Article Date: 4/1/2012

VEGF Inhibitors: Changing the Landscape of Retina Care
retina

VEGF Inhibitors: Changing the Landscape of Retina Care

The authors review how these therapies have proven effective in treating choroidal neovascularization and retinal edema.

Mark Street, O.D., M.S., AND Andrew S. Gurwood, O.D., F.A.A.O., DIPL.

Philadelphia, Pa.

Retinal angiogenesis refers to the development of new capillary structures from existing retinal vasculature and blood vessel networks. In a healthy retina, angiogenesis is an integral component of normal growth, development and maintenance of the tissue. The process of angiogenesis involves activation of vascular endothelial cells, which triggers a cascade of cell proliferation and migration. Angiogenesis is also inherently involved in vascular maturation and remodeling processes, which include targeted degradation of the extracellular matrix promoting natural tissue repair.1,2 When ocular conditions are normal, negligible cell proliferation occurs within the retinal and choroidal vasculatures. In a diseased retina, angiogenesis can turn destructive.

In this article, we discuss the pathophysiology of this destructive angiogenesis, as well as a review of treatment options.

Pathophysiology of retinal disease

Endothelial cells integral to the vascular structure are naturally resistant to neovascular stimuli. This stasis results from the balance between proangiogenic factors, such as vascular endothelial growth factor (VEGF), and antiangiogenic factors, such as pigment epithelium-derived factor released from the retinal pigment epithelium (RPE) and other pivotal structures into the retinal cellular environment. In a diseased retina, infectious, inflammatory and ischemic vectors induce the release of cytokines and chemoattractants that can influence the regulation of these angiogenic factors and shift the balance toward destructive angiogenesis. This imbalance, characterized as an increase in proangiogenics or a decrease in antiangiogenics, can create a cellular environment that increases vascular permeability and the potential for intraretinal or subretinal neovascularization.1-4

Although VEGF receives much attention as an angiogenic factor, it is, in fact, a permeability factor with a potency to induce vascular leakage of 104 compared with other common ocular permeability factors, such as histamine. Elevated levels of VEGF have been quantified within retinal and vitreal structures in cases of acute and persistent macular edema associated with diabetic retinopathy and retinal vein occlusion.4,5

VEGF, specifically VEGF-A, has been implicated in proliferative ocular disease in animal model research and human clinical studies.1-5 VEGF-A is a homodimeric glycoprotein that occurs naturally in four major isoforms: VEGF165, VEGF121, VEGF189 and VEGF206.1-5 These isomers are categorized by their molecular weights and extracellular diffusion characteristics. Each of them may be degraded to VEGF110 and rendered inactive by plasmin. VEGF is an integral factor in angiogenesis mainly because:

► It has a high affinity and selectivity for endothelial cells, and its diffusion characteristics facilitate access to these target cells.
► It has a combined effect on multiple mechanisms of angiogenesis.
► It promotes plasminogen and collagenase, which degrade the extracellular matrix.
► It has the potent ability to increase vascular permeability.1,5

Early research exploring the utility of specific anti-VEGF therapies was confined to oncology.

Anti-VEGF for cancer treatment

Highly metabolic neoplasm requires inordinate quantities of oxygen and nutrients for growth and maintenance. Elevated levels of proangiogenic factors, such as VEGF, originate within the tumor environment and are presumed to trigger vascular proliferation in response to the up-regulated metabolic need. Researchers postulated that targeting and inactivating cellular VEGF would prevent neovascularization, thus “starving” the neoplasm and arresting its growth.6 This research led to the development of bevacizumab (Avastin, Genentech).

