The Past, Present, and Future of Exudative Age-Related Macular Degeneration Treatment

Abstract

Treatment of exudative age-related macular degeneration has been revolutionized within the last 6 years with the introduction of vascular endothelial growth factor neutralizing agents. Previously popular “destructive treatments,” such as laser photocoagulation and photodynamic treatment have either been abandoned or used as an adjunct to pharmacotherapy. Despite the increase in vision after antivascular endothelial growth factor (VEGF) agents, they require repetitive and costly intravitreal injections that also carry the inherit risks of infection, retinal tears, and detachment. Several new and more potent VEGF inhibitors are at different stages of development. The goal of evolving pharmacotherapy is to preserve the therapeutic effect while reducing or eliminating the discomfort of intravitreal drug delivery, as well as identify new therapeutic targets. Complement inhibitors, immunomodulators, integrin inhibitors are a few of the new class of drugs that are expected to be in our armamentarium soon. Current medications act to decrease leakage through abnormal subretinal choroidal vasculature and promote involution. However, these medications are only effective in treating the active stage of the choroidal neovascular membrane. Restoration of vision of a large number of patients with involuted choroidal neovascular membranes is warranted. For this purpose, tissue engineering techniques have been employed to reconstruct the subretinal anatomy. Discovery of biomarkers, pharmacogenetics, and very specific targeting holds the promise of increased potency and safety in the future.

INTRODUCTION

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among elderly patients in developed countries.¹,² AMD affects more than 1.75 million individuals in the United States. Nearly 2 million Americans over the age of 55 are diagnosed with AMD each year. Approximately, 230 000 of those affected have been declared legally blind. As the population of the US ages, AMD is projected to affect the sight of over six million people by 2020.³

Loss of visual acuity in patients with AMD can be secondary to geographic atrophy of the retinal pigment epithelium (RPE) and choriocapillaris, called “non-exudative AMD,” or secondary to the development of subretinal neovascular membrane (SRNVM) that results in exudates and hemorrhage, or “exudative AMD.” While nonexudative AMD accounts for 10% of the patients, exudative AMD is responsible for 90% of the cases with severe visual loss.⁴ Although considerable amount of resources has been devoted to develop several treatment modalities for AMD, a cure for this devastating disease remains distant.

Recent developments in understanding the pathogenesis of AMD have opened new horizons in developing more rational strategies for the prevention and effective treatment of AMD. In this review article, we summarize the current management and treatment of AMD and present prospects for future treatment modalities.

