Management of Neovascular Age-related Macular Degeneration: A Review on Landmark Randomized Controlled Trials.

In the last decade, a number of prospective clinical trials with carefully designed study protocols have been conducted for the treatment of neovascular age-related macular degeneration (AMD). These landmark clinical trials such as ANCHOR and MARINA and, more recently, the Comparison of AMD Treatment Trials and VIEW studies have revolutionized the management of neovascular AMD. While AMD continues to remain a leading cause of severe visual loss worldwide, advances in pharmacotherapeutics have led to substantial improvements in the outcome of these patients. The introduction of anti-vascular endothelial growth factor agents has resulted in improvement of visual outcomes and has had a positive impact on the quality of life among elderly population. While the contemporary management of neovascular AMD has been successful in tremendously reducing the visual morbidity, the financial burden of therapy has increased exponentially. To overcome these challenges, newer pharmacologic agents are evaluated for their efficacy and safety in AMD. Ground-breaking advances in bench to bedside research have led to discovery of new pathways that appear to be viable targets for preventing visual loss in AMD. In this review, study designs and results of landmark clinical trials in AMD from the past decade have been summarized.

INTRODUCTION

Neovascular age-related macular degeneration (AMD) is responsible for visual loss in a significant proportion of elderly population.1 Overall, it is the third major cause of blindness worldwide.123 Epidemiological studies estimate that more than 10% of the adults over 65 years of age develop visual loss due to AMD and are at significant risk for becoming legally blind.4 Thus, neovascular AMD significantly affects functioning, independence, and overall quality of life among geriatric population.

Development of choroidal neovascularization (CNV) leading to accumulation of intra- and/or sub-retinal fluid, heme, and exudates from the friable new vessels with subsequent fibrous scarring results in progressive loss of central vision in its natural course if left untreated. Thus, neovascular AMD significantly affects functioning, independence, and overall quality of life among geriatric population. A number of therapeutic strategies such as thermal laser photocoagulation56 and macular surgery7 have been evaluated without much success. Introduction of photodynamic therapy (PDT) with verteporfin expanded the therapeutic options for patients with subfoveal CNV although with very limited improvement in visual acuity.8 However, inhibition of vascular endothelial growth factor (VEGF) appears to be the most successful therapy for neovascular AMD with superior visual outcomes.91011 Anti-VEGF therapy has expanded the repertoire of treatment options for the various subtypes of CNV associated with AMD.

In this manuscript, we have comprehensively reviewed study designs and results of various landmark clinical trials in AMD from the past decade which have shown unprecedented rise of anti-VEGF drugs as the most efficacious treatment modality available for neovascular AMD to date.

PHOTODYNAMIC THERAPY

PDT with verteporfin was established as a safe and effective treatment for neovascular AMD.8 Over the past decade or more, a number of landmark clinical trials have compared the efficacy of PDT as a monotherapy as well as in combination with anti-VEGF agents. PDT essentially consists of phototherapy with laser that results in selective generation of free radicals in the subretinal tissue. These reactive oxygen species result in cytotoxic damage and chemical destruction of abnormal new vessels with regression of CNV after intravenous administration of verteporfin, a photosensitizing agent.

In 1999, the treatment of AMD with photodynamic therapy (TAP) study group consisting of 22 ophthalmology practices across Europe and North America published the 12-month primary endpoint results of two randomized clinical trials in AMD.12 TAP studies (n = 609) were two parallel, double-masked, placebo-controlled (2:1 randomization) trials that assessed safety and efficacy of 3 monthly PDT in patients with classic subfoveal CNV. Sixty-one percent of the patients who were treated with PDT lost <15 letters at month 12 compared with 46% with placebo (P < 0.001). Adverse events noted were minor with transient visual disturbances (18% vs. 12%), photosensitivity (3% vs. 0%), and injection site-related events (13% vs. 3%) among others.12 At 24 months follow-up, the percentage of patients losing <15 letters was significantly less in PDT group compared with controls (53% vs. 38%; P < 0.001).13 Another landmark trial, the Verteporfin in Photodynamic Therapy (VIP) study (Report 2), provided further evidence favoring the use of PDT in neovascular AMD.14 VIP was a randomized, double-masked, sham-controlled study investigating the efficacy of PDT in occult CNV (n = 339; 2:1 randomization). At 2 years, PDT was shown to decrease the risk of moderate and severe visual loss compared with placebo.14 Fifty-four percent of the PDT-treated patients lost 15 letters compared with 67% in the placebo-treated arm (P = 0.23) after a mean of 5 treatments over 24 months. However, both trials demonstrated that with PDT, only modest improvement in the best-corrected visual acuity (BCVA) can be expected among patients with neovascular AMD.