Bevacizumab is a recombinant, monoclonal immunoglobulin antibody that binds to and inhibits all active isoforms of VEGF. Administered intravenously, it was shown to limit the growth of metastatic tumors. In 2004, bevacizumab was approved by the FDA for the treatment of colorectal cancer. In subsequent years, FDA approval was expanded to include the following metastatic cancers: nonsmall cell lung (2006); renal (2009); glioblastoma (2009); and breast (2009, revoked in 2011).7

Researchers believed bevacizumab's relatively high molecular weight (149 kilodalton [kD]) would prevent it from penetrating the retina, thus making it inappropriate for intraocular use. Parallel research focused on ocular-specific agent development.1

First for the eye: pegaptanib

The first ocular-specific anti-VEGF agent was pegaptanib (Macugen, Eyetech), which received FDA approval in 2004 for the treatment of neovascular age-related macular degeneration (AMD).1 Pegaptanib is a pegylated nucleic acid aptamer that binds and inhibits the VEGF165 isoform of VEGF-A with high specificity. The binding of pegaptanib to the VEGF molecule prevents subsequent binding of the inactivated molecule to VEGF receptors on target cells.

The VEGF Inhibition Study in Ocular Neovascularization demonstrated that intravitreal injections of pegaptanib (0.3mg) administered at six-week intervals resulted in a modest reduction in the rate of moderate vision loss at 12 months in eyes with neovascular AMD compared with sham injection.8 These data suggested that anti-VEGF therapy could have utility not only to stop vision loss but perhaps to recover visual acuity without the destructive side effects seen in laser photocoagulation or the invasiveness of intravenous photodynamic therapy with verteporfin (Visudyne, QLT).9-16

The chief limitation of pegaptanib is its inability to inactivate alternate VEGF isoforms, which reduces its efficacy. Also, because of the sustained nature of the destructive angiogenic imbalance in the diseases that induce choroidal and intraretinal neovascularization, pegaptanib, as well as all current intraocular anti-VEGF agents, must be administered repeatedly to maintain its effect.8,17,18

Most-studied: ranibizumab

The most-studied ocular-specific intravitreal anti-VEGF agent is ranibizumab (Lucentis, Genentech), which received FDA approval in 2006 for the treatment of neovascular AMD.1 Ranibizumab is a recombinant monoclonal antibody fragment that binds and inhibits all isoforms of VEGF-A. Ranibizumab was developed as a truncated form of the full-length murine monoclonal antibody from which bevacizumab is derived. The fragment design of ranibizumab reduces its molecular weight to 48 kD compared with 149 kD of bevacizumab. Early theoretical research indicated the smaller molecule could completely diffuse through all retinal layers with reduced intraocular inflammation upon injection. A shorter systemic half-life compared with bevacizumab was also seen as an advantage. In addition, targeted amino acids were substituted along the fragment to increase affinity to various VEGF isoforms. Laboratory research indicated a 100-fold increase in affinity to VEGF compared with that of bevacizumab.17

The Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) study demonstrated that 0.5mg intravitreal injections of ranibizumab administered at four-week intervals resulted in significant maintenance (94.6%) and improvement (33.8%) of visual acuity at 12 months compared with sham injection.19 In addition, the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) study demonstrated that 0.5mg intravitreal injections of ranibizumab administered at four-week intervals also resulted in significant maintenance (96.4%) and improvement (40.3%) of visual acuity at 12 months compared with conventional photodynamic therapy (64.3% and 6.3%, respectively).20

Unlike in the MARINA study, subjects in the ANCHOR study had no recent disease progression as evidenced by visual acuity loss, hemorrhage or documented progression of choroidal neovascularization. The consistent improvement observed in both studies demonstrated the efficacy of ranibizumab in both acute and subacute stages of destructive angiogenesis.17

Many retina specialists have used bevacizumab off-label as a less-costly alternative to ranibizumab to treat neovascular AMD and macular edema.17,21 In response to this widespread practice, the National Institutes of Health initiated the Comparison of AMD Treatments Trials (CATT).22 (See “What CATT Revealed,” below.)

Recent approval: aflibercept

The most recently approved ocular-specific intravitreal anti-VEGF agent is aflibercept (Eylea, Regeneron), which received FDA approval in 2011 for the treatment of neovascular AMD.18,21 Aflibercept (molecular weight 115 kD) is a pharmacologically engineered protein, which binds and inhibits all isoforms of VEGF-A. Aflibercept also demonstrates binding affinity to placental growth factor (PlGF), a VEGF analogue also implicated in angiogenesis, especially in cases of inflammatory vascular disease.

