Expert
`4
`Opinion
`>wn
`
`1.
`
`Introduction
`Background
`Conclusion
`
`Expert opinion
`
`j nfo rma
`healthcare
`
`Drug Evaluation
`VEGFTrap-Eye for the treatment
`of neovascular age-related
`macular degeneration
`
`James A Dixon,Scott CN Oliver’, Jeffrey L Olson & Naresh Mandava
`University ofColorado Denver, Rocky Mountain Lions Eye Institute, Department ofOphthalmology,
`1675 North Aurora Court, PO Box 6510, Mail Stop F-731, Aurora, CO 80045-2500, USA
`
`Background: Age-related macular degeneration (AMD) affects > 14 million
`individuals worldwide. Although 90% of patients with AMD have the dry
`form, neovascular AMD accounts for the vast majority of patients who
`develop legal blindness. Until recently, few treatment options existed for
`treatment of neovascular AMD. The advent of anti-VEGF therapy has sig-
`nificantly improved the safe and effective treatment of neovascular AMD.
`In addition to two anti-VEGF drugs currently in widespread use, ranibizumab
`and bevacizumab, a number of medications that interrupt angiogenesis are
`currently under investigation. One promising new drugis aflibercept (VEGF
`Trap-Eye), a fusion protein that blocksall isoforms of VEGF-A andplacental
`growth factors-1 and -2. Objective: To review the currentliterature and clini-
`cal trial data regarding VEGF Trap-Eye for the treatment of neovascular
`AMD. Methods: Literature review. Results/conclusion: VEGF Trap-Eye is a
`novel anti-VEGF therapy, with Phase | and II trial data indicating safety, toler-
`ability and efficacy for the treatment of neovascular AMD. TwoPhaseIII clini-
`cal trials (VIEW-1 and VIEW-2) comparing VEGF Trap-Eye to ranibizumab are
`currently continuing andwill provide vital insight into the clinical applicability
`of this drug.
`
`Keywords; aflibercept, AMD, angiogenesis, neovascularization, VEGR VEGF inhibition, VEGFTrap
`
`Expert Opin. Investig. Drugs (2009) 18(10):1573-1580
`
`1. Introduction
`
`Age-related macular degeneration (AMD)affects > 1.75 million individuals in the
`USanditis estimated that by 2020 this numberwill increase to almost 3 million |1).
`Worldwide, AMDis estimared to affect 14 million people {2}. While the vast major-
`ity of patients suffering from AMD have the dry form, ~ 80 — 90% of patients who
`develop severe vision loss have the neovascular or ‘wet’ formof the disease (3). Until
`recently, healthcare professionals had few options when it cameto treating neovascular
`AMD.For many years, subfoveal choroidal neovascularization (CNV) was treated
`with argonlaser therapy according to guidelines from the Macular Photocoagulation
`Study (4-12). This treatment, in the setting of subfoveal disease, was unsatisfactory for
`a numberof reasons,
`including the limited benefits in visual stabilization and the
`high risk of inducing central vision deficits (13). Treatment outcomes improved with
`the introduction of photodynamic therapy (PDT) which utilized a photosensitizing
`dye (verteporfin) to selectively target CNV. While more efficacious than previous
`treatments, patients receiving PDT failed to recover vision and continued to experi-
`ence a decline in visual acuity [14] and the treatment was of questionable cost
`effectiveness {15].
`largely
`inhibit VEGF has
`that
`The more recent development of agents
`supplanted these previous treatments. The pathogenesis of CNV in the setting of
`
`10.1517/13543780903201684 © 2009 Informa UK Ltd ISSN 1354-3784
`All rights reserved: reprsctaka tlwaiapiepart not permitted
`atthe NLM and may be
`Subject US Copyright Laws
`
`1573
`
`CELLTRION - EXHIBIT 1006
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`CELLTRION - EXHIBIT 1006
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`VEGF Trap-Eye
`
`AMDis complex; however, there is overwhelming evidence
`that VEGFis a predominant mediator in its genesis. VEGF
`receptors are expressed by a number of importantcell types
`in the eye,
`including vascular endothelial cells, choroidal
`fibroblasts, retinal pigmentepithelial cells and inflammatory
`cells attracted by hypoxia (16-19). Higher levels of VEGF
`expression have been demonstrated in animal models (20,21)
`and human studies of eyes with AMD 17,2224] and antago-
`nism of VEGF in both settings have definitively demon-
`strated inhibition ofneovascularization and vascular permeability.