Visudyne in Occult CNV (VIO) was a randomized, double-masked, placebo-controlled trial that evaluated the efficacy of PDT among patients with subfoveal occult (with no classic) CNV due to neovascular AMD (n = 384; 2:1 randomization). At month 24, 47% of the patients with PDT compared with 53% of the patients receiving placebo lost ≥15 letters (not significant). No ocular or systemic adverse events were noted.15 The results of VIO provided strong evidence that lesions of occult CNV may not be amenable to treatment with PDT.

Following the successful approval of PDT for neovascular AMD, especially classic with no occult type, a large prospective longitudinal study was conducted in 45 ophthalmology departments in the UK (n = 7748) (Verteporfin Photodynamic Therapy Cohort Study Group).16 The study was designed in a way that the patients included in the trial would have been eligible for TAP trial (classic or predominantly classic CNV). The major highlight of the study was that patients required fewer numbers of treatments compared with the TAP trial (2.35 vs. 3.4 in year 1; P < 0.0001). Although the retreatment criteria were similar to TAP trial, fewer re-treatments in the index trial indicated that with experience, clinicians may not strictly adhere to protocols required by key licensing trials in routine practice.16 Despite this finding, a detailed cost-effectiveness analysis of the study cohort suggested that PDT is unlikely to be cost-effective as a monotherapy for AMD.17

Although PDT was one of the first successful pharmacological treatment options for AMD, its use as monotherapy is no longer recommended since the advent of anti-VEGF therapies. However, there has been a renewed interest in PDT for a specific subset of patients with AMD, especially in combination with anti-VEGF agents. Lucentis and PDT On polypoidal choroidal vasculopathy (LAPTOP) study (n = 93) randomized patients (1:1) with treatment-naïve polypoidal choroidal vasculopathy (PCV) to receive either PDT or ranibizumab (RBZ) monotherapy (0.5 mg) (3 monthly injections).18 While the visual outcomes were superior with RBZ compared with PDT (P = 0.004; month 24), PDT was able to efficiently induce regression of the PCV lesions.19 EVEREST study (n = 61), a Phase 4 randomized controlled trial, was the first indocyanine green angiography-based study for patients with PCV. The results of EVEREST study indicated that treatment with PDT + RBZ was superior to RBZ alone for achieving regression of polyps at month 6.20

ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR AGENTS

Ranibizumab

RBZ (Lucentis®, Genentech, California, USA) is a monoclonal antibody fragment (Fab) that inhibits VEGF and prevents ocular neovascularization in conditions such as AMD and diabetic macular edema (DME) among others. RBZ has been extensively evaluated for the management of AMD and has been approved by the United States Food and Drug Administration (FDA) in 2006 for this indication.9 At present, RBZ is regarded as an important breakthrough in the treatment for AMD although comparative trials and a recent Cochrane review have shown BCVA results comparable with bevacizumab (BCZ).11

Trials evaluating fixed-dosing or monthly regimen

Historically, the anti-VEGF Antibody for the Treatment of Predominantly Classic CHORoidal Neovascularization in AMD (ANCHOR) study (n = 423) was a landmark Phase 3, multicenter clinical trial that compared the efficacy of RBZ with PDT and conclusively established the superiority of RBZ in the management of predominantly classic neovascular AMD.21 In this study, patients received fixed monthly dose of RBZ (0.3 mg or 0.5 mg) plus sham verteporfin or sham intravitreal therapy plus PDT (1:1:1). The highlight of the study was improvement of ≥15 letters of BCVA in 35.7% of the patients belonging to the 0.3 mg RBZ group and 40.3% of the patients in the 0.5 mg group, compared with only 5.6% in the PDT arm (P < 0.001) at 1-year primary endpoint. Low rates of serious adverse events were noted with RBZ.21 BCVA improvements with RBZ were consistent through year 2 with ≥90% patients losing <15 letters in the RBZ arm compared with 65.7% in the PDT arm (P < 0.0001).22

The minimally classic/occult trial of the anti-VEGF Antibody RBZ in the Treatment of Neovascular AMD (MARINA) study (n = 716) was a 2-year, multicenter, double-masked, randomized controlled trial that included patients with either minimally classic or occult (with no classic lesions) CNV. The treatment consisted of fixed monthly RBZ (0.3 or 0.5 mg) or sham for 24 months. At month 12, compared with 62.2% in the sham group, 94.5% and 94.6% patients in the RBZ arm lost <15 letters (P < 0.001). Patients receiving RBZ gained a mean of 6.5 and 7.2 letters whereas those in the sham group lost 10.4 letters. This benefit was maintained at month 24.23 Thus, both ANCHOR and MARINA provided strong evidence of the efficacy of RBZ across the spectrum of neovascular AMD.