THE PAST

The first treatment for wet AMD involved laser photocoagulation. The macular photocoagulation study (MPS) showed that extrafoveal or juxtafoveal classic SRNVM treated with argon or krypton laser had better long-term visual acuity compared to baseline compared to patients who did not undergo therapy.⁵,⁶ MPS also compared the effect of laser ablation of subfoveal choroidal neovascularization to observation alone. In this study, subfoveal membranes smaller than 3.5 MPS disc areas in size and with a classic component and well defined borders; size of lesion ≤3.5 MPS disc areas were treated according to the MPS protocol.⁷ Laser photocoagulation was associated with an immediate reduction in central visual acuity, but at the end of the follow-up period of 48 months, laser-treated eyes had significantly better visual acuity than untreated eyes. This benefit became significant only after 6 months of photocoagulation. The effect of laser photocoagulation was most beneficial for small (<1 MPS disc area) or moderate (1–2 MPS disc area) size membranes that were associated with poor vision. At best, laser photocoagulation slowed down the visual loss that eventually progressed to loss of foveal vision. The main reason for this is the fact that thermal laser treatment coagulates new choroidal vessels at the cost of destroying nearby retinal cells and does not prevent recurrences.⁸ Another drawback of the MPS trials was the strict eligibility criteria for laser treatment that hinders general applicability to daily clinical practice.⁹ Such limitations fueled the search for safer and more effective treatments. Although thermal laser photocoagulation remains an FDA-approved treatment for exudative AMD it has practically been abandoned. Photodynamic therapy (PDT) with verteporfin (Visudyne^®, Novartis, East Hanover, NJ, USA) was approved by the FDA in April, 2000 for the treatment of predominantly classic SRNVM. PDT is based on the release of singlet oxygen species from verteporfin once irradiated with a 689 nm laser light. These highly-reactive oxygen molecules damage the choroidal neovascular endothelium and lead to the thrombosis of the subretinal choroidal network.¹⁰,¹¹ Due to the non-thermal nature of the process collateral damage to the adjacent retina is theoretically avoided, however occasional thrombosis of the retinal or choroidal vessels has been reported.¹² Clinical benefits from PDT were demonstrated in two large multicenter randomized clinical trials: the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) study, and the Visudyne in Photodynamic Therapy (VIP) Trial.¹³ These studies showed that patients with predominantly classic SRNVM (with the classic component comprising more than 50% of the entire lesion) were less likely to lose more than three lines of vision after undergoing verteporfin/PDT therapy than patients receiving placebo. The VIP trial identified small size (< 4 MPS disc areas) or relatively low visual acuity (<65 letters) as factors for favorable outcomes in cases of occult membranes treated with PDT. Although verteporfin treatment reduced the chance of significant visual loss, it rarely resulted in significant improvement in visual acuity. Additionally, cost-utility models proved these palliative treatments were highly cost-ineffective.¹⁴ The excitement created by the robust vision recovery after application of vascular endothelial growth factor (VEGF) inhibiting agents relegated PDT to an adjuvant role in combined treatment regimens by either increasing the efficacy of anti-VEGF agents¹⁴ or decreasing the frequency of intravitreal injections with the aim of reducing the cost.¹⁵

THE PRESENT

The treatment of “wet” AMD has been revolutionized with the introduction of anti-VEGF agents. VEGF is a signaling protein important in vasculogenesis and angiogenesis.¹⁶ VEGF stimulates vascular endothelial cell growth (i.e., proliferation) and survival. VEGF also stimulates hyper-permeability of vessels and has been shown to play a major role in the development and persistence of SRNVM in wet AMD.¹⁶ Currently available pharmacotherapeutic agents used for the treatment of exudative AMD block the biological effects of VEGF on neovascular endothelium by preventing VEGF to bind its receptor on the cell surface.

Pegaptanib (Macugen^®, Eyetech Pharmaceuticals, Palm Beach Gardens, FL, USA), no longer used as in monotherapy, was the first agent introduced in clinical practice in 2004.¹⁷ It is a pegylated anti-VEGF aptamer, a single strand of nucleic acid that competes to bind to the VEGF 165 isoform. Pegaptanib underwent two concurrent, prospective, randomized, double-blind, multicenter, dose-ranging, controlled clinical trials.¹⁷ VEGF Inhibition Study in Ocular Neovascularization (VISION) demonstrated efficacy in 1,186 patients that were randomized to receive pegaptanib at a dose of 0.3, 1, or 3 mg or a sham injection every 6 weeks over a period of 48 weeks. As early as 6 weeks after beginning therapy with the study drug, and at all subsequent points, the mean visual acuity among patients receiving 0.3 mg of pegaptanib was better than in those receiving sham injections (P<0.002). Unlike PDT, benefit from treatment was not restricted to a certain type or size of SRNVM. However, pegaptanib was only able to stabilize the visual acuity better than PDT and could not dominate the clinical armamentarium a sustained period of time.

Ranibizumab (Lucentis^®, Genentech, Inc., San Francisco, CA) completed phase III FDA clinical trials for the treatment of SRNVM in exudative AMD and was approved for use in June, 2006. Ranibizumab is a 48 kDa Fab fragment of a recombinant humanized IgG1 kappa monoclonal antibody that binds to VEGF-A, including the biologically active form VEGF₁₁₀.¹⁸ Efficacy and safety of intraocular ranibizumab injections were tested in five different trials: MARINA (minimally classic/occult trial of the anti-VEGF antibody ranibizumab in the treatment of neovascular age-related macular degeneration),¹⁹ ANCHOR (anti-VEGF Antibody for the treatment of predominantly classic choroidal neovascularization in age-related macular degeneration), FOCUS (RhuFab V2 Ocular Treatment Combining the Use of Visudyne to Evaluate Safety) studies), PIER (Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration),²⁰ and PrONTO (prospective optical coherence tomography imaging of patients with neovascular age-related macular degeneration treated with intraocular Ranibizumab).²¹,²²