What CATT Revealed
Although bevacizumab is designed as an intravenous agent, some retina specialists are using it off-label (prepared for intravitreous injection by compounding pharmacies) to treat neovascular AMD and macular edema. In response to this practice, the National Institutes of Health initiated the Comparison of AMD Treatments Trials (CATT) in 2008.1
The trials were designed to compare the efficacy and safety of intravitreal injection of bevacizumab vs. ranibizumab in clinical practice. According to data released in 2011, the CATT demonstrated that 2.5mg intravitreal injections of bevacizumab resulted in maintenance of vision and improvement of visual acuity with rates comparable to 0.5mg intravitreal injections of ranibizumab when both were administered at four-week intervals. 2 Despite these outcomes, bevacizumab is not currently approved by the FDA for the treatment of any ocular condition.

1. Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ; CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364:1897-1908.


Other Ocular Applications for VEGF Inhibitors
Researchers continue to explore the utility of VEGF inhibitors for treating ocular diseases, as evidenced by the following studies.
The VEGF Trap-Eye in Patients with Diabetic Macular Edema Study demonstrated that 0.2mg intravitreal injections of aflibercept administered at eight-week intervals resulted in significant improvement in visual acuity (64%) and mean macular thickness (–160 µm) compared with conventional focal laser photocoagulation treatment (32% and –68µm, respectively) at 24 weeks.1 A recent phase II/III study involving persistent diabetic macular edema not associated with capillary nonperfusion demonstrated that 0.3mg injections of pegaptanib administered at six-week intervals resulted in moderate improvement in visual acuity (36.8%) compared with sham injection (19.7%) at 12 months.2
The Branch Retinal Vein Occlusion (BRAVO) study demonstrated that 0.5mg injections of ranibizumab administered at four-week intervals resulted in significant improvement in visual acuity (61%) compared with sham injection at six months in cases of macular edema secondary to branch retinal vein occlusion. 3 Similarly, the Central Retinal Vein Occlusion (CRUISE) study demonstrated that 0.5mg injections of ranibizumab administered at four-week intervals resulted in significant improvement in visual acuity (46%) compared with sham injection (17%) at six months in cases of nonischemic central vein occlusion.4 A recent longitudinal study demonstrated that 0.5mg injections of ranibizumab administered at intervals of up to three months resulted in maintenance of visual acuity similar to the short-term improvements seen in the BRAVO and CRUISE studies at 24 months.5 Based in part on the results of these two key studies, ranibizumab received FDA approval in 2010 for the treatment of macular edema following retinal vein occlusion.6
Although studies have shown intravitreal anti-VEGF therapy reduces macular edema and improves visual acuity, their shortterm efficacy and the need for multiple treatments are disadvantages compared with conventional focal laser photocoagulation. 7 While these studies demonstrate a role for the new agents, they are currently not considered replacements for standard focal laser photocoagulation protocols. Due to their potential to reduce edema and alter the faulty hydrodynamics produced in retinal diseases, they are frequently considered for use as adjunctive pretreatments to intraretinal disease conditions that were previously managed with focal laser photocoagulation alone.

1. Do DV, Schmidt-Erfurth U, Gonzalez VH, et al. The DA VINCI Study: phase 2 primary results of VEGF Trap-Eye in patients with diabetic macular edema. Ophthalmology. 2011;118:1819-1826.
2. Sultan MB, Zhou D, Loftus J, Dombi T; Macugen 1013 Study Group. A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. Ophthalmology. 2011;118:1107-1118.
3. Campochiaro PA, Heier JS, Feiner L, et al; BRAVO Investigators. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117:1102-1112.
4. Brown DM, Campochiaro PA, Singh RP, et al; CRUISE Investigators. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117:1124-1133.
5. Campochiaro PA, Hafiz G, Channa R, et al. Antagonism of vascular endothelial growth factor for macular edema caused by retinal vein occlusions: two-year outcomes. Ophthalmology. 2010;117: 2387-2394.
6. Nicholson BP, Schachat AP. A review of clinical trials of anti-VEGF agents for diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 2010;248:915-930.

