Antivascular endothelial growth factor therapy for neovascular
`age-related macular degeneration
`Thomas A. Ciullaa and Philip J. Rosenfeldb
`
`aVitreoretinal Service, Midwest Eye Institute,
`Indianapolis, Indiana and bDepartment of
`Ophthalmology, Bascom Palmer Eye Institute,
`University of Miami Miller School of Medicine, Miami,
`Florida, USA
`
`Correspondence to Thomas A. Ciulla, MD, Vitreoretinal
`Service, Midwest Eye Institute, 201 Pennsylvania
`Parkway, Indianapolis, IN 46280, USA
`Tel: +1 317 506 0334; fax: +1 317 817 1898;
`e-mail: thomasciulla@yahoo.com
`
`Current Opinion in Ophthalmology 2009,
`20:158–165
`
`Purpose of review
`The most important recent advance in the treatment of neovascular age-related macular
`degeneration (AMD) is the development of antivascular endothelial growth factor
`(anti-VEGF) therapeutic agents that preserve and improve visual acuity by arresting
`choroidal neovascular growth and reducing vascular permeability. This review describes
`the current literature on the use of this therapeutic approach in the management of
`neovascular AMD.
`Recent findings
`Two anti-VEGF agents, pegaptanib sodium and ranibizumab, are currently approved by
`the United States Food and Drug Administration for the treatment of neovascular AMD.
`In addition, off-label use of a third anti-VEGF agent, bevacizumab, as a treatment option
`for neovascular AMD has become common worldwide. Other anti-VEGF agent
`strategies that have shown efficacy include small interfering RNA agents to silence the
`VEGF gene and receptor and the fusion protein VEGF trap.
`Summary
`The accumulation of preclinical and clinical evidence implicating VEGF-A in the
`pathogenesis of neovascular AMD has provided a strong rationale for the development of
`anti-VEGF agents for this disease. Anti-VEGF therapies have been used successfully in
`the clinic, encouraging their use in the treatment of other neovascular eye diseases.
`
`Keywords
`bevacizumab, macular degeneration, neovascularization, pegaptanib sodium,
`ranibizumab
`
`Curr Opin Ophthalmol 20:158–165
`ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
`1040-8738
`
`Introduction
`Ocular diseases involving neovascularization, including
`neovascular age-related macular degeneration (AMD),
`diabetic retinopathy, diabetic macular edema (DME),
`and retinal vein occlusion (RVO), are the primary causes
`of clinically significant vision loss in the developed world
`[1–3], particularly among the working and elderly popu-
`lations. In the United States, neovascular AMD affects
`1.75 million individuals aged more than 40 years and is the
`leading cause of blindness in those over 65 years [4]. It is
`characterized by the growth of choroidal blood vessels
`through Bruch’s membrane into the subretinal pigment
`epithelial (RPE) space, usually leading to accumulation of
`fluid in the sub-RPE space and detachment of the RPE [5].
`
`Inhibition of angiogenesis
`Normal and pathologic angiogenesis is a complex balance
`of positive and negative regulators, and vascular endo-
`thelial growth factor-A (VEGF-A; also referred to as
`VEGF) is one of the most important positive regulators
`of angiogenesis [6] and vascular permeability [7,8].
`
`VEGF-A has been implicated in the pathogenesis of a
`variety of disorders including neovascular AMD, prolif-
`erative diabetic retinopathy (PDR), and other neovascu-
`lar eye diseases, as well as in tumorigenesis. Therefore,
`VEGF inhibition may be expected to lead not only to
`inhibition of further angiogenesis but also to regression of
`newly formed blood vessels.
`
`Therapeutic agents that inhibit VEGF-A – pegaptanib
`sodium (Macugen; OSI/Eyetech, Inc., Melville, New
`York, USA) and ranibizumab (Lucentis; Genentech,
`Inc., South San Francisco, California, USA) – are Food
`and Drug Administration (FDA) approved for the treat-
`ment of choroidal neovascularization (CNV) secondary to
`AMD. Of the two agents, ranibizumab offers substantial
`clinical benefit in neovascular AMD. A third anti-VEGF
`agent, bevacizumab, has been used off label for neovas-
`cular AMD and other exudative retinal diseases. These
`anti-VEGF agents, as well as others in clinical develop-
`ment, have great potential to treat eye diseases character-
`ized by neovascularization. Here, we present an overview
`of the current knowledge on anti-VEGF therapies in
`neovascular AMD.