`VEGF-A is the predominant member of the VEGF family
`targeted by drugs currently in widespread use; however,
`the
`group is also comprised of VEGF-B, VEGF-C, VEFG-D and
`placental growth factors-1 and -2.
`Systemic administration of bevacizumabis effective against
`neovascular AMD; however, systemic complications limit its
`use [25]. Accordingly, all anti-VEGF agents for neovascular
`AMD are administered only byintravitreal injection. The two
`largest studies examining anti-VEGFtherapy, the MARINA(26)
`and the ANCHOR(27,28) trials, were randomized, controlled,
`double-masked Phase III clinical trials that together evaluated
`monthly ranibizumab for the treatmentofall types of neovas-
`cular AMD.In both trials, 94% of patients with neovascular
`AMD lost fewer than 15 letters of visual acuity at 12 and
`24 months when treated with ranibizumab. Surprisingly, as
`many as 40% of patients in the two trials improved by > 15
`letters from baseline at 2 years. Ranibizumab received the
`FDA approval for all types of neovascular AMD in 2006.
`Based on theresults of these two landmark studies, anti-VEGF
`therapies for neovascular AMD have largely replaced previous
`treatment modalities.
`
`Macular Degeneration Treatment ‘Trial (CATT) is a 2-year,
`multi-centered, randomized clinical
`trial comparing ranibi-
`zumab and bevacizumab for neovascular AMD. Enrollment
`began in February 2008. Despite the off-label status of beva-
`cizumab,it continues to be a popular treatmentchoice in the
`US because of thesignificantly reduced price of treatment
`($ 50 — 100 for bevacizumab versus $ 2000 for ranibizumab
`(2008pricing)).
`the MARINA (26) and the
`As previously mentioned,
`ANCHOR(27,28) trials examined the efficacy of ranibizumab
`when administered monthly. The time and financial burden
`of monthly injections has led to the initiation of studies to
`examine the efficacy ofalternative dosing schedules. In the
`PIER study (30), patients initially received monthly injections
`of ranibizumab for 3 months followed by quarterly injec-
`tions. Although patient visual acuities actually improved at
`3 months, during the quarterly dosing segmentvisual acuity
`returned to baseline. The PrONTO study (29) looked at as
`needed (p.t.n.) dosing of ranibizumabafter three consecutive
`monthly doses. The need for further injections was made on
`the basis of recurrent CNV as evidenced by worsening
`vision, retinal thickening on ocular coherence tomography
`(OCT) or abnormalities on fluorescein angiogram (FA). At
`2 years of follow up, 78% of patients had maintained vision
`and vision had improved by > 3 lines in 43% of patients
`with an average of five injections a year. These later studies
`seem to indicate that quarterly dosing is associated with
`poorer outcomes but it may be possible to extend the time
`between injections if the patient is frequently monitored.
`However, even with the p.r.n. dosing utilized in the PONTO
`study, patients are still required to make monthlyvisits to the
`office with frequent and expensive testing.
