasic treatment effect raised the possi-
`bility that, after the initial 3-month loading phase, mainte-
`nance of VA gain may be achieved with less frequent treat-
`ments. A PIER trial evaluated ranibizumab administered
`monthly for 3 months, followed by quarterly injections, and
`compared this with sham treatment. Under this schedule,
`ranibizumab did provide a significant VA benefit; a signifi-
`cantly greater number of patients achieved VA stabilization
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`3
`
`(a)
`
`(c)
`
`(e)
`
`T
`
`N
`
`(b)
`
`(d)
`
`(f)
`
`T
`
`N
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`Figure 1: Fundus photograph of patients with hemorrhagic PED secondary to AMD. Fluorescein angiogram shows large hypofluorescence
`due to hemorrhage at macular lesion. Optical coherence tomography with large PED and subretinal fluid. (a, c, e) Same section after 3 rani-
`bizumab intravitreal injections. Complete resolution of the hemorrhagic PED with edema is illustrated. There was also improvement in
`visual acuity (b, d, f).
`
`at 24 months compared with patients receiving sham treat-
`ment. However, subgroup analysis revealed that VA gains
`observed during the first 3 months of treatment were only
`maintained in 40% of patients over the duration of the trial,
`and for the remaining 60% quarterly dosing was not suitable
`[22, 23]. Results for both ranibizumab doses in the PIER
`trial (0.3 and 0.5 mg) showed an initial mean improvement
`in BCVA during the initiation phase with monthly dosing,
`but after month 3 in the maintenance phase with quarterly
`dosing, there was a gradual decline in mean BCVA to below
`the pretreatment baseline ( 2.2 letters) at 12 months, which
`remained unchanged at 24 months [23] (Figure 1).
`More recently, the Efficacy and Safety of Ranibizumab in
`Patients with Subfoveal Choroidal Neovascularization Sec-
`ondary to Age-Related Macular Degeneration (EXCITE)
`study directly compared the PIER regimen with a fixed
`monthly treatment arm (0.3 mg ranibizumab) [24]. Al-
`though BCVA outcomes in the two quarterly treatment arms
`fared better than those in the PIER study at 12 months (2.2
`and 3.1 letters with 0.3 and 0.5 mg ranibizumab, resp.), nei-
`ther was as good as monthly dosing (0.9 letters). These sub-
`optimal results demonstrate that, on average, quarterly treat-
`ment is inferior to monthly treatment; thus, it has never been
`
`adopted in practice. Subsequent to the PIER trial, further
`investigation of a flexible dosing approach was carried out.
`The EXCITE trial directly compared a maintenance phase
`of quarterly injections against the monthly regimen. Consis-
`tent with previous observations, an initial gain was made in
`the first 3 months, after which patients receiving monthly
`injections contributed to gain VA, whilst those receiving
`quarterly injections showed a decrease from their 3-month
`VA levels.
`The current norm in clinical practice with ranibizumab
`or bevacizumab is to implement an initiation/induction
`phase followed by an individualized maintenance phase that
`is modeled after one of two basic approaches: traditional
`PRN [25] or “treat and extend” [26, 27]. Traditional PRN in-
`volves both regular followup and treatment until the macula
`is more or less free of exudation, with treatment thereafter
`during the maintenance phase only in the presence of recur-
`rent exudation. The original prospective studies that eva-
`luated a PRN approach to the maintenance phase were
`the Prospective Optical Coherence Tomography Imaging
`of Patients with Neovascular AMD Treated with Intra-
`Ocular Lucentis (PrONTO) study [28] and the Secondary to
`Age-Related Macular Degeneration (SAILOR) study [29].
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`More recently, the Study of Ranibizumab in Patients with
`Subfoveal Choroidal Neovascularization Secondary to Age-
`Related Macular Degeneration (SUSTAIN) study has con-
`tributed additional data [30]. In each of these trials, patients
`received three consecutive, monthly intravitreal injections
`of ranibizumab for induction, followed by monthly office
`visits. Thereafter, a PRN maintenance phase adhered to the
`following retreatment criteria: loss of at least five ETDRS
`letters, increase in central macular thickness on OCT of at
`least 100 µm, or new hemorrhage.
`Of the three studies, the PrONTO study demonstrated
`the best visual acuity results. The PrONTO study evaluated
`an OCT guided, variable-dosing regimen with ranibizumab
`(0.5 mg) and showed that mean visual acuity improved by
`9.3 ETDRS letters at 12 months. Over a 2-year period, mean
`BCVA outcomes were similar to MARINA and ANCHOR
`with a mean of 9.9 injections (5.6 in the first year and 4.3 in
`the second). In comparison, results from the SAILOR study
`were not as good. In this study, the mean change in BCVA at
`12 months from baseline was 0.5 and 1.7 letters in the treat-
`ment-naive and previously treated groups, respectively, at the
`0.3 mg dose and 2.3 letters in both groups at 0.5 mg. It is
`worth noting that participants were not monitored as closely
`in SAILOR as compared with PrONTO, averaging nine visits
`through 1 year and a mean of 4.9 injections.