`
`1040-8738 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
`
`DOI:10.1097/ICU.0b013e32832d25b3
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`CELLTRION - EXHIBIT 1074
`
`

`

`Antivascular endothelial growth factor therapy Ciulla and Rosenfeld 159
`
`Vascular endothelial growth factor-A in
`vascular permeability, inflammation, and
`ocular disease
`In the various pathologic conditions in which it is impli-
`cated, overexpression of VEGF-A has been found to
`promote angiogenesis by inducing endothelial cell pro-
`liferation, migration, and survival [9].
`
`Vascular endothelial growth factor-A isoforms
`VEGF-A is a member of the VEGF family of growth
`factors that also includes VEGF-B, VEGF-C, VEGF-D,
`and placental growth factor (PlGF), which have dif-
`ferent binding affinities for the three VEGF receptors,
`VEGFR1, VEGFR2, and VEGFR3 [10,11]. VEGF-A also
`binds to neuropilin-1, a membrane protein on developing
`neurons that plays a role in embryonic neural blood vessel
`formation as well as neural tip guidance [12,13]. Alterna-
`tive RNA splicing of the human VEGF-A gene results in
`the formation of four major isoforms (VEGF121, VEGF165,
`VEGF189, and VEGF206) and at least five minor isoforms
`(VEGF145, VEGF148, VEGF162, VEGF165b, and VEGF183)
`[14–16]. VEGF165 and VEGF121 have been suggested to
`have the strongest mitogenic and vascular permeability-
`promoting potential [17–19].
`
`Vascular endothelial growth factor-A and vascular
`permeability
`In addition to promoting angiogenesis, VEGF-A also
`affects vascular permeability by inducing formation of
`pores in the vascular endothelial cells [20] and by dis-
`rupting the intercellular junction between these cells
`[21]. The angiogenic and vascular permeability effects of
`VEGF-A on the endothelium are mediated by the trans-
`membrane receptor VEGFR2 [flk-1/kinase insert
`domain receptor (KDR)] and involve diverse down-
`stream signaling partners, such as Src family kinases
`and/or protein tyrosine phosphatases, disrupting and
`uncoupling the endothelial cell– cell
`junctions [22].
`This, in turn, leads to extravasation of fluid, proteins,
`and circulating cells [22]. In neovascular ocular diseases,
`the edema from new, permeable blood vessels can dis-
`rupt the retinal anatomy and separate the retina from
`underlying structures, potentially causing severe vision
`loss.
`
`VEGF-A, promotion of local angiogenesis, and increasing
`the severity of inflammation.
`
`Vascular endothelial growth factor-A and neovascular
`ocular diseases
`Evidence from preclinical and clinical studies implicates
`VEGF-A in the pathogenesis of neovascular eye diseases.
`In streptozotocin-induced diabetic rats, VEGF-A gene
`expression was significantly increased in the ganglion
`and inner nuclear retinal cell layers compared with con-
`trol rats [23]. Laser-induced RVO in rabbits [24] and
`monkeys [25] also led to increased VEGF-A mRNA
`expression; VEGF-A protein expression was localized
`to ischemic regions of the retinal layers affected by laser
`treatment [24]. Furthermore, VEGF-A inhibition pre-
`vented retinal neovascularization in an ischemia-induced
`mouse model [26] and iris neovascularization in a monkey
`model [27]. VEGF-A inhibition also prevented laser-
`induced CNV in monkeys or shortened its duration [28].
`
`In clinical studies, increased VEGF-A expression was
`found in the RPE [29], subfoveal fibroblasts [30], and
`surgically excised CNV membranes [31] from eyes of
`neovascular AMD patients. VEGF-A is also over-
`expressed in the aqueous and vitreous fluid of patients
`with subretinal neovascularization, diabetic retinopathy,
`central RVO (CRVO), branch RVO (BRVO), iris neo-
`vascularization, retinal detachment, and retinopathy of
`prematurity (ROP) [32–35] and in all retinal nuclear
`layers of ischemic CRVO eyes [36]. The consistent
`association of pathologic ocular neovascularization with
`increased VEGF-A expression provides
`a
`strong
`rationale for exploring the therapeutic potential of anti-
`VEGF agents in neovascular AMD.