`The development of new drugs for neovascular AMD has
`thus focused on both improving efficacy and extending
`2.1 Overview of the market (unmet needs,
`duration of action. Most new compounds in development
`are targeted toward inhibition of various steps in the VEGF
`competitor compounds/in clinical development)
`signaling pathway. There are a number of drugs in develop-
`By far the most commonly used anti-VEGF drugs currently
`in use for neovascular AMDare ranibizumab and bevaci-
`ment that inhibit the downstream tyrosine kinase cascade
`activated by the binding of VEGF with its
`receptor
`zumab. Pegaptanib was the first anti-VEGF drug approved
`by the FDAfor the treatment of AMD; however, it proved
`(VEGFR). Vatalanib is an oral formulation that binds to all
`three VEGFRs and has recently completed Phase I/II study
`less efficacious than current treatments [13] (possibly due to
`as adjuvant to PDT and ranibizumab [33]. Topical tyrosine
`its selective binding of VEGF-165) and is no longer widely
`kinase inhibitors currently undergoing Phase II clinical stud-
`used in most countries. Ranibizumab is the only drug in
`ies include pazopanib (34) and TG100801 (35). Another
`widespread use currently approved by the FDA for treat-
`approach utilizes siRNA to silence genes which express pro-
`mentof neovascular AMD andis byfar the most extensively
`teins involved in angiogenesis. Bevasiranib, an siRNA that
`studied (26,27,29,30]. It is a recombinant monoclonal antibody
`fragment with a high binding affinity for all
`isotypes of
`targets VEGF-A mRNA,showed encouraging Phase I and II
`VEGF-A. Bevacizumab, currently being used off-label for
`data, but the Phase III trial was halted in March 2009 for
`the treatment of AMD in the US,
`is a humanized whole
`projected failure to meet
`the primary end point
`(36). An
`extra antiangiogenic target being developed is pigment
`antibody to VEGF-A used in oncology regimens that also
`binds all
`isotypes of VEGF-A. Although ranibizumab has
`epithelium-derived factor (PEDF), a potent inhibitor of new
`vessel growth, AdGVPEDE11D uses an adenovector
`to
`been shown to have a higheraffinity for VEGF-A,it is not
`deliver the PEDF geneto targetcells, resulting in the local
`clear if ranibizumab has superior efficacy to bevacizumab.
`Retrospective and small randomized studies have suggested
`production of PEDFin the treated eye. AAGVPEDE11D
`similar efficacy profiles(31,32). The Comparisons ofAge-Related
`has recently completed Phase I clinical trials (37). Another
`1574
`
`2. Background
`
`Expert Opin. Investig. Drugs (2009) 18(10)
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`

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`Dixon,Oliver, Olson & Mandava
`
`recently discovered alternative pathway for decreasing angio-
`that end in proteolysis, which are presumed to be similar to
`pathways that metabolize antibodies. At very high doses, free
`genesis involves inhibition of nicotinic acetylcholine recep-
`aflibercept has a terminal half-life of ~ 17 days in the circu-
`tors. AT'G3 (mecamylamine), a topical formulation that
`lation. The half-life of human intravitreal doses is unknown.
`inhibits the nicotinic acetylcholine receptors, has shown
`promising results in animal and PhaseItrials and is currently
`Intravitreal primate doses of ranibizumab have a half-life of
`undergoing a Phase II study (25).
`~ 3 days [38]. At low blood levels, clearance offree afliber-
`ceptis rapid as a result of binding to VEGF with picomolar
`affinity (39).
`
`2.2 Introduction to compound
`VEGF Trap-Eye is a novel anti-VEGF drug currently in
`commercial development for the treatment of neovascular
`AMD by Regeneron Pharmaceuticals, Inc. (Tarrytown, NY,
`USA)in the US andin collaboration with Bayer HealthCare
`(Leverkusen, Germany)
`in global markets. Structurally,
`VEGFTrap-Eye is a fusion protein of key binding domains
`of human VEGFR-1 and -2 combined with a human IgG
`Fc fragment (Figure 1). Functionally, VEGF Trap-Eyeacts as
`a receptor decoy with high affinity for all VEGF isoforms,
`binding more tightly than their native receptors. Unlike
`anti-VEGF drugs currently in use, VEGF Trap-Eye is
`designed to inhibit placental growth factors-1 and -2 in
`addition to all isoforms of VEGF-A.
`
`2.3 Chemistry
`VEGFTrap-Eye andaflibercept (the oncology product) have
`the same molecular structure, but there are substantial dif-
`ferences between the preparation of the purified drug prod-
`uct and their formulations. Both aflibercept and VEGF
`Trap-Eye are manufactured in bioreactors from industry
`standard Chinese hamster ovary cells that overexpress the
`fusion protein. However, VEGF Trap-Eye undergoes further
`purification steps during manufacturing to minimize risk of
`irritation to the eye. VEGF Trap-Eye is also formulated with
`different buffers and at different concentrations (for buffers
`in common) suitable for
`the comfortable, non-irritating,
`direct injection into the eye.