PIER study (n = 184) was designed to evaluate fixed-dosing strategy with RBZ to reduce the treatment burden.24 PIER study was a multicenter, double-masked, sham-controlled trial that randomized patients with subfoveal CNV (with or without classic CNV) to receive mandatory doses of either RBZ (0.3 or 0.5 mg) or sham (1:1:1) monthly for 3 months, followed by quarterly treatments. At 1 year, the mean changes in BCVA were −16.3, −1.6, and −0.2 letters in the sham, 0.3 mg, and 0.5 mg groups (P < 0.0001 for RBZ vs. sham), respectively. Detailed analysis revealed that there was a 4.5 letters decline in BCVA between months 3 and 12 in both RBZ groups with quarterly treatment.24 During the year 2, the study protocol was amended so that all the patients in the trial, including the sham group, received monthly 0.5 mg RBZ after a careful review of ANCHOR,22 MARINA, and 12-month PIER study results. Subsequently, after 4 months of monthly treatment, patients in the RBZ arm gained a mean of 2.2 and 4.1 letters (0.3 mg and 0.5 mg arms, respectively).25

EXCITE study (n = 353) was a multicenter, randomized, double-masked trial that compared the quarterly fixed-dosing regimen employed in the PIER trial to monthly RBZ therapy.26 The study randomized patients (1:1:1) to receive RBZ (0.3 mg: Arm A or 0.5 mg: Arm B) 3 initial monthly doses followed by quarterly injections or monthly 0.3 mg RBZ (Arm C). The study results demonstrated higher BCVA gain in the monthly dosing arm compared with the quarterly treatment arm of RBZ (4.9, 3.8, and 8.3 letters).26 PIER and EXCITE study established the superiority of monthly dosing regimen over quarterly fixed-dosing schedule.

Trials evaluating pro re nata regimen

The pro re nata (PRN) therapy consists of needed dosing with anti-VEGF agents so that the burden and risks of frequent dosing are minimized. The Prospective optical coherence tomography (OCT) Study with Lucentis for Neovascular AMD Prospective Optical Coherence Tomography Imaging of Patients with Neovascular AMD treated with intraocular Ranibizumab (PrONTO) study (n = 40) was an open-label, prospective, nonrandomized trial that evaluated OCT-based PRN approach to RBZ dosing.27 Patients in the study received monthly 0.5 mg RBZ for 3 months followed by PRN dosing (if there was persistent fluid on OCT or a thickness increase of >100 µm, apart from other criteria). At month 12, patients gained a mean of 9.3 letters (P < 0.001) with 5.6 injections.27 During year 2, the study protocol was amended and retreatment was offered in the presence of any qualitative change in the OCT suggestive of recurrent fluid, such as enlargement of pigment epithelial detachment. The mean BCVA gain was 11.1 letters with 9.9 injections in 2 years.28 PrONTO study results provided strong clinical evidence encouraging the use of OCT-based PRN therapy for the management of neovascular AMD.

The Study to Evaluate RBZ in Subjects With CNV Secondary to AMD Safety Assessment of Intravitreous Lucentis for AMD (SAILOR Study) (n = 4300) was a multicenter, randomized/open-label clinical trial of 3 initial monthly doses followed by PRN dosing of RBZ (0.3 or 0.5 mg) (1:1) (either OCT-based criteria or physician discretion).29 The mean BCVA improvement in the cohort of treatment-naïve patients (n = 2378) was 0.5 and 2.3 letters (0.3 and 0.5 mg groups, respectively), and patients who had previously received treatments (n = 1929) had improvements of 1.7 and 2.3 letters (0.3 and 0.5 mg cohorts).29 The results of the SAILOR suggested inferior outcomes with PRN dosing but encouraged further investigations to establish optimal dosing regimen for AMD.

The Study of RBZ in Patients with Subfoveal CNV Secondary to AMD (SUSTAIN) study (n = 513) was a multicenter, open-label study evaluating efficacy of PRN RBZ after 3 initial mandatory doses. The mean number of re-treatments after month 3 was 2.7. Mean BCVA gain was +5.8 letters at month 3 but declined to +3.6 at month 12.30 Similar to the SAILOR trial, SUSTAIN study provided further evidence that PRN dosing may not be the optimal strategy for AMD.