`
`Genetic case–control studies [37] have shown that the
`VEGF gene may influence an individual’s tendency to
`develop AMD. Analyses of single nucleotide polymorph-
`isms (SNPs) in the VEGF-A promoter and gene have
`associated specific VEGF-A haplotypes with neovascular
`AMD [38]. In particular, the VEGF SNP 936C/T [when
`present with the complement factor H (CFH) Y402H]
`has been associated with an increased risk of developing
`wet AMD [39].
`
`Vascular endothelial growth factor-A and inflammation
`Chronic inflammation occurs in response to infection,
`autoimmune disease, injury, tumors, and other diseases
`and involves the release of various cytokines at specific
`sites in the body by inflammatory cells such as T cells,
`B cells, macrophages, natural killer cells, neutrophils, and
`granulocytes. The proinflammatory cytokines include
`tumor necrosis factor (TNF)-a, interleukin (IL)-6, IL-8,
`and IL-1a, IL-1b, and oncostatin M, which participate
`in a cascade of events leading to increased levels of
`
`Antivascular endothelial growth factor
`therapies in neovascular age-related macular
`degeneration
`Intravitreal pegaptanib sodium, an RNA aptamer that
`targets VEGF165 and possibly its larger isoforms, and
`intravitreal ranibizumab, a mAb antigen-binding frag-
`ment that targets all VEGF isoforms and their bioactive
`cleavage products, received FDA approval for the treat-
`ment of neovascular AMD in 2004 and 2006, respectively
`(Table 1). Bevacizumab (Avastin; Genentech, Inc.), a
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`

`160 Retinal, vitreous and macular disorders
`
`Table 1 Antivascular endothelial growth factor agents currently available or in development for the treatment of neovascular
`age-related macular degeneration
`
`Agent
`
`Class
`
`Molecular target
`
`Drug development stage
`
`Manufacturer
`
`Pegaptanib (Macugen)
`Ranibizumab (Lucentis)
`Bevacizumab (Avastin)
`
`Aptamer
`mAb fragment
`mAb
`
`VEGF trap
`
`Triamcinolone acetonide
`(Kenalog-40)
`
`Decoy receptor
`
`Corticosteroid
`
`Bevasiranib (Cand5)
`AGN211745 (Sirna-027)
`ATG003
`
`siRNA
`siRNA
`Topical mecamylamine
`
`Quark
`
`siRNA
`
`VEGF165 isoform
`All VEGF-A isoforms
`All VEGF-A isoforms
`
`All VEGF-A isoforms,
`VEGF-B, and PlGF
`Antiangiogenic; specific
`targets unknown,
`possibly VEGF and
`others
`VEGF-A mRNA
`VEGF-R1 mRNA
`Antiangiogenic; a3b4
`nicotinic Ach receptor
`
`JSM6427
`
`Small molecule integrin
`a5b1-antagonist
`
`Antiangiogenic;
`integrin a5b1
`
`FDA approved
`FDA approved
`Various international
`phase III trials
`Phase III
`
`OSI/Eyetech
`Genentech
`Genentecha
`
`Regeneron
`
`Phase III
`
`Bristol-Myers Squibb
`
`Phase III
`Phase II
`Phase II
`
`Phase I, II
`
`Phase I
`
`OPKO Health
`Allergan
`CoMentis, South San
`Francisco, California, USA
`Quark Inc., Denver, Colorado,
`USA; Pfizer, New York,
`New York, USA
`Jerini AG, Berlin, Germany
`
`Ach, acetylcholine; FDA, Food and Drug Administration; PlGF, placental growth factor; siRNA, small interfering RNA; VEGF, vascular endothelial
`growth factor; VEGF-R1, vascular endothelial growth factor receptor 1.
`a Investigations of the clinical use of bevacizumab in ocular diseases are independent of Genentech.
`
`full-length humanized mAb, was derived from the same
`murine anti-VEGF mAb as ranibizumab. Similar to rani-
`bizumab, bevacizumab targets all isoforms and bioactive
`cleavage products of VEGF-A. Bevacizumab is FDA
`approved for use in combination with chemotherapy
`for the systemic treatment of metastatic colorectal, lung,
`and breast cancer. Systemic and intravitreal bevacizumab
`have also recently been used off label in neovascular
`AMD and other exudative eye diseases. The successful
`treatment of neovascular AMD with these agents as
`presented in the overview below serves as a proof-of-
`concept for the clinical use of anti-VEGF in neovascular
`eye diseases.