The phase III MARINA study¹⁹ was a multicenter, randomized, double-masked, sham-controlled trial comparing ranibizumab (0.3 or 0.5 mg) to sham injections in patients with minimally classic or occult SRNVM secondary to AMD. At 24 months, 92% of the patients who were administered 0.3 mg of ranibizumab and 90% of patients administered 0.5 mg lost fewer than 15 letters, as compared with 52.9% of patients receiving sham injections (P<0.001). Visual acuity actually improved by 15 or more letters in 24.8% of the 0.3-mg group and 33.8% of the 0.5-mg group, as compared with 5.0% in the sham-injection group (P<0.001). Mean increases in visual acuity were 5.4 letters in the 0.3-mg group and 6.6 letters in the 0.5-mg group, as compared with a decrease of 14.9 letters in the sham-injection group (P<0.001). The gain in visual acuity was maintained for 24 months.

The phase III ANCHOR study¹⁴ was a multicenter, randomized, double-masked, active-treatment-controlled clinical trial comparing ranibizumab with PDT in predominantly classic SRNVM. Four hundred and twenty three patients were enrolled in the study and randomized to verteporfin PDT therapy plus sham intravitreal injections, or monthly intravitreal ranibizumab (0.3 or 0.5mg) injections plus sham PDT treatments. The primary end point was loss of <15 letters of visual acuity. At 24 months 90% of patients treated with ranibizumab injections lost <15 letters of vision (three lines) compared with 65.7% of verteporfin PDT patients (P<0.0001). Thirty four percent of patients receiving the 0.3 mg dose of ranibizumab and 41.0% of patients receiving the 0.5 mg dose gained ≥ 15 letters (vs. 6.3% of the PDT group); on average, visual acuity improved from baseline by 8.1 letters (0.3 mg dose) and 10.7 letters (0.5 mg dose) compared to a mean decline of 9.8 letters in the PDT group.

Although the profile for systemic side effect of ranibizumab was excellent in clinical trials, concerns were raised whether these studies were adequately designed to determine possible systemic thromboembolic complications.²³ These concerns were fueled with demonstration of the biological effect of anti-VEGF drugs in the fellow eye via systemic absorption.²⁴ A recent meta-analysis of clinical trials with ranibizumab indicated an association between intravitreal injections of ranibizumab and the subsequent incidence of cerebrovascular thromboembolic events.²⁵ The safety assessment of Intravitreous Lucentis for AMD (SAILOR) study²⁶ was a phase IIIb follow-up study to the MARINA and ANCHOR studies to evaluate the long-term safety and efficacy of ranibizumab. Study results revealed a difference in stroke rate between doses, with a higher rate in the 0.5 mg dose group compared with the 0.3 mg dose group. The total number of events were low, and the difference was not confirmed statistically.

Bevacizumab (Avastin^®, Genentech, Inc., San Francisco, CA) is also a recombinant humanized IgG1 monoclonal antibody that binds to the active forms of VEGF-A. It differs from ranibizumab in being the complete IgG molecule with a weight of 149 kDa. Bevacizumab binds all isoforms of VEGF. Bevacizumab is FDA approved to treat metastatic colorectal, breast, and lung cancer.