HORIZON study (n = 853) was an open-label extension study that enrolled patients who completed 2 years of ANCHOR,22 MARINA, and FOCUS trials. Study patients were eligible to receive PRN treatments at physician's discretion with 0.5 mg RBZ (without any prespecified criteria). The study participants had either had prior treatment (n = 600) or were prior control patients who crossed over into treatment (n = 190) or were RBZ-naïve (n = 63). Patients who had previously had monthly injections lost a mean of 5.3 letters from baseline. Similarly, patients in the crossover and naïve cohorts lost a mean of 2.4 and 3.1 letters, respectively.31

Thus, studies employing the PRN strategy clearly demonstrate suboptimal BCVA outcomes compared with monthly treatment regimen. Moreover, the burden of frequent clinic visits is not reduced with PRN dosing. This necessitated further research employing alternate treatment strategies for neovascular AMD.

Trials evaluating treat-and-extend regimen

Recent clinical trials have evaluated the treat-and-extend strategy to optimize the dosing regimen of RBZ. This dosing strategy consists of extending the interval of the next visit if the lesions are found to be inactive. SALUTE study (n = 104) was a randomized, multicenter, open-label study that evaluated the currently preferred treat-and-extend regimen of RBZ for neovascular AMD in a Turkish cohort. In SALUTE study, at month 12, the median change in BCVA was similar between PRN and treat-and-extend groups (−0.12 vs. −0.18; P = 0.267).32 The study results were significant as it highlighted potential advantages of the treat-and-extend strategy in decreasing the burden of frequent clinic visits.

TREX-AMD study is a similar trial that compares monthly RBZ to treat-and-extend regimen (n = 60; 1:2 randomization). At month 12, the mean BCVA gain was 9.2 and 10.5 letters in the monthly and treat-and-extend cohorts (P = 0.60).33 TREX-AMD results are significant as it provides level I evidence favoring the use of treat-and-extend strategy in managing patients with active AMD.

Trials evaluating combination therapies with ranibizumab

Following the successful use of RBZ in the treatment of neovascular AMD, investigators attempted to evaluate the combination of anti-VEGF therapies with verteporfin PDT since it was believed that both the agents target different components in the pathogenesis of AMD. It was hoped that the two agents will have synergistic effect and further improve visual outcomes in AMD. SUMMIT clinical program was launched with an aim to evaluate the safety and efficacy of RBZ + PDT in neovascular AMD and consisted of MONT BLANC (Europe)34 and DENALI (The United States and Canada)35 studies.

MONT BLANC was a Phase 2, multicenter, double-masked randomized controlled trial (n = 255) that randomized patients with predominantly classic, minimally classic, or occult CNV (1:1) to receive either PRN PDT + RBZ (0.5 mg) or PRN RBZ + Sham (5% dextrose infusion). Patients in the PDT + RBZ arm received combination treatment on day 1 followed by injection RBZ at months 1 and 2. Following this initiation period, PDT + RBZ was repeated as per protocol-defined criteria on PRN basis. In this study, the combination arm did not show benefits in terms of BCVA gain (+2.5 vs. +4.4 letters; P < 0.0048) or reduction in the number of RBZ re-treatments (1.9 vs. 2.2 injections; P = 0.1373) at month 12. Thus, while the combination therapy was well tolerated, there were no clear advantages of combining the two treatment strategies.34

DENALI study (n = 321) was a similar multicenter, double-masked randomized controlled trial that included patients with subfoveal CNV secondary to AMD. The subjects were randomized (1:1:1) to receive PDT (standard fluence [SF]) + RBZ (0.5 mg), PDT (reduced fluence [RF]) + RBZ (0.5 mg), or sham PDT + 0.5 mg RBZ. Similar to MONT BLANC study, subjects in the combination arms in the DENALI received PDT + RBZ on day 1 followed by RBZ at months 1 and 2, and PRN PDT + RBZ until month 11. However, patients in the sham PDT + RBZ arm received mandatory monthly RBZ until month 11. At month 12, RBZ monotherapy arm performed better than the combination arms (+8.1 letters compared with +4.4 letters in SF PDT arm and +5.3 letters in RF PDT arm).35 Thus, SUMMIT trials (DENALI and MONT BLANC) did not provide encouraging results for the use of PDT + RBZ combination in clinical practice.