`
`2.6 Clinical efficacy
`2.6.1 Phase |
`A Phase I, randomized, double-blind, placebo-controlled trial
`of intravenous aflibercept (oncology formulation) was com-
`pleted in 25 patients with AMD. Although systemic afliber-
`cept did demonstrate a dose-dependent decrease in retinal
`thickness,
`the study was halted due to concerns of dose-
`dependent toxicity when one patient developed hypertension
`and anotherproteinuria (40).
`Thesafety, tolerability and biological activity of intravitreal
`VEGF Trap-Eye in treatment of neovascular AMD was eval-
`uated in the two-part Clinical Evaluation of Anti-angiogenesis
`in the Retina-1 (CLEAR-IT-1) study (41). The first part was
`a sequential cohort dose-escalation study in which 21 patients
`were monitored for safety, changes in foveal
`thickness on
`OCT, best corrected visual acuity (BCVA) andlesion size on
`FA for 6 weeks. No adverse systemic or ocular events were
`noted and visual acuity remained stable or improved 2 3
`lines in 95% of patients with a mean increase in BCVA
`of 4.6 letters at 6 weeks [42]. Patients showed substantially
`decreased foveal thickness (41).
`In the second part, 30 patients received a single intravitreal
`injection of either 0.5 or 4 mg of VEGF Trap-Eye and were
`followed for 8 weeks. All patients were evaluated for their
`rates of retreatment, changes in BCVA, foveal thickness as
`well as change in total lesion size and area of CNV. Patients
`had ETDRS (Early Treatment of Diabetic Retinopathy
`Study) BCVAranging from 20/40 to 20/320 with any angio-
`graphic subtype of CNV at baseline. No serious adverse
`events or ocular
`inflammation was identified during the
`study. At 8 weeks, the mean decrease in retinal thickness in
`the low dose group was 63.7 ym compared to 175 pm for
`the high dose group. Of the first 24 patients to complete the
`study, 11 out of 12 patients in the 0.5 mg dose group
`required retreatment in a median of 64 days, compared with
`4 out of 12 in the 4 mg dose group who required retreatment
`in a median of 69 days (43).
`VEGF Trap-EFye has also undergone a small open-label
`safety study for the treatment of diabetic macular edema
`(DME) (44). The drug was administered as a single 4 mg
`intravitreal injection to five patients with longstanding dia-
`betes and several previous treatments for DME. Thesingle
`2.5 Pharmacokinetics and metabolism
`injection resulted in a median decrease of central macular
`Aflibercept is cleared from circulation through two pathways:
`thickness measured by OCT of 79 um. BCVA increased by
`9 letters at 4 weeks and regressed to a 3 letter improvement
`by binding to VEGF to form an inactive VEGF-aflibercept
`at 6 weeks,
`complex and by Fc-receptor or pinocytotic mediated pathways
`
`
`2.4 Pharmacodynamics
`Theaflibercept dose that is administered in oncology settings
`is either 4 mg/kg every 2 weeks or 6 mg/kg every 3 weeks,
`which corresponds to 2 mg/(kg week) with either schedule.
`The highest intravitreal dose being used in pivotal trials for
`VEGF Trap-Eye is 2 mg/month, which corresponds to at
`least a 280-fold lower potential systemic exposure than in the
`oncology setting. Early trials with aflibercept administered
`intravenously for AMD indicated that doses of 0.3 mg/kg
`(21 mg total) were inadequate to fully capture systemic
`VEGE. Thus,
`the low intravitreal dose of 2 mg allows for
`extended blocking of VEGF in the eye, but would be pre-
`dicted to give negligible systemic activity as it will be rapidly
`bound to VEGFand inactivated.
`
`Expert Opin. Investig. Drugs (2009) 18(10)
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`1575
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`retinal thickness versus baseline of 143 ym (p < 0.0001) in the
`2.0 mg group and 125 pm (p < 0.0001) in the 0.5 mg group
`at 52 wecks as measured by OCT (45).
`Patients in the three quarterly dosing groups also showed
`mean improvements in BCVA andretinal thickness; how-
`ever,
`they were generally not as profound as the monthly
`injection group [45].