Bevacizumab was initially used systemically for the treatment of exudative AMD in the SANA (Systemic Avastin for neovascular AMD) trial. Fifteen patients were treated with systemic bevacizumab (5 mg/kg) followed by 1 or 2 additional doses given at 2-week intervals. In all patients visual acuity increased with a decrease in central retinal thickness. The only adverse event identified was a mild elevation of systolic blood pressure which was controlled by either changing or initiating antihypertensive medication.²⁷ The use of intravitreal bevacizumab was first reported in 2005 by Rosenfeld et al.²⁸ in a patient with recurrent neovascular AMD who had previously failed verteporfin PDT with intravitreal triamcinolone acetonide and intravitreal pegaptanib therapy. Since then there have been multiple studies, both prospective and retrospective, of bevacizumab treatment for wet AMD in the literature. Schouten et al.²⁹ reviewed and compiled all the trials from the literature and evaluated the combined efficacy of bevacizumab (n=1435 patients/26 studies) for treating wet AMD. They²⁹ found the weighted mean gain in visual acuity was 12.8 letters (range, 11–14 letters) for patients treated with intravenous bevacizumab, and a weighted mean gain of 8.6 letters (range, 2–26 letters) of visual acuity in patients treated with intravitreal bevacizumab. Within a short period of time, off-label use of intravitreal bevacizumab became a strong alternative to ranibizumab due to the lower cost, comparable efficacy, longer duration of action and thus potentially less frequent repeat injections. The 1 year results of comparison of age-related macular degeneration treatments trials³⁰ (CATT), a NIH-supported randomized, multicenter, single-blind, noninferiority clinical trial that was launched to assess the relative efficacy and safety of ranibizumab and bevacizumab. CATT³⁰ was designed to determine whether an as-needed regimen (PRN) was as effective in preserving long-term visual acuity, compared to a monthly regimen. Patients were randomly assigned into four groups and received ranibizumab or bevacizumab, either on a PRN or regular monthly basis, for one year.³⁰ In the monthly dosing groups, patients received an initial intravitreal injection of the drug which was followed by subsequent injections at every 28 days regardless of the response.³⁰ Patients in the PRN groups received an initial treatment and were then examined every 28 days to determine medical need for additional treatment.³⁰ The PRN groups received subsequent treatment when there were signs of active disease clinically or on OCT imaging.³⁰ Although the CATT³⁰ study was a head-to-head comparison of both drugs, there were several intrinsic differences that were not considered. For example, ranibizumab is produced by affinity maturation and has 14 times greater affinity to the VEGF molecule. Similarly, bevacizumab can bind to Fc receptors on the cell surface and trigger internalization.³¹ This creates an intracellular reservoir of the drug that explains the longer bioeffect seen with bevacizumab despite its rapid clearance from the intraocular fluids.³² Most importantly, the amount of the agents injected into the vitreous cavity favored ranibizumab, since the molar amount of ranibizumab was 24% greater than bevacizumab. Regardless of these differences, visual acuity improved from baseline in all four study groups.³⁰ Monthly bevacizumab was equivalent to monthly ranibizumab in terms of average visual gain (8.0 and 8.5 letters, respectively).³⁰ A comparable therapeutic benefit was also observed between PRN bevacizumab and PRN ranibizumab (gains of 5.9 and 6.8 letters, respectively).³⁰ Cross-comparisons revealed that PRN Ranibizumab was equivalent to monthly ranibizumab treatments; however, the comparison between bevacizumab PRN and monthly treatments was inconclusive.³⁰ The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, P=0.03). A slightly higher proportion of patients that received bevacizumab developed at least one serious adverse event (24% vs. 19%); however, the significance of this difference is not clearly understood.³⁰ Considering that serious adverse events were not attributable to any specific organ and occurred in more patients who received less anti-VEGF drugs, the likelihood that this difference occurred either by chance or by the baseline differences of general health of the patients is high. Due to the low incidence of thromboembolic events, even in an aged cohort, larger sample sizes are required to clearly demonstrate the difference in the safety of both drugs.

Similar comparative studies between the two drugs are in progress in several different countries, such as IVAN study in Great Britain (http://www.controlled-trials.com/ISRCTN92166560), the EQUAL study in the Netherlands (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1331), the LUCAS study in Norway (http://clinicaltrials.gov/ct2/show/NCT01127360), the GEFAL study in France (http://clinicaltrials.gov/ct2/show/NCT01170767), the MANTA study in Austria (http://clinicaltrials.gov/ct2/show/NCT00710229),and the VIBERA study in Germany (http://clinicaltrials.gov/ct2/show/NCT00559715).