In summary, based on the extensive evaluations of RBZ, this agent is regarded as highly efficacious with an overall acceptable safety profile for neovascular AMD at a dose of either 0.3 mg (US) or 0.5 mg. HARBOR study was a recent trial that evaluated the safety and efficacy of 2 mg RBZ for AMD. However, the study results did not favor the use of high dose RBZ (2 mg).3637 Thus, a majority of modern clinical protocol designs testing novel agents for AMD consist of 0.3 or 0.5 mg RBZ as the active comparator.

Aflibercept

Aflibercept (AFL) (Eylea, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA) (VEGF Trap-Eye) is a 115 kDa recombinant fusion protein that consists of portions of human VEGF receptor-1 (VEGFR-1) and VEGFR-2 fused to the Fc domain of human immunoglobulin G1.38 This compound exhibits higher affinity than RBZ for VEGF-A/-B and binds all the VEGF isoforms, forming an inert stable complex.39

The Clinical Evaluation of Anti-angiogenesis in the Retina Intravitreal Trial (CLEAR-IT) 1 study (n = 21) was an early Phase 1 dose-escalation, multicenter, interventional clinical trial evaluating the safety, tolerability, and biological activity of intravitreal VEGF Trap-Eye in neovascular AMD.40 Patients were monitored for adverse events, changes in central retinal thickness, BCVA, and CNV lesion size on fluorescein angiography for 6 weeks. The study results demonstrated that intravitreal dose of up to 4 mg was well tolerated with no evidence of local ocular adverse events. BCVA remained stable or improved ≥3 lines in 95% of patients with a mean increase in BCVA of 4.6 letters at 6 weeks.40 In the part 2 of the CLEAR-IT 1 study, 28 patients received single intravitreal injection of 0.15 or 4 mg VEGF Trap-Eye (the range of doses demonstrating clinical activity in part 1) followed by 8 weeks of observation.41 The 4 mg dose significantly reduced central retinal/lesion thickness (CR/LT) compared with 0.15 mg dose at weeks 4 and 6 (P < 0.03) and higher number of patients in 4 mg arm gained ≥10 letters compared with 0.15 mg group at week 8 (6/14 compared with 1/14 patients, respectively). No serious adverse event or ocular inflammation was reported in either group.41

CLEAR-IT 2 study (n = 157; 159 randomized) was a Phase 2 prospective, randomized, multicenter trial evaluating VEGF Trap-Eye at different doses and dosing intervals.42 Patients were randomized to five dose groups (1:1:1:1:1) with two groups receiving monthly doses of either 0.5 or 2.0 mg for 12 weeks (at weeks 0, 4, 8, and 12), and three groups receiving 3-monthly doses of 0.5, 2.0, or 4.0 mg for 12 weeks (at weeks 0 and 12). Following this initial dosing period, patients were treated with the same dose of VEGF Trap-Eye on PRN basis until week 52. After 12 weeks of treatment, there was a mean decrease in CR/LT of 119 μm from baseline in all groups.42 Beginning week 16, patients were treated on a PRN basis with their assigned dose.43 The week-52 results demonstrated continued improvement in BCVA and CR/LT in all the groups (P < 0.0001). The median time to first reinjection in all groups was 129 days and 19% of patients required no more injections after week 12. Repeated dosing with VEGF Trap-Eye was well tolerated over 52 weeks of treatment.43

Following encouraging results from early clinical trials, AFL was tested in larger, Phase 3 clinical trials across multiple clinical centers throughout the world. VIEW 1 and VIEW 2 (VEGF Trap-Eye: Investigation of efficacy and safety in wet AMD) were two parallel, pivotal Phase 3, double-masked, randomized multicenter clinical trials comparing AFL and RBZ in patients with neovascular AMD (noninferiority study design).44 VIEW 1 study (n = 1217) was carried out in North America (July 2007 – July 2011), and VIEW 2 study (n = 1240) was carried out in Europe, the Middle East, the Asia-Pacific region, and Latin America (April 2008 – August 2011). Both the studies evaluated percentage of patients who maintained visual acuity, defined as loss of <15 letters BCVA on the Early Treatment of Diabetic Retinopathy Study chart at 52 weeks. Patients were randomized to four groups: three groups receiving AFL at different dosing regimen (0.5 mg every 4 weeks, 2 mg every 4 weeks, and 2 mg every 8 weeks [following 3 initial monthly injections]) compared with RBZ 0.5 mg every 4 weeks.44