`
`2.6.3 PhaseIII
`A two part Phase III trial of VEGF Trap-Eye was initiated in
`August of 2007. The first part, VIEW 1
`(VEGF Trap:
`Investigation of Efficacy and safety in Wet age-related macular
`degeneration) (46) will enroll ~ 1200 patients with neovascu-
`lar AMDin the US and Canada. This non-inferiority study
`will evaluate the safety and efficacy of intravitreal VEGF
`Trap-Eye at doses of 0.5 and 2.0 mg administered at 4-week
`dosing intervals and 2.0 mg at an 8 weck dosing interval
`(following three monthly doses), compared with 0.5 mg of
`ranibizumab administered every 4 weeks. After the first year
`of the study, patients will enter a second year of p.r.n. dosing
`evaluation. The VIEW 2 147) study has a similar study design
`and is currently enrolling patients in Europe, Asia Pacific,
`Japan and Latin America. In both trials, the primary out-
`comewill be the proportion of patients who maintain vision
`at week 52 (defined as a loss of < 15 ETDRS letters).
`
`VEGF Trap-Eye
`
`VEGFR1
`
`VEGFR2
`
`VEGF
`Trap
`
`Fe
`Kp
`VEGFR1 10-30pM
`VEGFR2 100-300pM
`
`
`
`@®
`
`@ @ € S
`
`@
`@
`
`
`
`| VEGFTrapEye~0.5pM
`
`Figure 1. Schematic diagram of VEGF Trap-Eye, a fusion
`protein of binding domains of VEGF receptors-1 and -2
`attached to the Fc fragment of human IgG.
`
`2.6.2 Phase Il
`randomized,
`(45) was a prospective,
`CLEAR-IT-2 trial
`2.7 Safety and tolerability
`multi-center, controlled dose- and interval-ranging Phase II
`Based on Phase II study data, VEGF Trap-Eye seems to be
`trial in which 157 patients were randomized to five dose
`generally well tolerated with no serious drug-related adverse
`groups and treated with VEGF Trap-Eye in one eye. The
`events, In the 157 patients enrolled in CLEAR-IT 2 cial,
`mean age of the group was 78.2 years andall angiographic
`there was one reported case of culture-negative endophthal-
`subtypes of CNV were represented at baseline. The mean
`mitis not deemed to be related to the study drug. There
`were also two deaths (one from pre-existing pulmonary
`ETDRS BCVAin letters at baseline was 56. Two groups
`received monthly dosesof either 0.5 or 2.0 mg for 12 weeks
`hypertension and one from pancreatic carcinoma) and one
`(at weeks 0, 4, 8 and 12) and three groups received quar-
`arterial thromboembolic event(in a patient with a history of
`terly doses of either 0.5, 2.0 or 4.0 mg for 12 weeks
`previous stroke) that occurred during the study period, but
`(at weeks 0 and 12). Following this fixed dosing period,
`no serious systemic adverse events were deemed related to
`patients were treated with the same dose of VEGF Trap-Eye
`VEGFTrap-Eye administration. The most common adverse
`on a p.tn.basis. Criteria for re-dosing included an increase in
`events reported in the study included conjunctival hemor-
`central retinal thickness of 2 100 pm by OCT,aloss of 2 5
`rhage (38.2%),
`transient
`increased intraocular pressure
`ETDRS letters in conjunction with recurrent fluid by OCT,
`(18.5%), refraction disorder (15.9%), retinal hemorrhage
`persistent fluid as indicated by OCT, new onset classic neo-
`(14.6%), subjective visual acuity loss
`(13.4%), vitreous
`vascularization, new or persistent leak on FA or new macular
`detachment (11.5%) and eye pain (9.6%) (45).
`subretinal hemorrhage.