A more recent concern about the long-term efficacy of current anti-VEGF agents has been the gradual decrease in their bio-efficacy due to tachyphylaxis.³³ A possibly remedy for this problem would be the combination of therapeutic agents with different modes of actions.

THE FUTURE

Combined treatments

In its current form, anti-VEGF pharmacotherapy can improve visual acuity but, in most cases, the improvement can only be sustained with repeated intravitreal injections. In order to try and reduce the number of injections while maintaining the gain in visual acuity, intravitreal anti-VEGF injections in combination with different therapies as well as different treatment protocols have been explored. An industry-sponsored SUMMIT clinical trial program which investigated the efficacy and safety of combining Visudyne and Lucentis versus Lucentis monotherapy includes the DENALI (USA), MONT BLANC (Europe), and EVEREST (Asia) studies.

The DENALI (http://www.qltinc.com/newsCenter/documents/100615.pdf) study was a Phase IIIb, multicenter, randomized, double-masked study comparing standard fluence and reduced-fluence Visudyne-Lucentis combination therapies to monthly Lucentis monotherapy in 321 subjects with CNV secondary to wet AMD. Twelve-month outcomes of the DENALI study did not demonstrate a lower gain in visual acuity gain for Visudyne combination therapy compared with Lucentis monthly monotherapy. Thus, the overall benefit for patients was a reduced frequency of Lucentis to at least three months during the study.

In the MONT BLANC double-masked, multicenter study, patients with subfoveal choroidal neovascularization due to AMD were randomized to receive either PDT with ranibizumab or ranibizumab alone. The monotherapy group received three loading doses of the drug and then received injections on a monthly basis as-needed. At the 1-year follow up visit, the mean acuity in the combination group improved by 2.5 letters compared to an improvement of 4.4 letters in the monotherapy group. Ninety-six percent of the combination patients had a 3-month interval during which they did not require a treatment versus 92% of the monotherapy group though combination therapy showed a trend toward reducing Lucentis re-treatments. This difference was not statistically significant.

Another attempt to combine different treatments was the use of Macugen (pegaptanib sodium) as a maintenance agent after the induction of the treatment with ranibizumab. The results of the LEVEL trial has been documented (http://www.eyetech.com/content/pr/LEVEL StudyPressReleaseFINALMay-18-2010.pdf). In this large, open-label, uncontrolled, exploratory study, 568 patients who had been treated one to three times for neovascular AMD, primarily with a nonselective VEGF-inhibitor such as ranibizumab or bevacizumab were enrolled. After the induction phase, the mean visual acuity improved by 15.9 letters (49.6 to 65.5 letters). Once patients enrolled into the study, the injections were switched to Macugen, and treated if needed. Half of the patients required an additional treatment during the study, which was performed approximately 5 months postbaseline on average. Of those who received an additional treatment, 46% required only one treatment. At the end of the 54-week maintenance phase, final mean visual acuity was 61.8 letters.

The QLT-sponsored Phase-II, RADICAL study (The Reduced-fluence Visudyne/Anti-VEGF/ Dexamethasone in Combination for AMD Lesions Study, http://www.drugs.com/clinical_trials/qlt-announces-final-results-radical-study-evaluating-verteporfin-pdt-visudyne-combination-therapy-9675.html) assessed the efficacy of triple therapy with PDT, dexamethasone, and ranibizumab. This multicenter, randomized, single-masked study of 162 patients with SRNVM secondary to AMD compared four groups: quarter-fluence PDT followed by ranibizumab and then dexamethasone; half-fluence PDT, then ranibizumab and dexamethasone; half-fluence verteporfin followed by ranibizumab; ranibizumab monotherapy. The second combination group had statistically significantly fewer re-treatments (mean: 3) compared to monotherapy (5.4 visits). At 12 months, the average visual acuity in that second triple-therapy group improved 6.8 letters from baseline vs. an improvement of 6.5 letters in the monotherapy group.

