Expert
`Opinion
`pwn
`
`Introduction
`Background
`Conclusion
`
`Expert opinion
`
`i nfo rma
`healthcare
`
`Drug Evaluation
`VEGF Trap-Eyefor 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, Departnent ofOphthalmology,
`1675 North Aurora Court, PO Box 6510, Matl 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 drug is aflibercept (VEGF
`Trap-Eye), a fusion protein that blocks all isoforms of VEGF-A and placental
`growth factors-1 and -2. Objective: To review the current literature 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. Two Phase III clini-
`cal trials (VIEW-1 and VIEW-2) comparing VEGF Trap-Eye to ranibizumab are
`currently continuing and will provide vital insight into the clinical applicability
`of this drug.
`
`Keywords:aflibercept, AMD,angiogenesis, neovasctilarization, VEGR VEGFinhibition, VEGFTrap
`
`Expert Opin. Investig. Drugs (2009) 18(10):1573-1580
`
`1. Introduction
`
`Age-related macular degeneration (AMD)affects > 1.75 million individuals in the
`US andit is estimated that by 2020 this number will increase to almost 3 million (11.
`Worldwide, AMD is estimated to affect 14 million people (2). While the vast major-
`ity of patients suffering from AMD have the dry form, ~ 80 — 90% ofpatients who
`develop severe vision loss have the neovascular or ‘wet’ form of the disease (3). Until
`recently, healthcare professionals had few options when it cameto treating neovascular
`AMD.For manyyears, 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 number of 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 treacment 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: OSHSgUGHTAWASAEBart not permitted
`atthe NLM and may be
`Subject US Copyright Laws
`
`1573
`
`
`
`
`Apotex Exhibit 1006
`Apotex Exhibit 1006
`Page 1 of 9
`Page 1 of 9
`
`

`

`VEGFTrap-Eye
`
`Macular Degeneration Treatment Trial (CATT) is a 2-year,
`multi-centered, randomized clinical
`trial comparing ranibi-
`zumab and bevacizumab for neovascular AMD.Enrollment
`
`AMDis complex; however, there is overwhelming evidence
`that VEGF is a predominant mediatorin its genesis. VEGF
`receptors are expressed by a number of importantcell types
`in the eye,
`including vascular endothelial cells, choroidal
`fibroblasts, retinal pigment epithelial 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
`AMDare administered only by intravitreal 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 ranibizumabfor 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% ofpatients 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 havelargely replaced previous
`treatment modalities.
`
`2. Background
`
`began in February 2008. Despite the off-label status of beva-
`cizumab,it continues to be a popular treatment choice in the
`US because of the significantly reduced price of treatment
`($ 50 — 100 for bevacizumab versus $ 2000 for ranibizumab
`(2008 pricing)).
`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 theinitiation of studies to
`examine the efficacy of alternative dosing schedules. In the
`PIER study(30), patients initially received monthlyinjections
`of ranibizumab for 3 months followed by quarterly injec-
`tions. Although patient visual acuities actually improved at
`3 months, during the quarterly dosing segment visual acuity
`returned to baseline. The PrONTO study (29) looked at as
`needed (p.r.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% ofpatients had maintained vision
`and vision had improved by > 3 lines in 43% ofpatients
`with an averageof 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 thep.r.n. dosing utilized in the PRONTO
`study, patients are still required to make monthly visits 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
`competitor compounds/in clinical development)
`are targeted toward inhibition of various steps in the VEGF
`signaling pathway. There are a number of drugs in develop-
`By far the most commonly used anti-VEGF drugs currently
`in use for neovascular AMD are ranibizumab and bevaci-
`ment that inhibit the downstream tyrosine kinase cascade
`activated by the binding of VEGF with its
`receptor
`zumab. Pegaptanib was thefirst anti-VEGF drug approved
`(VEGER). Vatalanib is an oral formulation that binds to all
`by the FDA for the treatment of AMD; however, it proved
`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 PhaseII 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-
`ment of neovascular AMDandis by far the most extensively
`teins involved in angiogenesis. Bevasiranib, an siRNA that
`studied (26,27,29,30]. It is a recombinant monoclonal antibody
`targets VEGF-A mRNA, showed encouraging Phase I and II
`fragment with a high binding affinity for all
`isotypes of
`data, but the Phase III trial was halted in March 2009 for
`VEGF-A. Bevacizumab, currently being used off-label 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. AdGVPEDF11D uses an adenovector
`to
`been shown to have a higher affinity for VEGF-A,it is not
`deliver the PEDF geneto target cells, resulting in the local
`clear if ranibizumab has superior efficacy to bevacizumab.
`Retrospective and small randomized studies have suggested
`production of PEDF in the treated eye. AAGVPEDE11D
`similar efficacy profiles (31,32). The ComparisonsofAge-Related
`has recently completed Phase I clinical trials (37). Another
`1574
`
`Expert Opin. Investig. Drugs (2009) 18(10)
`
`
`
`
`Apotex Exhibit 1006
`Apotex Exhibit 1006
`Page 2 of 9
`Page 2 of 9
`
`