`Patients initially treated with 2.0 or 0.5 mg of VEGF Tirap-
`Eye monthly achieved mean improvements of9.0 (p < 0.0001)
`and 5.4 (p < 0.085) ETDRS letters with 29 and 19% gaining,
`respectively, > 15 ETDRS letters at 52 weeks. During the
`p.r.n. dosing period, patients initially dosed on a 2.0 mg
`monthly schedule received an average of 1.6 more injections
`and those initially dosed on a 0.5 mg monthly schedule
`received an average of 2.5 injections. The median timeto first
`reinjection in all groups was 110 days and 19% ofpatients
`required no more injections at week 52. Patients in these two
`monthly dosing groups also displayed mean decreases in
`
`3. Conclusion
`
`Anti-VEGF therapy has vastly improved the treatment of
`neovascular AMDin terms of both safety and efficacy. The
`ANCHOR(26) and MARINA 127.28)
`trials have established
`ranibizumab as an effective therapy when dosed monthly. It
`has been shown tostabilize vision in 94% of patients and in
`almost 40% of patients vision will actually improve by 3 or
`more lines. However, the monthly dosing schedules used in
`these trials present a financial and time burden to patients
`and healthcare practitioners. The more recent PIER (30) and
`
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`Expert Opin. Investig. Drugs (2009) 18(10)
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`Dixon, Oliver, Olson & Mandava
`
`trials have shown that ranibizumab is less
`PrONTO 29)
`effective when dosed quarterly, but it may be possible to
`extend the time between injections when patients are
`followed closely with frequent examinations and ancillary
`testing. The most effective dosing regimen and monitoring
`program for anti-VEGF therapy has yet to be firmly estab-
`lished but new treatments are aimed at extending and
`improving on the efficacy of ranibizumab. VEGF Trap-Eye
`differs from established anti-VEGF therapies in its higher
`binding affinity for VEGF-A andits blockage ofplacental
`growth factors-1 and -2. Phase I data demonstrated accept-
`able safety and tolerability of VEGF Trap-Eye in the treat-
`ment of neovascular AMD.In Phase II study data, patients
`dosed in a similar fashion to the PrONTO trial demon-
`strated stabilization of their vision that was similar to previ-
`ous studies of ranibizumabat 1] year. Ofthe greatest interest,
`patients dosed at 2.0 mg during the initial monthly dosing
`period required 1.6 injections on average during the p.r.n.
`dosing phase. While this number is difficult
`to compare
`directly to the number of injections required during the
`p-t.n. phase of the PONTO ranibizumab study,it is prom-
`ising. A direct comparison ofthe efficacy of VEGF Trap-Eye
`versus ranibizumab will be possible with the completion of
`two Phase III trials, the VIEW-1 and -2 studies.
`
`encapsulated cell technology for sustained-release anti-VEGF
`therapy; no investigational drugs or devices have progressed
`yet to clinical trial enrollment.
`VEGFTrap-Eye represents the most promising anti-VEGF
`investigational drug that is currently in Phase III trial. VEGF
`Trap-Eye, a decoy VEGFreceptorprotein, bindsall isoforms
`of free VEGF with high affinity,
`in addition to placental
`growth factor. In contrast to current anti-VEGFantibodies,
`which are rapidly cleared, the VEGF—-VEGF Trap complex
`is relatively inert, and is degraded more slowly. Due toits
`high binding affinity and the ability to safely inject high
`doses into the eye, VEGF Trap-Eye may have longer dura-
`tion ofeffect in the eye. Two Phase III studies in wet AMD,
`VIEW 1 and VIEW 2,are currently under way and seek to
`compare monthly ranibizumab to monthly or bimonthly
`VEGF Trap-Eye.
`Data from the Phase II study with VEGF Trap-Eye were
`positive and the results from the non-inferiority Phase III
`trials will establish its efficacy versus ranibizumab. Its adop-
`tion into clinical practice will depend on efficacy at 4 and
`8 week intervals. If effective at 4 week intervals only, VEGF
`Trap-Eye will be adopted into clinical practice if it offers a
`competitive price advantage over ranibizumab.If effective at
`8 week intervals, VEGF Trap-Eye offers the opportunity to
`significantly reduce treatment burden on patients and physi-
`cians, and would probably find wide acceptance. The second
`p.tn. dosing stage of the Phase III trial will also provide
`insight into whether VEGF Trap-Eye offers longer duration
`The advent ofanti-VEGFtherapy for treatment of neovascu-
`of treatment effectiveness than ranibizumab.