At 52 weeks (primary endpoint), VIEW 1 study showed that in AFL groups, BCVA was maintained in 96% of patients receiving 0.5 mg monthly, 95% of patients receiving 2 mg monthly, and 95% of patients receiving 2 mg every 2 months, which was noninferior and clinically equivalent to the group receiving RBZ 0.5 mg monthly, where 94% of patients maintained vision. Adverse events reported in the 52-week results included nonfatal strokes, nonfatal myocardial infarction, or death from vascular events or an unknown cause. The VIEW 2 study results were almost identical. In AFL groups, BCVA was maintained in 96% of patients receiving AFL 0.5 mg monthly, 96% of patients receiving 2 mg monthly, and 96% of patients receiving 2 mg every 2 months.44

Based on the robust evidence from Phase 3 study results, AFL received FDA approval for the treatment of neovascular AMD in November 2011. The approved dose was 2 mg and the approved treatment regimen was a loading dose of 3 monthly injections followed by dosing every 8 weeks thereafter.

The 2nd year of the VIEW studies (week 52 through 96) (n = 2457) was designed in a way that patients received retreatment with AFL on a PRN schedule on protocol-defined criteria based on their original dosing assignment.45 However, mandatory dosing was required at least every 12 weeks. Week 96 results echoed previous results with more than 91% patients maintaining BCVA across all treatment groups. Patients in AFL group required fewer injections compared with the RBZ arm in the PRN phase (P < 0.001; post-hoc analysis). AFL demonstrated similar safety profile compared with RBZ.4546 Further analysis revealed that the incidence of postinjection rise in intraocular pressure was lesser with AFL compared with RBZ.47

These studies demonstrate that AFL is an effective and preferred treatment option for neovascular AMD with a potential to reduce the burden and associated risks associated with monthly RBZ or BCZ injections.48

Bevacizumab

BCZ (Avastin®, Genentech Inc., San Francisco, USA) is a recombinant humanized monoclonal antibody that binds and inhibits VEGF.49 Due to its biological similarity to RBZ, it is the most widely used anti-VEGF agent (off-label) for the treatment of neovascular AMD.50

Intravitreal BCZ for CNV caused by AMD (IBeNA) (n = 45) was a Phase 1, prospective, nonrandomized, open-label study that evaluated safety of three dose regimens (1.0, 1.5, and 2.0 mg) of BCZ for subfoveal CNV.51 The results from this trial indicated that BCZ is safe and well-tolerated. At week 12, improvement in BCVA from baseline was noted (P < 0.001) with stabilization/decrease in the CNV area (P < 0.001).51 Intravitreal BCZ in combination with verteporfin PDT for CNV associated with AMD (IBeVe) (n = 11) study investigated the role of combination therapy with PDT and intravitreal BCZ (1.5 mg dose). Study results suggested that a possible synergistic effect may arise from the combination of BCZ and verteporfin PDT for the treatment of neovascular AMD.52

BCZ for neovascular AMD (ABC trial) was one of the first largest studies that assessed the safety and efficacy of BCZ in the management of neovascular AMD.53 The study enrolled 131 patients from three centers in the UK and randomized the subjects (1:1) to receive either 1.25 mg BCZ (three loading doses 6 weeks apart followed by PRN therapy) or standard of care (PDT for predominantly classic type, or pegaptanib or sham for occult or minimally classic type). At 54 weeks, 32% patients in BCZ arm gained ≥15 letters from baseline compared with 3% in the standard of care group (P < 0.001). Mean BCVA gain in the BCZ arm was 7.0 letters. Low rates of serious adverse events were recorded.53 Encouraged by the results of the ABC trial, a number of trials employing BCZ were initiated world over.

An open-label, single-center, randomized, controlled clinical trial (n = 28) compared 1 mg BCZ (0.04 ml) and verteporfin PDT combined with 4 mg intravitreal triamcinolone (IVTA) in neovascular AMD.54 The improvement in mean BCVA in the BCZ arm was significantly better than the combined PDT plus IVTA arm at each follow-up visit up to 6 months (P = 0.03). Despite small sample size and limited follow-up of 6 months, this study emphasized the potential of BCZ in neovascular AMD.54

More recently, clinical trials have focused on optimizing the dosing regimen of BCZ. In 2013, the BCZ in patients with minimally classic and occult CNV (BeMoc) Trial,55 a prospective randomized controlled open-label study (n = 99), was conducted to compare the outcomes of PRN regimen with three initial mandatory doses of 1.25 mg BCZ and PRN regimen without any initial mandatory loading dose. The study subjects were patients with minimally classic or occult CNV secondary to AMD. The results from this trial showed that patients in the former group had a higher mean BCVA gain (2.08 vs. 0.86 letters, P > 0.05).55 Thus, with initial mandatory dosing, there may be slightly better BCVA outcome.