A new approach putting anti-VEGF treatment into clinical practice has been the “treat-and-extend” protocol.³⁴ According to this protocol patients are treated monthly with intravitreal bevacizumab injections until no intraretinal or subretinal fluid is observed on optical coherence tomography. The treatment intervals then are lengthened sequentially by 2 weeks until the signs of exudation recur. The treatment is then intensified to maintain an exudation-free macula. This approach results in significant visual improvement while decreasing the patient visits, injections, and direct annual medical cost compared with monthly injections.

The PrONTO approach is the administration of three monthly injections of ranibizumab subsequently, patients are treated as needed based on changes in visual acuity, biomicroscopic examination, and OCT imaging. Using this approach patient visual acuity can be maintained with only 9.9 injections over a 2-year period at a comparable level to pivotal trails where monthly injections were employed.²¹

Pharmacotheraphy

Several more potent VEGF neutralizing drugs are currently under development.

The VEGF Trap (Regeneron, Tarrytown, NY, USA) is a fusion protein that combines the ligand-binding elements from the extracellular domains of VEGF receptors VEGFR-1 and VEGFR-2 and the Fc constant region of IgG1. It is specifically designed to bind all forms of Vascular Endothelial Growth Factor-A (VEGF-A) and placental growth factor (PLGF). VEGF trap is smaller than a full-length antibody and penetrates through retina. It has a higher affinity than the currently available anti-VEGF agents. The VIEW 1/VIEW 2 studies are phase III clinical studies comparing VEGF trap's efficacy to Lucentis in the treatment of wet AMD.³⁵ Early results indicated that all VEGF Trap-Eye dosing groups were non-inferior and clinically equivalent to ranibizumab dosed monthly for the primary endpoint of maintenance of vision. All treatment arms revealed generally favorable safety profiles and VEGF trap-eye dosed every two months demonstrated similar efficacy and safety to ranibizumab dosed monthly (American Society of Cataract and Refractive Surgery, 29^th Annual Meeting, August 20-24, 2011, Boston, MA).

An alternative strategy to inhibit the biological effects of VEGF is to target the downstream signaling cascade by inhibiting the tyrosine kinases. Currently several tyrosine kinases are in different stages of development. Vatalanib (Novartis, Basil, Switzerland) is a tyrosine kinase inhibitor that binds to the intracellular kinase domain of all VEGF receptors subtypes. Due to its high bioavailability it carries the advantage of being used orally.³⁶ Another tyrosine kinase inhibitor, Pazopanib (Glaxo-Smith-Kline, Philadelphia, PA), selectively inhibits vascular endothelial growth factor receptors (VEGFR)-1, -2 and -3, c-kit and platelet derived growth factor receptors (PDGF-R) and topical application is also being evaluated for the treatment of exudative AMD.³⁷ Other topically applied tyrosine kinase inhibitors such as TG100801 and TG101095 (Targegen, San Diego, CA, USA) have also shown beneficial effects in early trials.

Bevasiranib (Opko, Miami, FL, USA) is an RNA induced protein silencing complex (siRNA) that is designed to silence VEGF-A mRNA. The phase II Cand5 Anti-VEGF RNAi Evaluation study (CARE) did not show a robust effect. The visual acuity of the patients receiving bevasiranib decreased and their lesion size increased. These results were explained by the failure of neutralizing the cellular pool. For this reason, Phase III was designed to test the efficacy of bevasiranib in combination with Lucentis.³⁸

Volociximab (Ophthotech, Princeton, NJ, USA) is a chimeric monoclonal antibody that inhibits the functional activity of a5ß1 integrin, a protein found on activated endothelial cells. Blocking the activity of a5ß1 integrin has been found to prevent angiogenesis. Volociximab is currently being investigated as an adjuvant therapy with ranibizumab.³⁹