`
`Pegaptanib sodium
`The landmark phase III VEGF Inhibition Study In
`Ocular Neovascularization (VISION)
`clinical
`trials
`showed that intravitreal pegaptanib sodium slows visual
`loss in neovascular AMD, with 70% of treated patients
`losing more than 15 letters of visual acuity compared with
`55% of controls [40,41]. Moreover, 6% of pegaptanib
`sodium-treated patients gained at least 15 letters com-
`pared with 2% of the patients in the control group [40].
`Fluorescein angiography at 30 and 54 weeks showed that
`the pegaptanib-treated group had a significant reduction
`(P < 0.01) in the rate of growth of the total area of their
`CNV lesions and the severity of leakage compared with
`the control group [40].
`
`Ranibizumab
`The pivotal phase III Minimally Classic/Occult Trial of
`the Anti-VEGF Antibody Ranibizumab in the treatment
`of Neovascular AMD (MARINA) [42] and Anti-VEGF
`
`Antibody for the Treatment of Predominantly Classic
`CNV in AMD (ANCHOR) [43] trials established ranibi-
`zumab as the first FDA-approved agent that prevents
`vision loss and improves vision in a substantial proportion
`of patients with all subtypes of neovascular AMD. At 12
`and 24 months in the MARINA trial, 90–95% of patients
`treated with 0.3 or 0.5 mg ranibizumab lost less than 15
`letters of visual acuity compared with 53–64% of control
`patients; also at 12 and 24 months, 25–34% of ranibizu-
`mab-treated patients had gained at least 15 letters of
`visual acuity compared with 4–5% of control patients
`[42]. The ANCHOR trial, which compared ranibizumab
`with verteporfin photodynamic therapy (PDT), had
`similar findings at 12 and 24 months: 90–96% of the
`ranibizumab-treated versus 64–66% of the PDT-treated
`patients lost less than 15 letters of visual acuity, whereas
`34–41% of the ranibizumab group versus 6% of the PDT
`group gained more than 15 letters [43] (Brown DM,
`personal communication).
`
`Analyses of fluorescein angiography in both the MAR-
`INA and ANCHOR studies also revealed statistically
`significant decreases in mean area and total CNV, leakage
`from CNV, serous sensory retinal detachment (SSRD),
`and disciform scar/subretinal fibrosis at both 12 and
`24 months after ranibizumab treatment [43,44]. A retro-
`spective analysis of optical coherence tomography
`(OCT)/fluorescein angiography prospectively collected
`in a subset of 46 patients from the MARINA study
`showed a statistically significant decrease at 12 months
`(final OCT) in mean foveal center point thickness of
`the ranibizumab-treated group compared with the sham-
`treated group [44].
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`

`Antivascular endothelial growth factor therapy Ciulla and Rosenfeld 161
`
`Clinical studies such as Prospective OCT Imaging
`of Patients With Neovascular AMD Treated With
`Intraocular Lucentis (PrONTO) and Phase IIIb, Multi-
`center, Randomized, Double-Masked, Sham Injection–
`Controlled Study of the Efficacy and Safety of Ranibi-
`zumab in Patients with Subfoveal CNV with or without
`Classic CNV Secondary to AMD (PIER) have investi-
`gated alternative,
`less-frequent
`ranibizumab dosing
`strategies in an attempt to lower rates of potential treat-
`ment-related adverse events. The 2-year phase I/II open-
`label PrONTO trial evaluated an OCT-guided, variable-
`dosing regimen of monthly intravitreal
`ranibizumab
`(0.5 mg) for 3 months followed by intravitreal ranibizu-
`mab as needed based on OCT-defined retreatment
`criteria in 40 patients with all subtypes of neovascular
`AMD [45]. At 1 year, 95% (38/40) of treated patients had
`lost less than 15 letters of visual acuity; 35% (14/40) of
`treated patients had gained at least 15 letters of visual
`acuity, and the mean change in visual acuity was þ9.3
`letters for treated patients. The mean number of injec-
`tions for the first year was 5.6 (range 3–13); the most
`common reason for reinjection was a loss of at least five
`letters of visual acuity in association with presence of
`macular fluid. The earliest signs of recurrent fluid in the
`macula following cessation of treatment were OCT
`detectable. At 12 months after treatment, the mean
`central retinal thickness (CRT) as measured by OCT
`decreased by 178 mm (P < 0.001). At 24 months, the
`results were virtually identical [a mean visual acuity
`change of þ11.1 letters, a mean CRT/OCT decrease
`of 215 mm, and a mean number of injections of 10 (range
`3–25) over 2 years] (Rosenfeld PJ, personal communi-
`cation). The PrONTO trial showed that in future clinical
`trials it may be possible to use qualitative OCT to
`determine the basis for retreatment.