Presently, BCZ is the most commonly used anti-VEGF agent for the treatment of active neovascular AMD at no <4 weekly intervals. A recent, single-center trial evaluated the safety and efficacy of rapid induction BCZ (every 2 weekly for first three injections) in treatment-naïve patients. However, biweekly BCZ did not demonstrate significant anatomic or functional benefit compared with monthly induction or PRN, but rather increased the risk of development of subretinal fibrosis.56 To decrease the treatment burden, another prospective open-labeled randomized study (n = 120) compared OCT-based variable dosing regimen of BCZ with fixed-interval dosing. No significant differences were noted in the final BCVA (P = 0.81), but the treatment burden decreased with OCT-based variable regimen (3.8 vs. 9.5 injections at 1 year; P < 0.001).57

Trials comparing anti-vascular endothelial growth factor agents for neovascular age-related macular degeneration

A number of randomized clinical trials have been conducted to evaluate the safety and efficacy of anti-VEGF agents for the treatment of neovascular AMD in varying dosing frequencies. These studies have enabled clinicians to better define the role of anti-VEGF agents in the management of neovascular AMD.

The inhibition of VEGF in age-related CNV (IVAN) Study was a multicenter, randomized, noninferiority trial (n = 628 randomized; 610 treated).58 The study subjects were randomized to four treatment arms: RBZ or BCZ, given either every month (continuous) or PRN (discontinuous) (1:1:1:1). While the primary outcome was at 2 years, the interim analysis at 1 year revealed inconclusive results with no significant difference between the two drugs or the two dosing regimens.58

At 2 years primary endpoint, the BCVA was similar between RBZ and BCZ groups, and the continuous and discontinuous treatment groups. The mean difference in BCVA between BCZ and RBZ was −1.37 letters (95% confidence interval [CI]: −3.75–1.01; P = 0.26) and −1.63 letters (95% CI: −4.01–0.75; P = 0.18) between the continuous and discontinuous groups. However, near visual acuity and contrast sensitivity were significantly worse with the discontinuous regimen (P = 0.04 and 0.01 respectively). No significant differences were observed in the frequency of systemic arteriothrombotic events between any groups. But the overall mortality was lower with continuous treatment compared with discontinuous treatment (P = 0.05). The study results of IVAN established that RBZ and BCZ appear to have similar efficacy for neovascular AMD.59

The Multicenter Anti-VEGF Trial in Austria (MANTA) was another prospective, multicenter, randomized trial (n = 317) in which patients were randomized to receive three initial monthly injections of 0.5 mg RBZ or 1.25 mg BCZ (1:1) followed by PRN based on protocol-defined criteria.60 No significant difference was found in the mean improvement in BCVA between RBZ and BCZ (P = 0.78) at 1 year. In addition, no difference was found in the number of patients gaining 5 or 15 letters (P = 0.31 and 0.42 respectively) or the patients losing 5 or 15 letters (P = 0.11 and P = 0.23, respectively) between the two groups. On comparing the frequency of adverse events, the incidence was found to be low in the overall analysis, with slightly more adverse events in the BCZ group compared with the RBZ group (12.3% vs. 9.2%), but the differences were not statistically significant.60

The Groupe d’Evaluation Français Avastin versus Lucentis (GEFAL) was another trial conducted in Europe similar to the MANTA study, comparing PRN dosing of RNZ and BCZ.61 The study was a prospective, multicenter, noninferiority, double-masked, randomized clinical trial (n = 501) performed across 38 French ophthalmology centers. BCZ was found to be noninferior to RBZ (Difference of +1.89 letters; P < 0.0001). The mean number of injections was similar for both drugs (6.8 for BCZ and 6.5 for RBZ; P = 0.39). Both drugs caused a similar reduction in the central subfield macular thickness (mean decrease of 95 µm with BCZ and 107 µm with RBZ; P = 0.27).61 The study results were in line with previous studies confirming the noninferiority of BCZ compared with RBZ, although RBZ tended to have slightly better anatomical outcomes in patients with neovascular AMD.