Aflibercept was designed to mimic the natural structure and position of VEGF1 and VEGF2 receptors on target cells. Using this mechanism of action, aflibercept “traps” both PlGF and VEGF in concert rather than as a free binding agent. The two separate binding domains of aflibercept increase its binding affinity and potentially lengthen periods of efficacy between doses, when compared with pegaptanib and ranibizumab.18,23

The Clinical Evaluation of Antiangiogenesis in the Retina (CLEAR) studies demonstrated that 0.4mg intravitreal injections of aflibercept resulted in a mean increase in visual acuity of 13.5 letters with a mean retreatment interval of 150 days.23 Two later parallel studies, VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW1 [US], VIEW2 [Europe]) demonstrated that 2.0mg intravitreal injections of aflibercept administered at eight-week intervals resulted in significant maintenance (95%) of visual acuity at 12 months comparable to 0.5mg injections of ranibizumab (94%) administered at four-week intervals. 18 Current FDA guidelines for intravitreal aflibercept are based on the 2.0mg dosage and eight-week interval schedule.

Intravitreal injection

Intravitreal injections are generally performed using a sterile disposable 27- or 30-gauge needle and syringe, depending on the solute's size in a given injection solution. For example, intravitreal steroids generally require a 27-gauge needle, while anti-VEGF agents can be administered using a 30-gauge needle. The volume of the solution for injection is generally 0.1ml, and the anti-VEGF agent solution is formulated to deliver the desired quantity in this dosage.

Prior to injection, a topical anesthetic, such as tetracaine, is instilled followed by 5% povidone iodine as a disinfectant. The periocular skin, eyelids and eyelashes are swabbed with 5% or 10% povidone iodine. The external surface is dried, and an ocular drape may or may not be used. An ocular speculum is inserted to position and stabilize the eyelid.

An inferotemporal injection site is preferred, and the patient is directed to position his gaze away from the site. The needle is inserted perpendicularly into the sclera 3.0mm (aphakic) to 4.0mm (phakic) from the limbus to avoid contact with the posterior lens capsule. The agent is injected and the needle removed while maintaining the perpendicular positioning. The speculum is removed, and the patient is instructed to close the eye. Gentle ocular massage may be applied to help reduce any acute increase in intraocular pressure (IOP). The patient may be directed to instill topical antibiotics, pre- and post-procedure, at the discretion of the retina specialist.24,25

Adverse effects

The most common adverse effects of intravitreal injection are ocular discomfort and irritation from the topical anesthetic and disinfecting agent. Self-limiting subconjunctival hemorrhage is also a common adverse effect of intravitreal injection.

Systematic reviews of documented intravitreal injection procedures indicate a prevalence of endophthalmitis of 0.2% per injection for all compounds, while those limited to anti-VEGF agents indicate a prevalence of 0.04% per injection. Similarly, the overall prevalence of iatrogenic cataract development was 1.8% per injection, with an observed decrease involving specific anti-VEGF agents. Neurosensory retinal tear or detachment, retinal hemorrhage, RPE detachment and sustained increase in IOP are potential adverse effects for any intravitreal injection and have been documented with anti-VEGF agents.

Intravenous bevacizumab used in oncology has been associated with elevated systemic hypertension, thrombosis and cerebral vascular accident. Although anti-VEGF agents administered intravitreally can potentially pass through the blood-eye barrier and enter systemic circulation, these adverse angiogenic effects have not been significantly demonstrated in clinical practice.26,27

Future challenges

The development of injectable intraocular anti-VEGF agents has changed the treatment strategy for various ocular conditions characterized by choroidal and intraretinal neovascularization with associated edema, especially in cases involving the macula. (See “Other Ocular Applications for VEGF Inhibitors,” page 51.) While conventional laser photocoagulation destroys the RPE and the neurosensory retina as well as the neovascular membrane, VEGF inhibitors have a mechanism of action that preserves retinal structure and architecture. Thus, anti-VEGF therapy has the potential not only to preserve vision but, in some cases, improve visual function. Anti-VEGF agents temporarily treat the disease process, specifically reducing proangiogenic factors, creating an environment that is not conducive to neovascular growth. The relative shortcoming of VEGF inhibitors: Frequent retreatment is required to maintain efficacy.