`The 2-year PIER trial [46] examined the efficacy and
`safety of 0.3 or 0.5 mg ranibizumab monthly for 3 months
`followed by quarterly dosing. The first-year data showed
`that a significantly greater proportion of patients receiv-
`ing ranibizumab lost less than 15 letters of visual acuity
`(83.3% of patients in the 0.3 mg group and 90.2% of
`patients in the 0.5 mg group) compared with 49.2% of
`patients in the sham treatment group (P < 0.0001 for each
`dose level versus sham). However, there was no signifi-
`cant difference in the proportion of patients who gained
`at least 15 letters: 11.7 and 13.1% of treated patients
`(0.3 and 0.5 mg, respectively) compared with 9.5% in
`the sham group. Although the overall safety profile of
`ranibizumab in the PIER trial was similar to the first
`year of the MARINA and ANCHOR trials, the efficacy
`outcomes of the PIER trial were less beneficial than
`the MARINA and ANCHOR trials because some
`patients required more frequent dosing than quarterly
`dosing to achieve maximal benefit. On the basis of the
`PrONTO and PIER trials, OCT-guided administration
`
`of less-frequent ranibizumab retreatment appears to
`be beneficial.
`
`The recently completed Safety Assessment of Intra-
`vitreal Lucentis for AMD (SAILOR) trial was a single-
`masked, multicenter phase IIIb study to evaluate the
`safety and tolerability of two doses of intravitreal rani-
`bizumab in patients with neovascular AMD. Safety
`assessments showed higher stroke rates with increased
`dosage (0.7 and 1.2% for the 0.3 and 0.5 mg groups,
`respectively), but the difference was not statistically
`]. Prior stroke was the most significant
`significant [47
`risk factor for stroke. Frequencies of cardiovascular
`events and ocular serious AEs were similar for the
`two dose groups [47,48]. A subgroup analysis of this
`study showed an association between greater improve-
`ments in visual acuity and central foveal thickness in
`patients presenting with a higher baseline visual acuity
`[49].
`
`Intravitreal bevacizumab
`Although systemic bevacizumab (5 mg/kg) has been
`shown to reduce leakage from CNV, decrease CRT,
`and significantly improve vision in neovascular AMD
`[50–52], intravitreal administration is perceived to be
`safer and requires less frequent retreatment [50,51]. In
`the first-reported case study [53] of intravitreal bevaci-
`zumab, a patient with recurrent CNV secondary to AMD,
`who had previously been treated with pegaptanib and
`with PDT in combination with triamcinolone acetonide,
`experienced resolution of visual distortion within 1 week
`in parallel with resolution of subretinal fluid and a
`reduction in CRT following a single injection of
`1.0 mg bevacizumab. Subsequently, several retrospec-
`tive [54 –67] and prospective [68– 79] studies of intra-
`vitreal bevacizumab (dose range 1.0– 2.5 mg)
`in
`neovascular AMD have been published,
`invariably
`demonstrating clinically significant
`improvement
`in
`mean visual acuity, reduction in fluorescein angiography
`leakage and CRT, and resolution of edema in up to 90%
`of bevacizumab-treated patients. Most studies were
`small (up to 100 patients) uncontrolled studies with
`different retreatment criteria and outcome measures.
`Systemic and ocular AEs were rare; the most common
`ocular side effects were endophthalmitis, uveitis, sub-
`macular hemorrhage, and RPE tears. In a recent retro-
`spective safety assessment of intravitreal bevacizumab
`involving 1173 patients, 18 (1.5%) reported systemic
`AEs, including five (0.4%) deaths, whereas ocular AEs
`included subconjunctival hemorrhage [838 cases (19% of
`4303 injections)] and increased intraocular pressure
`(IOP), endophthalmitis, and tractional retinal detach-
`ment [seven cases (0.16%) each] [67]. The low rates of
`systemic complications in these studies were consistent
`with those reported in an earlier survey of 5228 patients
`[80].