`The 12-month results from SUSTAIN were slightly better
`than those from SAILOR (mean BCVA from baseline of 3.6
`letters), yet still not as good as the monthly treatment trials.
`In contrast to SAILOR, participants in the SUSTAIN trial
`were followed monthly (more like PrONTO) and the mean
`number of injections over the first year was higher at 5.6.
`Other relatively large studies using a traditional PRN
`approach have recently been published [31–33]. An analysis
`of these reports highlights an important trend: the best visual
`acuity results come from the study with the greatest mean
`number of treatments and closest followup, whereas the
`poorest outcomes were observed in the study with the lowest
`mean number of treatments and office visits. Unlike tradi-
`tional PRN, a treat and extend approach initially involves
`regular and frequent treatment until the macula is dry,
`followed by a gradual extension of the treatment interval and
`corresponding followup visit. Treatment interval extension
`continues until there are signs of recurrence, at which point
`the treatment interval is then reduced.
`Kang and Roh [34, 35] recently published a retrospective
`analysis that monthly injections were not given in contrast to
`the three injections during the initial treatment period in the
`PIER and PrONTO trials. This study minimized the num-
`ber of injections given during 12 months of follow-up (a
`mean of 4.07 injections were given over the 12 months). The
`decreased need for retreatment is of great benefit to both
`patients and clinicians. These results may raise doubts about
`the need for the three initial loading injections. They repor-
`ted another study [35]; the mean number of injections given
`in the 12 months period was 4.2 (range, 1–6). Patients were
`also offered reinjection with ranibizumab on an “as needed”
`basis. Data showed that the percentage of patients (71.9%)
`with no visual loss or improved visual acuity was comparable
`to the percentages in the monthly injection-based studies.
`
`In addition, Gupta et al. evaluated a treat and extend ap-
`proach with bevacizumab and found nearly identical results
`at 12 months following a mean of 7.3 injections in the first
`year [33]. Although various methods for individualizing
`maintenance therapy have been proposed, the optimal non-
`monthly dosing regimen does not remain clear.
`
`3.3. Combination Therapy: Photodynamic Therapy and Anti-
`VEGF Therapy. The development and propagation of CNV
`membranes involve proangiogenic factors, vascular permea-
`bility molecules, and inflammatory proteins. Current stan-
`dard treatment with monthly intravitreal injections of anti-
`VEGF monotherapy can be limited to the angiogenic com-
`ponent of CNV development and burdensome for both the
`physician and patient. Patients are subjected to increased risk
`with monthly treatments that may be lessened with treat-
`ment options given with less frequency [36]. Combination
`therapy with PDT proven to be effective may not only have
`a role in the treatment of CNV development but also may
`provide synergy through blocking adverse effects.
`Photodynamic therapy was approved in 2000 by the FDA
`for the treatment of CNV secondary to AMD. Treatment
`involves intravenous administration of a light-sensitive dye
`called verteporfin followed by laser-guided, location-specific
`activation within the CNV membrane. Activation of the ver-
`teporfin molecules incites a phototoxic event within blood
`vessels, induces endothelial cell damage, platelet aggregation,
`and eventually leads to thrombosis of vascular channels.
`Treatment size is limited by the greatest linear diameter of
`the CNV lesion being treated [37, 38].
`While PDT is intended to specifically target CNV vessels,
`collateral damage to surrounding blood vessels may lead to
`ischemia of healthy tissue. Following PDT of a CNV mem-
`brane, induced ischemia can lead to production of proangio-
`genic factors, especially VEGF. Therefore, combining verte-
`porfin PDT and anti-VEGF therapy may be beneficial com-
`pared with either modality alone, yielding longer treatment-
`free intervals and requiring fewer intravitreal injections [37].
`The RhuFab V2 Ocular Treatment Combining the Use of
`Visudyne to Evaluate Safety (FOCUS) study is a multicen-
`ter, randomized, single-blind study designed to evaluate the
`safety and efficacy of standard fluence Photodynamic therapy
`(sfPDT) in combination with intravitreal ranibizumab [39,
`40]. It compared sfPDT to combination sfPDT and intravit-
`real ranibizumab in the treatment of predominantly classic
`CNV secondary to AMD. One-year data showed greater
`visual stability in the patients treated with combination ther-
`apy and 23.8% of patients experienced improvement in
`visual acuity, compared with 5% of patients treated with PDT
`monotherapy alone. The number of retreatments with sfPDT
`was decreased as well with 91% of patients treated with
`sfPDT monotherapy requiring repeat treatment while only
`28% of patients treated with combination therapy requiring
`retreatment. Two-year data showed similar results with 88%
`of combination-treated patients losing less than 15 lines of
`vision versus 75% of sfPDT-alone treated patients. Combi-
`nation therapy required an average of 0.4 repeat PDT treat-
`ments compared with an average of 3.0 in the sfPDT group.