`

`Dixon, Oliver, Olson & Mandava
`
`recently discovered alternative pathway for decreasing angio-
`genesis involves inhibition of nicotinic acetylcholine recep-
`tors. ATG3 (mecamylamine), a topical
`formulation that
`inhibits the nicotinic acetylcholine receptors, has shown
`promising results in animal and PhaseI trials and is currently
`Intravitreal primate doses of ranibizumab haveahalf-life of
`undergoing a Phase IT study [25].
`~ 3 days [38]. At low blood levels, clearance of free afliber-
`cept is rapid as a result of binding to VEGF with picomolar
`affinity [39].
`
`that end in proteolysis, which are presumed to be similar to
`pathways that metabolize antibodies. At very high doses, free
`aflibercept has a terminal half-life of ~ 17 days in the circu-
`lation. The half-life of human intravitreal doses is unknown.
`
`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,
`VEGFTiap-Eye is a fusion protein of key binding domains
`of human VEGFR-1 and -2 combined with a human IgG
`Fe fragment (Figure 1). Functionally, VEGF Trap-Eye acts 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.
`
`2.6 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-
`dependenttoxicity when one patient developed hypertension
`and another proteinuria [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 ofAnti-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 G weeks [42). Patients showed substantially
`decreased foveal thickness [41].
`In the second part, 30 patients received a single intravitreal
`injection ofeither 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) BCVA ranging 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 um compared to 175 pm for
`the high dose group. Ofthe 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-Eye 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
`thickness measured by OCT of 79 pm. BCVA increased by
`Afliberceptis cleared from circulation through two pathways:
`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 Fe-receptor or pinocytotic mediated pathways
`
`
`2.3 Chemistry
`VEGF Trap-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.
`
`2.4 Pharmacodynamics
`The aflibercept 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 VEGFandinactivated.
`
`Expert Opin. Investig. Drugs (2009) 18(10)
`
`1575
`
`
`
`
`Apotex Exhibit 1006
`Apotex Exhibit 1006
`Page 3 of 9
`Page 3 of 9
`
`