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`

`162 Retinal, vitreous and macular disorders
`
`A randomized, prospective clinical trial compared verte-
`porfin PDT with bevacizumab (2.5 mg) for the treatment
`of predominantly classic CNV secondary to AMD and
`found that at month 6, all 32 eyes (100%) receiving
`bevacizumab lost 15 letters or less in visual acuity com-
`pared with 73.3% of the PDT-receiving eyes (P¼ 0.002)
`[76]. Mean CRT was significantly better at 3 and 6 months
`in patients treated with bevacizumab versus the PDT
`group (P¼ 0.04 and P¼ 0.002, respectively). The study
`showed overall benefit of treatment with bevacizumab
`compared with PDT.
`
`Combination therapy
`Small short-term studies evaluating the combination of
`intravitreal bevacizumab with PDT versus PDT alone
`[81–83] and bevacizumab as well as pegaptanib sodium
`[84] for neovascular AMD have demonstrated clinical
`benefits (visual acuity improvement and resolution of
`edema), suggesting possible synergistic effects. How-
`ever, these findings require confirmation in large random-
`ized controlled trials. Currently, combinations of two or
`three therapies, compared with anti-VEGF monother-
`apy, are being tested for their ability to reduce the
`intervention rate with equivalent efficacy and safety
`outcomes. These include the combination of ranibizu-
`mab as well as PDT, bevacizumab monotherapy versus
`bevacizumab as well as PDT, or bevacizumab as well as
`PDT and triamcinolone, and bevacizumab as well
`as triamcinolone.
`
`An ongoing phase I trial (http://www.clinicaltrials.gov,
`NCT00569140) is evaluating the safety, tolerability,
`and pharmacokinetic profile of
`intravitreal E10030
`(Ophthotech Corporation, Princeton, New Jersey, USA)
`in patients with neovascular AMD receiving ranibi-
`zumab or bevacizumab. E10030 is a pegylated aptamer
`that targets platelet-derived growth factor (PDGF). The
`rationale for the study is that PDGF and VEGF have
`independent angiogenic activities, and preclinical studies
`have demonstrated that the combination of E10030 and
`anti-VEGF agents has more potent antiangiogenic results
`than anti-VEGF treatment alone (Ophthotech Corpor-
`ation press release, 12 February 2008).
`
`Sorafenib (Nexavar; Bayer HealthCare Pharmaceuticals,
`Wayne, New Jersey, USA) is a tyrosine kinase inhibitor
`that diminishes VEGF signaling by inhibiting VEGFR
`and has been approved for the treatment of certain
`cancers. Recently, a report described two neovascular
`AMD patients who received off-label oral sorafenib
`(200 mg three times per week) in combination with
`ongoing intravitreal ranibizumab treatment in an attempt
`to decrease the number of ranibizumab injections [85].
`Both patients experienced stable or improved visual
`acuity and improvement in CRT after initiation of sor-
`afenib therapy. Therefore, it will be of interest to evalu-
`
`ate the effects of sorafenib in combination with ranibi-
`zumab or as monotherapy in larger patient cohorts,
`especially in patients with refractory or recurrent neo-
`vascular AMD.
`
`The safety and efficacy of a unique combination therapy
`consisting of focal strontium-90 beta radiation delivered
`via the Epi-Rad90 Ophthalmic System (NeoVista,
`Fremont, California, USA) as well as ranibizumab,
`versus ranibizumab alone, is being evaluated in neo-
`vascular AMD in the ongoing randomized, open-label,
`active control phase III CNV secondary to AMD treated
`with Beta Radition Epiretinal Therapy (CABERNET)
`trial (http://www.clinicaltrials.gov; NCT00454389).
`
`Other strategies to inhibit vascular endothelial growth
`factor signal transduction
`Several different anti-VEGF and antiangiogenic agents
`have demonstrated efficacy in neovascular AMD. A phase
`II randomized, double-masked trial of VEGF trap
`(Regeneron Pharmaceuticals, Tarrytown, New Jersey,
`USA), a fusion protein of VEGF receptor ligand-binding
`domains and the immunoglobulin G type 1 (IgG1) Fc
`region, demonstrated increases in visual acuity from
`baseline of 9.0 letters (P < 0.0001) and 5.4 letters
`(P < 0.085) at 52 weeks after fixed monthly or quarterly
`dosing (0.5, 2, or 4 mg) for 12 weeks followed by another
`40 weeks on an as-needed basis in neovascular AMD
`(AZ-Regeneron press release, 28 September 2008).