Future advancements in ocular anti-VEGF treatment will likely involve the development of molecules that will extend efficacy periods between injections. Other research: the development of depot mechanisms that will provide sustained release of antiangiogenic agents.18,21 OM

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9. Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. Ophthalmology.1981;88:583-600.
10. Penman A, Serjeant G. Recent advances in the treatment of proliferative sickle cell retinopathy. Curr Opin Ophthalmol. 1992;3:379-388.
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12. Mohamed Q, McIntosh RL, Saw SM, Wong TY. Interventions for central retinal vein occlusion: an evidence-based systematic review. Ophthalmology. 2007;11:507-519,524
13. Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy. Three-year results from randomized clinical trials. Arch Ophthalmol. 1986;104:694-701.
14. Virgili G, Bini A. Laser photocoagulation for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2007;189:CD004763.
15. Michels S, Schmidt-Erfurth U. Photodynamic therapy with verteporfin: a new treatment in ophthalmology. Semin Ophthalmol. 2001;16:201-206.
16. Chan WM, Lim TH, Pece A, Silva R, Yoshimura N. Verteporfin PDT for non-standard indications--a review of current literature. Graefes Arch Clin Exp Ophthalmol. 2010;248:613-626.
17. Bressler NM. Antiangiogenic approaches to age-related macular degeneration today. Ophthalmology. 2009;116:S15-S23.
18. Zampros I, Praidou A, Brazitikos P, Ekonomidis P, Androudi S. Antivascular endothelial growth factor agents for neovascular age-related macular degeneration. J Ophthalmol. 2012; 319728:1-12.
19. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431.
20. Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1432-1444.
21. Do DV. Antiangiogenic approaches to age-related macular degeneration in the future. Ophthalmology. 2009;116(10Suppl):S24-S26.
22. Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ; CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364:1897-1908.
23. Dixon JA, Oliver SC, Olson JL, Mandava N. VEGF Trap-Eye for the treatment of neovascular age-related macular degeneration. Expert Opin Investig Drugs. 2009;18(10):1573-1580.
24. Amoaku W, Pearce I, Browning A. Guidelines for Intravitreal Injections Procedure 2009. Royal College of Ophthalmologists. http://www.rcophth.ac.uk/core/core_picker/download.asp?id=167. Accessed March 22, 2012.
25. American Academy of Ophthalmology Policy Statement: Intravitreal Injections 2008. www.aao.org/about/policy/upload/Intravitreal-Injections-2008.pdf. Accessed March 22, 2012.
26. van der Reis MI, La Heij EC, De Jong-Hesse Y, Ringens PJ, Hendrikse F, Schouten JS. A systematic review of the adverse events of intravitreal anti-vascular endothelial growth factor injections. Retina. 2011;31:1449-1469.
27. Tolentino M. Systemic and ocular safety of intravitreal anti-VEGF therapies for ocular neovascular disease. Surv Ophthalmol. 2011;56:95-113.

Dr. Street is an adjunct faculty member at the Pennsylvania College of Optometry at Salus University and clinical preceptor at its Eye Institute as well as a staff optometrist at the Coatesville Veterans Affairs Medical Center. Contact him at mstree@salus.edu.
Dr. Gurwood is a professor of Clinical Sciences at the Eye Institute of the Pennsylvania College of Optometry at Salus University. Contact him at Agurwood@salus.edu. To comment on this article, e-mail optometric manage ment@gmail.com.


Optometric Management, Volume: 47 , Issue: April 2012, page(s): 48 - 52