`lar AMD has revolutionized therapy for a commonblinding
`Data from the VIEW-1 and VIEW-2trials will need to
`disease. Before the development of pegaptanib, ranibizumab
`be interpreted byclinicians in the context of emerging adju-
`and bevacizumab,
`the diagnosis of neovascular AMD por-
`tended a prognosis of nearly universal decline in vision, and
`vanttherapies that may extend the time between anti-VEGF
`therapy injections. Manyclinicians now treat patients with
`frequently loss of useful vision in the affected eye.
`Current treatment regimens with either ranibizumab or
`anti-VEGFtherapies in combination with verteporfin PDT.
`bevacizumab now afford stabilization of vision in > 90%
`Randomized, open-label studies and one large retrospective
`case series database seem to indicate lower retreatment rates
`of patients, with significant vision gain in one-third ofall
`patients treated. There have been no significant, proven
`and improved visual outcomes when compared with mono-
`therapy [52-55]. As a result, at least two prospective, randomized
`adverse systemic effects with the intraocular use of cither
`drug. However, limitations of current therapy include the
`trials are currently underway to further examine combination
`need for
`frequent
`intraocular
`injections,
`as often as
`verteporfin PDT and anti-VEGF treatments (56,57). An extra
`monthly, without a defined stopping point. Each injection
`combination treatment currently under study is the use of
`subjects patients to risks of cataract, intraocular inflamma-
`epiretinal brachytherapy with Strontium-90 combined with
`tion, retinal detachment and endophthalmitis. A signifi-
`bevacizumab. A recently published small pilot study showed
`good safety and efficacy with a single application ofepiretinal
`cant
`time and financial burden falls on patients during
`their treatment course.
`radiation and two bevacizumab injections after 12 months (58).
`Desirable attributes for emerging therapies for neovascular
`A larger, multi-center Phase III trial is underway(59).
`Anti-VEGF agents are currently only approved for the
`AMDinclude higher visual improvement rates and decreased
`treatment of exudative AMD. The multifactorial nature of
`dosing intervals. For other indications, time-release delivery
`methods have met with some success, including the follow-
`DME,including non-VEGF mediated causes such as peri-
`cyte and endothelial cell damage and tractional mecha-
`ing agents: intraocular steroids, including polymeric fluoci-
`nisms, has made treatmentofthis condition difficult using
`nolone and dexamethasone, lasting 3 years and 6 months,
`respectively [48-50], and for a single biologically active
`current modalities. Clinical studies are underway with anti-
`VEGFagents in DMEandretinal vein occlusion. VEGF
`cytokine, ciliary neurotrophic factor, which is released for a
`Trap-Eye is under Phase II
`investigation in DME and
`period greater than 1 year by encapsulated, bioengineered,
`PhaseIII investigation in central retinal vein occlusion. The
`implanted cells (51). While efforts are underway to develop
`1577
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`4. Expert opinion
`
`Expert Opin. Investig. Drugs (2009) 18(10)
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`

`VEGF Trap-Eye
`
`FDAapproval of VEGF Trap-Eye for these indications would
`significantly add to the ophthalmologists’ armamentarium for
`treatmentof retinal vascular disease.
`Eventually,
`injectable agents targeting the VEGF pathway
`may be supplanted by implantable devices that deliver polymer-
`bound drug or manufacture the protein im vivo. Further thera-
`pies for neovascular AMD such as targeted radiation may confer
`extra treatment benefit. In the meantime, VEGF Trap-Eye is a
`
`promising investigational drug that, if approved, will improve
`ophthalmologists’ ability to treat neovascular AMD.
`
`Declaration of interest
`
`investigator for Genentech and
`SCN Oliver is a clinical
`Alcon. JL Olson and N Mandava are clinical investigators
`for Genentech, Regeneron and Alcon.
`
`Bibliography
`Papers ofspecial note have been highlighted
`as either ofinterest (*) or ofconsiderable
`interest (**) to readers.
`
`1.
`
`Friedman DS, O’Colmain BJ, Munoz B,
`et al. Prevalence of age-related macular
`degeneration in the United States.
`Arch Ophthalmol 2004;122(4):564-72
`2. Magnitude and causes ofvisual impairment
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