`Patients receiving monthly VEGF trap (2.0 or 0.5 mg
`for the first 12 weeks) also experienced mean reductions
`in CRT of 143 and 125 mm, respectively, at week
`52 (P < 0.0001 for both from baseline). Currently, two
`randomized, international phase III studies (VIEW-1 and
`VIEW-2) (http://www.clinicaltrials.gov; NCT00509795,
`NCT00637377) are comparing intravitreal VEGF trap
`with ranibizumab.
`
`interfering RNA (siRNA) agents designed to
`Small
`silence the VEGF gene and the VEGFR have been shown
`in preclinical studies to inhibit ocular neovascularization
`and vascular permeability in animal models [86,87].
`Bevasiranib (previously called Cand5; OPKO Health,
`Inc./Acuity Pharmaceuticals, Miami, Florida, USA) and
`AGN211745 (previously called Sirna-027; Allergan,
`Inc., Irvine, California, USA) are currently being studied
`in phase II and III clinical trials, respectively, in neovas-
`cular AMD. In a phase II randomized trial, bevasiranib
`(single intravitreal injections at baseline and week 6) was
`shown to be well tolerated after 12 weeks of follow up,
`with mild AEs related primarily to the injection pro-
`cedure and with no systemic exposure. Bevasiranib
`stabilized visual acuity in most patients and improved
`visual acuity in more than one-third of patients (Acuity
`Pharmaceuticals press release, 11 September 2006). The
`Combining Bevasiranib and Lucentis (ranibizumab)
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`

`Antivascular endothelial growth factor therapy Ciulla and Rosenfeld 163
`
`Therapy in Wet AMD (COBALT) phase III trial (http://
`www.clinicaltrials.gov; NCT00499590) is currently eval-
`uating the safety and efficacy of bevasiranib given every
`8 or 12 weeks after ranibizumab pretreatment com-
`pared with ranibizumab alone every 4 weeks. Another
`phase III study (CARBON) (http://www.clinicaltrials.
`gov; NCT00557791) will assess the safety and efficacy
`of three doses of bevasiranib as maintenance therapy for
`AMD following three doses of ranibizumab. Data from a
`phase I study of AGN211745 in neovascular AMD indi-
`cated that after 3 months of follow up, single injections of
`AGN211745 stabilized visual acuity in 24 of 26 (92%)
`patients and improved vision in five of 26 (19%) patients
`(Sirna Therapeutics, Inc., press release, 10 August 2006).
`A recently completed phase I/II trial
`(http://www.
`clinicaltrials.gov; NCT00363714) evaluated the safety
`and effect of AGN211745 on retinal anatomy, CNV, and
`visual acuity; another phase II trial assessing the efficacy
`of multiple doses of this agent is ongoing (http://www.
`clinicaltrials.gov; NCT0035057). However, the speci-
`ficity of the aforementioned siRNA drugs was recently
`called into question by a recent study [88] showing
`that the antiangiogenic activity of siRNA may be due to a
`class immune effect associated with activation of the cell
`surface toll-like receptor 3 (TLR3) rather than to a target
`sequence-specific interaction. Moreover, these siRNA
`drugs could theoretically cause vision loss via activation
`of the TRL3, which may promote the formation of
`geographic atrophy in genetically susceptible individuals
`[89].
`
`In early clinical studies [90–93], triamcinolone acetonide
`(Kenalog; Bristol-Myers Squibb, New York, New York,
`USA), an antiangiogenic corticosteroid, helped stabilize
`and, to a lesser extent, improve visual acuity when used in
`combination with PDT in neovascular AMD. Intravitreal
`triamcinolone acetonide (IVTA) combined with PDT
`can stabilize vision in the majority of treated eyes,
`whereas only a small proportion (9%) of patients had
`improved visual acuity [92]. IVTA did not prevent visual
`loss in a substantial number of patients, although most
`studies assessed only single-dose regimens, unlike the
`periodic-dosing regimens used for the anti-VEGF agents
`discussed above. Additionally, IVTA introduces AEs not
`seen with PDT alone, including increases in IOP and
`cataract progression [92]. Currently, triamcinolone acet-
`onide appears to be most useful in reducing the need for
`PDT retreatment [90–92]. Other agents being investi-
`gated for neovascular ocular diseases are listed in Table 1.