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`3.4. Vascular Endothelial Growth Factor Trap-Eye. The most
`effective dosing regimen and monitoring program for anti-
`VEGF therapy has yet to be firmly established but new treat-
`ments are aimed at extending and improving on the efficacy
`of ranibizumab. VEGF Trap-Eye is a promising new anti-
`VEGF drug (aflibercept ophthalmic solution; Regeneron
`Pharmaceuticals Inc., Tarrytown, NY, USA). Structurally,
`VEGF Trap-Eye is a fusion protein of key binding domains
`of human VEGFR-1 and -2 combined with a human IgG
`Fc fragment. Functionally, VEGF Trap-Eye acts as a receptor
`decoy with high affinity for all VEGF isoforms, binding more
`tightly. VEGF Trap-Eye differs from established anti-VEGF
`therapies in its higher binding affinity for VEGF-A and its
`blockage of placental growth factors-1 and -2 [41, 42].
`Recently, the 1-year results of two parallel randomized,
`double-masked phase 3 clinical trials (VIEW 1 and VIEW 2)
`on the efficacy and safety of VEGF Trap-Eye for the treatment
`of neovascular AMD were reported [42]. Phase I data de-
`monstrated acceptable safety and tolerability of VEGF Trap-
`Eye in the treatment of neovascular AMD, and in Phase II
`study data, patients dosed in a similar fashion to the
`PrONTO trial demonstrated stabilization of their vision
`that was similar to previous studies of ranibizumab at 1
`year. All dosing regimens of VEGF Trap-Eye, including 2 mg
`bimonthly, met the primary endpoint of noninferiority com-
`pared with monthly 0.5 mg ranibizumab with regard to the
`percentage of patients with maintenance (loss of <15 ETDRS
`letters) or improvement in vision. A greater mean improve-
`ment in visual acuity compared with monthly 0.5 mg ranibi-
`zumab at 1 year versus baseline represented the secondary
`endpoint of the study. In both the North American study
`(VIEW 1) and international study (VIEW 2), more than 95%
`of patients in each of the following VEGF Trap-Eye dosing
`groups achieved maintenance of vision compared with 94%
`of patients on monthly ranibizumab: 0.5 mg monthly, 2 mg
`monthly, and 2 mg every 2 months. In VIEW 1, patients on
`2 mg monthly dosing achieved the secondary endpoint with
`a mean gain of 10.9 ETDRS letters compared with 8.1 for
`monthly ranibizumab (P < 0.01) [42].
`In contrast to current anti-VEGF antibodies, which are
`rapidly cleared, the VEGF Trap-Eye is relatively degraded
`more slowly. Due to its high binding affinity and the ability to
`safely inject high doses into the eye, VEGF Trap-Eye may have
`longer duration of effect in the eye. Its adoption into clini-
`cal practice will depend on efficacy at 4- and 8-week intervals.
`If effective at 4- and 8-week intervals, VEGF Trap-Eye offers
`a competitive price advantage over ranibizumab and the op-
`portunity to significantly reduce treatment burden on pa-
`tients and physicians.
`
`3.5. Future Therapies for Age-Related Macular Degeneration.
`AMD is a complex mechanism in which a variety of medi-
`ators are likely to be involved. Any of these could serve as a
`potential target for the treatment of ocular neovasculariza-
`tion. In preclinical and clinical studies, several targets have
`already been evaluated. For example, treatment regimes of
`a drug blocking the transduction of the signaling cascade
`within the cell (tyrosine kinase) and one inhibiting the fur-
`ther intracellular production of VEGF (small interfering
`
`RNA) might achieve a better visual outcome [43]. Yet the
`efficacy, safety, treatment interval, and cost of these treat-
`ments remain undetermined. But the increasing number of
`drugs affecting neovascular growth and leakage by different
`mechanisms will potentially allow various combination stra-
`tegies.
`
`4. Conclusion
`
`Age-related macular degeneration (AMD) affects the many
`elderly population. Before the development of anti-VEGF,
`the diagnosis of neovascular AMD meant frequently loss of
`useful vision. But targeted anti-VEGF therapy has signifi-
`cantly improved the treatment of neovascular AMD.
`The appropriate method, dose, and types of combination
`therapy remain undetermined but randomized trials are cur-
`rently continuing and will provide critical insight into the cli-
`nical applicability of new regimens. It hopefully can help in
`the treatment of resistant CNV with longer duration and less
`frequency between treatments.
`
`Disclosure
`
`No author has financial or proprietary interests in any mate-
`rial or method mentioned.
`
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