`

`VEGFTrap-Eye
`
`VEGFR1
`
`VEGFR2
`
`VEGF
`Trap
`
`@
`@
`@
`©
`&
`@
`@
`
`@
`@
`&
`¢
`&
`6
`@
`
`
`
`
`
`Fe
`"
`VEGFR1 10-30pM
`VEGFR2 100-300 pM
`
`
`
`
`|, VEGFTrapEye~0.5pM
`
`
`
`retinal thickness versus baseline of 143 pm (p < 0.0001) in the
`2.0 mg group and 125 pm (p < 0.0001) in the 0.5 mg group
`at 52 weeks 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 Phase lif
`A two part PhaseIII trial of VEGF Trap-Eye was initiated in
`August of 2007. The first part, VIEW 1
`(VEGF Trap:
`Investigation of Efficacy andsafety 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 week 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 [47] 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).
`
`3. Conclusion
`
`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 humanIgG.
`
`2.6.2 Phase Il
`randomized,
`a prospective,
`(45) was
`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-IT2trial,
`mean age of the group was 78.2 years and all 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
`ETDRS BCVA in letters at baseline was 56. Two groups
`were also two deaths (one from pre-existing pulmonary
`received monthly dosesofeither 0.5 or 2.0 mg for 12 weeks
`hypertension and one from pancteatic 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
`VEGF Trap-Eye administration. The most common adverse
`patients were treated with the same dose of VEGF Trap-Eye
`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 > 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 onsetclassic 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 Trap-
`Eye monthly achieved mean improvements of 9.0 (p < 0.0001)
`and 5.4 (p < 0.085) ET'DRS letters with 29 and 19% gaining,
`Anti-VEGF therapy has vastly improved the treatment of
`respectively, 2 15 ETDRS letters at 52 weeks. During the
`neovascular AMD in terms of both safety and efficacy. The
`ANCHOR [26] and MARINA [27,28]
`trials have established
`p.tn. dosing period, patients initially dosed on a 2.0 mg
`monthly schedule received an average of 1.6 more injections
`ranibizumab as an effective therapy when dosed monthly. It
`has been shown to stabilize vision in 94% of patients and in
`and those initially dosed on a 0.5 mg monthly schedule
`almost 40% of patients vision will actually improve by 3 or
`received an average of 2.5 injections. The median timetofirst
`reinjection in all groups was 110 days and 19% ofpatients
`more lines. However, the monthly dosing schedules used in
`required no moreinjections at week 52. Patients in these two
`these trials present a financial and time burden to patients
`monthly dosing groups also displayed mean decreases
`in
`and healthcare practitioners. The more recent PIER [30] and
`1576
`
`Expert Opin. Investig. Drugs (2009) 18(10)
`
`
`
`
`Apotex Exhibit 1006
`Apotex Exhibit 1006
`Page 4 of 9
`Page 4 of 9
`
`

`

`PrONTO 29 trials have shown that ranibizumab is less
`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 and its blockage of placental
`growth factors-1 and -2. Phase I daca 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 ranibizumab at 1 year. Of the greatest interest,
`patients dosed at 2.0 mg during theinitial monthly dosing
`period required 1.6 injections on average during the p.rn.
`dosing phase. While this number is difficult
`to compare
`directly to the number of injections required during the
`p-tn. phase of the PRONTO ranibizumabstudy, it is prom-
`ising. A direct comparison ofthe efficacy of VEGF Trap-Eye
`versus ranibizumab will be possible with the completion of
`two PhaseIII trials, the VIEW-1 and -2 studies.
`
`
`4. Expert opinion
`
`The advent of anti-VEGF therapy for treatment of neovascu-
`lar AMD has revolutionized therapy for a commonblinding
`disease. Before the development of pegaptanib, ranibizumab
`and bevacizumab,
`the diagnosis of neovascular AMD por-
`tended a prognosis of nearly universal decline in vision, and
`frequently loss of useful vision in the affected eye.
`Current treatment regimens with either ranibizumab or
`bevacizumab now afford stabilization of vision in > 90%
`of patients, with significant vision gain in one-third ofall
`patients treated. There have been no significant, proven
`adverse systemic effects with the intraocular use of either
`drug. However, limitations of current therapy include the
`need for
`frequent
`intraocular
`injections,
`as often as
`monthly, without a defined stopping point. Each injection
`subjects patients to risks of cataract, intraocular inflamma-
`tion, retinal detachment and endophthalmitis. A signifi-
`cant time and financial burden falls on patients during
`their treatment course.
`
`Dixon, Oliver, Olson & Mandava
`
`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 drugthat is currently in Phase IIItrial. VEGF
`Trap-Eye, a decoy VEGFreceptor protein, 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 to its
`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
`VEGFTrap-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-t.n. dosing stage of the Phase III trial will also provide
`insight into whether VEGF Trap-Eye offers longer duration
`of treatmenteffectiveness than ranibizumab.
`Data from the VIEW-1 and VIEW-2 trials will need to
`be interpreted by clinicians in the context of emerging adju-
`vant therapies that may extend the time between anti-VEGF
`therapy injections. Many clinicians now treat patients with
`anti-VEGFtherapies in combination with verteporfin PDT.
`Randomized, open-label studies and one large retrospective
`case series database seem to indicate lower retreatment rates
`and improved visual outcomes when compared with mono-
`therapy [52-55]. As a result, at least two prospective, randomized
`trials are currently underway to further examine combination
`verteporfin PDT and anti-VEGF treatments [56.57]. An extra
`combination treatment currently under study is the use of
`epiretinal brachytherapy with Strontium-90 combined with
`bevacizumab. A recently published small pilot study showed
`goodsafety and efficacy with a single application of epiretinal
`radiation and two bevacizumabinjections after 12 months (58).
`A larger, multi-center Phase III trial is underway [59].
`Anti-VEGF agents are currently only approved for the
`treatment of exudative AMD. The multifactorial nature of
`
`Desirable attributes for emerging therapies for neovascular
`AMDinclude highervisual improvementrates and decreased
`dosing intervals. For other indications, time-release delivery
`DME,including non-VEGF mediated causes such as peri-
`methods have met with some success, including the follow-
`cyte and endothelial cell damage and tractional mecha-
`ing agents: intraocular steroids, including polymeric fluoci-
`nisms, has made treatment ofthis condition difficult using
`nolone and dexamethasone, lasting 3 years and 6 months,
`current modalities. Clinical studies are underway with anti-
`respectively (48-50), and for
`a single biologically active
`VEGF agents 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,
`Phase III investigation in central retinal vein occlusion. The
`implanted cells [51]. While efforts are underway to develop
`1577
`
`Expert Opin. Investig. Drugs (2009) 18(10)
`
`
`
`
`Apotex Exhibit 1006
`Apotex Exhibit 1006
`Page 5 of 9
`Page 5 of 9
`
`