`
`Conclusion
`The accumulation of preclinical and clinical evidence
`implicating VEGF-A in the pathogenesis of neovascular
`eye diseases has provided a strong rationale for exploring
`the therapeutic potential of anti-VEGF agents in these
`
`diseases, including AMD. Over the past decade, the
`management of neovascular AMD has progressed con-
`siderably from being limited to laser photocoagulation to
`contain the spread of CNV to the use of anti-VEGF-A
`agents to inhibit neovascularization and prevent vision
`loss. Three such agents – pegaptanib sodium, ranibizu-
`mab, and bevacizumab – have been used successfully for
`this purpose. Their clinical success in neovascular AMD
`has provided the proof-of-concept needed to pursue
`similar treatment strategies in other neovascular eye
`diseases.
`
`Acknowledgements
`The support for third-party medical writing assistance was provided by
`Genentech USA, Inc.
`
`Dr Ciulla has received grant support from Alcon, Alimera, Allergan,
`Genentech, GlaxoSmithKline, Jerini, OPKO, Othera, and Regeneron, is
`a consultant for Neovista, and serves on the advisory boards for Pfizer
`and Regeneron. Dr Rosenfeld has received grant support from Alcon,
`CoMentis, Genentech, Othera, Potentia, and Quark/Pfizer, is on the
`speakers bureau of Carl Zeiss Meditec, and is an advisory board
`member of CoMentis, Othera, and Neovista.
`
`References and recommended reading
`Papers of particular interest, published within the annual period of review, have
`been highlighted as:
`
`of special interest
` of outstanding interest
`
`1
`
`Bird A. Age-related macular disease. Br J Ophthalmol 1996; 80:2–3.
`
`2 Ciulla TA, Amador AG, Zinman B. Diabetic retinopathy and diabetic macular
`edema: pathophysiology, screening, and novel therapies. Diabetes Care
`2003; 26:2653–2664.
`
`3 Cugati S, Wang JJ, Rochtchina E, Mitchell P. Ten-year incidence of retinal vein
`occlusion in an older population: the Blue Mountains Eye Study. Arch
`Ophthalmol 2006; 124:726–732.
`
`4 Chakravarthy U, Augood C, Bentham GC, et al. Cigarette smoking and age-
`related macular degeneration in the EUREYE Study. Ophthalmology 2007;
`114:1157–1163.
`
`5 Campochiaro PA, Soloway P, Ryan SJ, Miller JW. The pathogenesis of
`choroidal neovascularization in patients with age-related macular degenera-
`tion. Mol Vis 1999; 5:34.
`
`6
`
`7
`
`8
`
`9
`
`Leung DW, Cachianes G, Kuang WJ, et al. Vascular endothelial growth factor
`is a secreted angiogenic mitogen. Science 1989; 246:1306–1309.
`
`Senger DR, Galli SJ, Dvorak AM, et al. Tumor cells secrete a vascular
`permeability factor that promotes accumulation of ascites fluid. Science
`1983; 219:983–985.
`
`Keck PJ, Hauser SD, Krivi G, et al. Vascular permeability factor, an endothelial
`cell mitogen related to PDGF. Science 1989; 246:1309–1312.
`
`Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth
`factor (VEGF) and its receptors. FASEB J 1999; 13:9–22.
`
`10 Eriksson U, Alitalo K. Structure, expression and receptor-binding properties of
`novel vascular endothelial growth factors. Curr Top Microbiol Immunol 1999;
`237:41–57.
`
`11 Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat
`Med 2003; 9:669–676.
`
`12 Gerhardt H, Ruhrberg C, Abramsson A, et al. Neuropilin-1 is required for
`endothelial tip cell guidance in the developing central nervous system. Dev
`Dyn 2004; 231:503–509.
`
`13 Kawasaki T, Kitsukawa T, Bekku Y, et al. A requirement for neuropilin-1 in
`embryonic vessel formation. Development 1999; 126:4895–4902.
`
`14 Tischer E, Mitchell R, Hartman T, et al. The human gene for vascular
`endothelial growth factor. Multiple protein forms are encoded through alter-
`native exon splicing. J Biol Chem 1991; 266:11947–11954.
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`

`164 Retinal, vitreous and macular disorders
`
`15 Ferrara N. Vascular endothelial growth factor: basic science and clinical
`progress. Endocr Rev 2004; 25:581–611.
`
`1