Other rapidly developing treatments for exudative AMD are chemotherapeutic/immune modulating drugs. Inflammation and the immune system (specifically macrophages) have been shown to play a role in the development of SRNVM. Infliximab (Remicade^®, Centocor OrthoBiotech) is a monoclonal antibody that binds and neutralizes tumor necrosis factor alpha. A case series has reported efficacy,⁴⁰ and further studies are under way. Methotrexate inhibits dihydrofolate reductase, inhibiting lymphocyte proliferation. It is also being investigated as a potential therapy for wet AMD.⁴¹ Sirolimus (Rapamune^®, Wyeth) is another drug being studied to treat wet AMD. Sirolimus inhibits the response of the immune system to IL-2 and blocks activation of T- and B-cells. This small, highly lipophilic compound has the advantage of being used locally.⁴²

Complement inhibitors are a new class of drugs that have started to emerge after the discovery of the role of the complement system in AMD pathogenesis. POT-4 is a peptide that binds and inhibits complement factor C3. It is currently being studied in the treatment of choroidal neovascularization.³⁷ Another molecule being studied in the treatment of wet AMD is ARC1905. It is an aptamer that inhibits activation of complement factor 5.³⁷

Radiotheraphy

Radiation therapy is also being investigated for the treatment of wet AMD. Epiretinal strontium-90 application alone or in combination with bevacizumab showed promising results. Long-term safety is still pending. Epiretinal radiation treatment requires pars plana vitrectomy. The radiation is delivered via a probe intravitreally, minimizing damage to surrounding tissue.⁴³,⁴⁴ Oraya Therapeutics (Newark, CA, USA) is developing the IRay externally-applied stereotactic orthovoltage irradiation for the treatment of exudative AMD.⁴⁵ This procedure will be clinic based and will not require pars plana vitrectomy. The CNV Secondary to AMD Treated with Beta Radiation Epiretinal Therapy (CABERNET, CLH002) study is a phase 3 multicenter, randomized, controlled trial of epimacular brachytherapy using a prototype device. The trial recently completed its recruitment target of 450 patients at 45 clinical centers worldwide with phase 3 results from CABERNET on the immediate horizon, epimacular brachytherapy may become a viable therapeutic option capable of reducing the treatment burden to health care systems globally. The VIDION^®, a epimacular brachytherapy device by Neovisa Inc., has been approved in Europe (2009) for the treatment of wet AMD. Proton beam radiation is another method of radiation delivery that is currently being studied.⁴⁶

Tissue engineering (maculoplasty)

Within the last 5 years we have witnessed major advances in the treatment of exudative AMD. The common characteristic of current treatment techniques for exudative AMD is that they all either obliterate the subretinal choroidal vasculature or decrease the leakage from the vasculature, disregarding the fact that restoration of the central vision requires reestablishment of a healthy choriocapillaris-RPE-photoreceptor subretinal interface. As a consequence of these treatments, at best a smaller fibrovascular scar develops beneath the photoreceptors but still disrupts the relationship between choriocapillaris, RPE, and photoreceptors. Deranged subretinal anatomy subsequently leads to photoreceptor cell death, and loss of central vision. Unfortunately, treatments that do not correct the altered subretinal milieu are far from being a cure for AMD and remain palliative measures. Also, these treatments can only be beneficial when the subretinal choroidal neovascularization is active. However, there is a large unmet need for many patients who have already lost vision from this condition. There are several clues that reconstitution of the normal subretinal architecture can lead to visual improvement in these individuals. For example, the main cause of visual loss in exudative AMD is not due to photoreceptor cell death but rather due to patchy loss of RPE cells and disruption of RPE-photoreceptor interface by the invading subretinal fibrovascular tissue.⁸ Histopathological studies revealed that 25% of the photoreceptors over a well-established subretinal neovascular complex are still viable.⁴⁷ Although this ratio drops to 14% over late disciform scars the residual photoreceptors are still adequate enough to allow better than 20/200 vision once placed on an intact RPE.⁴⁸ Establishing RPE-photoreceptor interface surgically has been attempted by translocating foveal photoreceptors to an adjacent area of intact RPE or placing a patch of free peripheral RPE-choroid graft under the fovea.⁴⁹ Although these surgeries are associated with high rates of surgical complications, they proved the principle that reconstruction of the altered subretinal architecture can restore the foveal vision. Early attempts of subfoveal membranectomy, RPE transplantation and macular translocation have been grouped under the new term “Maculoplasty.”⁵⁰ Maculoplasty is an overall tissue engineering attempt to reestablish the normal subretinal anatomy. It includes removal of subretinal neovascular complex, repair and refurbishment of Bruch's membrane, repopulation of RPE and choriocapillaris, restoration of healthy photoreceptor-RPE interface, and repair of photoreceptor defects. Several preliminary studies have already been performed to accomplish the goals of Maculoplasty:

1. Excision of the subretinal neovascular complex: although surgical removal of the SRNVM membrane was challenging, initial trials did not show any functional benefit.⁵¹ The main reason for this observation was the removal of the RPE cells surrounding the neovascular complex along with parts of the adherent Bruch's membrane. Absence of RPE was followed by closure of the underlying choriocapillaris and loss of photoreceptors.⁵²

2. RPE transplantation: several attempts to populate the RPE defects by RPE transplants have failed mainly because the transplanted RPE fail to attach to the aged and partially destroyed Bruch's membrane similar to the failure of the neighboring native RPE to repopulate these defects.⁵³ Unattached RPE cells eventually die by apoptosis.⁵³

3. Restoration of aged Bruch's membrane: early studies indicated that the dismal fate of RPE cells on aged Bruch's membrane can be reversed by chemical cleaning of the debris and recoating of the Bruch's membrane with extracellular-matrix molecules.⁵⁴ Thus, a rejuvenated Bruch's membrane can support proliferation and differentiation of RPE.⁵⁴

4. Replenishing cellular defects: the recent alleviation of the restrictions on the use of stem cell research has fueled the hopes of restoring the retinal cell mosaic by using these cells. Several studies have shown the differentiation of these cells into RPE⁵⁵ and photoreceptors.⁵⁶

CONCLUSION

There are many approaches that will target neovascularization, or inhibit and destroy existing SRNVM. However, the real goal of exudative AMD treatment lies in preventing subretinal choroidal neovascularization. Use of high-dose of antioxidants and vitamins according to age-related eye disease study (AREDS) formula has a marginal benefit in preventing exudative AMD.⁵⁷ Apart from AREDS formula change of life style, such as diet and cessation of smoking, has been shown to affect the development of AMD. A more definite risk assessment will be based on genotyping. Mapping the genotype has already proved useful in predicting the response to various treatment modalities.⁵⁸ As our understanding of molecular genetics of AMD improve, we may see patient-oriented treatments based on pharmacogenetics. Another rapidly evolving field is the search for a biomarker for the early diagnosis and monitoring of the subretinal choroidal neovascularization. Proteomic analysis of the donor eyes and serum has revealed higher amounts of plasma carboxyethylpyrrole (CEP) oxidative protein modifications in patients with exudative AMD. However, the sensitivity and specificity of the test is still below the desired level.⁵⁹

As we better understand the pathophysiology of AMD, earlier intervention to block cellular and molecular events causing the pathological mechanisms that lead to the development of choroidal neovascularization are likely. A good example is the recent discovery of hemoglobin production by human RPE cells. The common denominator in all forms of subretinal choroidal neovascularization, including idiopathic polypoidal choroidal vasculopathy, and retinal angiomatous proliferation, is subfoveal hypoxia. All major risk factors for AMD, such as aging,⁶⁰ presence of age-related maculopathy,⁶¹ smoking⁶² and systemic hypertension,⁶³ are associated with impaired subfoveal blood flow which subsequently upregulates VEGF. Discovery of RPE-hemoglobin synthesis and its oxidation by aging brings a new perspective to our understanding of AMD pathophysiology. Targeting upstream molecules will undoubtedly result in more rational and effective treatment strategies in the future.