`

`VEGFTrap-Eye
`
`FDAapproval of VEGF Trap-Eye for these indications would
`significantly add to the ophthalmologists’ armamentarium for
`treatment of retinal vascular disease.
`
`injectable agents targeting the VEGF pathway
`Eventually,
`may be supplanted by implantable devices that deliver polymer-
`bound drug or manufacture the protein # vivo. Further thera-
`pies for neovascular AMD such as targeted radiation may confer
`extra treatment benefit. In the meantime, VEGF Trap-Eyeis 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 Mandavaare clinical investigators
`for Genentech, Regeneron and Alcon.
`
`Bibliography
`Papetsofspecial note have been highlighted
`as either ofinterest (°} or of considerable
`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
`[fact sheet no. 282). Available from:
`hetp://www.who.int/mediacentre/factsheets/
`fs282/en/ [Accessed 1 Sep 2008]
`Congdon N, O’Colmain B, Klaver CC,
`et al. Causes andprevalence ofvisual
`impairment amongadults in the
`United States. Arch Ophthalmol
`20043122(4):477-85
`
`3.
`
`4,
`
`*
`
`5.
`
`Argon laser photocoagulation for
`neovascular maculopathy. Three-year results
`from randomizedclinical trials. Macular
`Photocoagulation Study Group.
`Arch Ophthalmol 1986;104(5):694-701
` Aseminal paper in its era, regarding the
`use oflaser photocoagulation for
`neovascular AMD.
`
`Kryptonlaser photocoagulation for
`neovascular lesions of age-related macular
`degeneration. Results of a randomized
`clinical trial. Macular Photocoagulation
`Study Group. Arch Ophthalmol
`19903108(6):816-24
`
`6.
`
`7.
`
`8.
`
` Subfoveal neovascular lesions in age-related
`macular degeneration. Guidelines for
`evaluation and treatmentin the macular
`photocoagulation study. Macular
`Photocoagulation Study Group.
`Arch Ophthalmol 1991;109(9):1242-57
`Laser photocoagulation of subfoveal
`recurrent neovascularlesions in age-related
`macular degeneration. Results of a
`randomized dinical trial. Macular
`Photocoagulation Study Group.
`Arch Ophthalmol 1991;109(9);1232-41
`Laser photocoagulation of subfoveal
`Moshfeghi AA, Rosenfeld PJ, Puliafito CA,
`neovascular lesions in age-related macular
`et al. Systemic bevacizumab (Avastin)
`degeneration. Results of a randomized
`therapy for neovascular age-related macular
`clinical trial. Macular Photocoagulation
`
`
`Study Group. Arch Ophthalmol
`1991;109(9):1220-31
`Laser photocoagulation of subfoveal
`neovascular lesions of age-related macular
`degeneration. Updated findings from two
`clinical trials. Macular Photocoagulation
`Study Group. Arch Ophthalmol
`19933111(9):1200-9
`
`Laser photocoagulation for juxtafoveal
`choroidal neovascularization. Five-year
`results from randomizedclinical trials.
`Macular Photocoagulation Study Group.
`Arch Ophthalmol 1994;112(4):500-9
`Occult choroidal neovascularization.
`Influence on visual outcomein patients
`with age-related macular degeneration.
`Macular Photocoagulation Study Group.
`Arch Ophthalmol 1996;114(4):400-12
`Fine SL, Hawkins B, Maguire M. Macular
`photocoagulation study. Arch Ophthalmol
`19845102(11):1583
`D’Amico DJ, Masonson HN,Patel M,etal.
`Pegaptanib sodium for neovascular
`age-related macular degeneration:
`two-year safety results of the two
`prospective, multicenter, controlled
`dinical trials. Ophthalmology
`2.00631 13(6):992-1001, e1006
`The first anti-VEGF agent proven
`to be effective for neovascular AMD
`‘was pegaptanib.
`Kaiser PK. Verteporfin therapy of
`subfoveal choroidal neovascularization in
`age-related macular degeneration: 5-year
`results of two randomized clinical trials
`with an open4abel extension: TAP report
`no. 8. Graefes Arch Clin Exp Ophthalmol
`2006;244(9):1132-42
`Wormald R, Evans J, Smeeth L, Henshaw K.
`Photodynamic therapy for neovascular
`age-related macular degeneration.
`Cochrane Database Syst Rev
`2007;(3):C1D002030
`Kvanta A. Ocular angiogenesis: the role of
`growth factors. Acta Ophthalmol Scand
`2006;84(3):282-8
`
`10,
`
`13.
`
`14,
`
`15.
`
`16.
`
`Shima DT, Adamis AP, Ferrara N,etal.
`Hypoxic induction of endothelial cell
`growth factorsin retinal cells: identification
`and characterization of vascular endothelial
`growth factor (VEGF)as the mitogen.
`Mol Med 199551(2):182-93
`Vinores SA, Xiao WH,Aslam §,etal.
`Implication of the hypoxia response element
`of the Vegfpromoter in mouse models of
`retinal and choroidal neovascularization,
`but notretinal vascular development.
`J Cell Physiol 2006;206(3):749-58
`Zhou J, Pham L, Zhang N,etal.
`Neutrophils promote experimental
`choroidal neovascularization. Mol Vis
`2005311:414-24
`Ishibashi T, Hata Y, Yoshikawa H,et al.
`Expression of vascular endothelial
`growth factor in experimental
`choroidal neovascularization.
`Graefes Arch Clin Exp Ophthalmol
`1997;235(3):159-67
`Krzystolik MG,Afshari MA, Adamis AP,
`et al. Prevention of experimental choroidal
`neovascularization with intravitreal
`anti-vascular endothelial growth factor
`antibody fragment. Arch Ophthalmol
`20023;120(3):338-46
`Frank RN, Amin RH,Eliott D, et al. Basic
`fibroblast growth facter and vascular
`endothelial growth factor are present in
`epiretinal and choroidal neovascular
`membranes. Am J Ophthalmol
`1996;122(3):393-403
`Kliffen M, Sharma HS, Mooy CM,etal.
`Increased expression of angiogenic growth
`factors in age-related maculopathy.
`Br J Ophthalmol 1997;81(2):154-62
`Kvanta A, Algvere PV, Berglin L, Seregard 8.
`Subfoveal fibrovascular membranesin
`age-related macular degeneration express
`vascular endothelial growth factor.
`Tnvest OphthalmolVis Sci
`1996;37(9):1929-34
`
`T?.
`
`18.
`
`19.
`
`20.
`
`21.
`
`22,
`
`23.
`
`24.
`
`25.
`
`1578
`
`Expert Opin. Investig. Drugs (2009) 18(10)
`
`
`
`
`Apotex Exhibit 1006
`Apotex Exhibit 1006
`Page 6 of 9
`Page 6 of 9
`
`

`

`Hariprasad S. Fluorescein angiographic
`Neovascularization Secondary to
`and OCToutcomesof a phaseI,
`Age-Related Macular Degeneration (AMD)
`dose-esca