The Lucentis Compared with Avastin Study (LUCAS) was a recent, multicenter, randomized, noninferiority trial (n = 441) conducted at 10 ophthalmological centers in Norway.62 Unlike MANTA60 and GEFAL,61 the LUCAS study evaluated treat-and-extend regimen of 0.5 mg RBZ and 1.25 mg BCZ for treatment-naïve neovascular AMD. LUCAS study showed that BCZ was equivalent to RBZ in terms of mean BCVA letters gained (7.9 vs. 8.2; P = 0.845). However, higher mean number of treatments were required for patients in the BCZ arm (8.9 vs. 8.0 at 1 year; P = 0.001). An interesting observation of the study was that fewer arteriothrombotic events were noted with BCZ (1.4%) compared with RBZ (4.5%) (P = 0.05) but higher cardiac events were noted with RBZ (P = 0.036). However, it is important to note that the two groups were not controlled for their baseline characteristics, leading to a potential bias.62 At present, the treat-and-extend regimen employed in the LUCAS trial is the most favored treatment strategy with anti-VEGF agents for neovascular AMD.9

The Comparison of AMD Treatment Trials (CATT) was a landmark, multicenter, single-blind, randomized, noninferiority trial which aimed to assess the relative efficacy and safety of 0.5 mg RBZ and 1.25 mg BCZ (repackaged in glass vials).63 The CATT Study enrolled 1208 patients across 44 clinical centers in the United States and was funded by the National Eye Institute. Patients were randomly assigned to one of four study groups: RBZ every 28 days, BCZ every 28 days, PRN RBZ and PRN BCZ. At 1 year, BCZ was equivalent to RBZ (99.2% CI for the difference in the mean change in BCVA within −5 to + 5 letters) (monthly as well as PRN regimen). The comparison between PRN BCZ and monthly BCZ, as well as PRN BCZ and monthly RBZ, was inconclusive. The mean increase in the number of letters from baseline was similar for all 4 groups (7.2 with monthly RBZ, 7.3 with monthly BCZ, 6.4 with PRN RBZ, and 6.1 with PRN BCZ; P = 0.53). The mean number of treatments over a 1 year period was 6.9 for PRN RBZ and 7.7 for PRN BCZ (P = 0.003). Monthly injections of either drug resulted in no increase in the mean lesion area, whereas there was a small increase with PRN regimen. The proportions of patients with arteriothrombotic events and other serious systemic adverse events were similar among the groups (P = 0.11). Thus at 1 year, BCZ and RBZ were found to have similar efficacy when administered according to the same dosing schedule.63

During the 2nd year of the study, patients initially assigned to monthly treatment were randomly reassigned to monthly or PRN treatment, without changing the drug assignment. There was no change in the regimen of the PRN treatment group. Among patients in the PRN arms, mean gain in BCVA was similar for both drugs (BCZ-RBZ difference: −1.4 letters; P = 0.21). At 2 years, the average BCVA gains were 8.8 and 7.8 letters in the monthly RBZ and BCZ groups, respectively. The corresponding PRN groups gained 6.7 and 5.0 letters, respectively. The mean BCVA gain was greater for monthly than for PRN treatment (difference: −2.4 letters; P = 0.046). Rates of death and arteriothrombotic events were similar for both drugs (P > 0.60). The proportion of patients with ≥1 systemic serious adverse events was higher with BCZ than RBZ (39.9% vs. 31.7%; adjusted risk ratio 1.30; P = 0.009).64

The results of the CATT study are very significant since it was the largest study that performed head-to-head analysis of two most commonly used drugs for neovascular AMD. For both the drugs, mean change in BCVA at 2 years was similar with PRN regimen, and the groups that switched from monthly to as-needed treatment.

The comparative efficacy of the anti-VEGF agents has not been evaluated using the popular treat-and-extend regimen employed in the SALUTE32 or LUCAS62 study. In addition, studies assessing the relative safety and efficacy of BCZ, RBZ and AFL for neovascular AMD, similar to Protocol T of Diabetic Retinopathy Clinical Research Network (for DME),65 have not been performed [Figure 1]. Is a brief timeline that summarizes important clinical trials in the management of neovascular AMD.

Figure 1

Timeline of major milestones in the field of pharmacotherapeutics for age-related macular degeneration. In the figure, a number of landmark randomized clinical trials that have brought a paradigm change in the management of neovascular age-related macular degeneration, and led to the approval (by United States Food and Drug Administration) of therapeutic agents such as ranibizumab and aflibercept, among others, have been chronicled. The month and the year of the studies refer to the publication date of the primary endpoint manuscript

FUTURE DIRECTIONS

There is a large unmet need for newer, more efficacious treatment options for neovascular AMD given its complex pathogenesis and potential blinding complications. Novel agents are being explored in well-designed prospective multi-center clinical trials for their safety and efficacy in AMD. Examples of such novel therapies include intravitreal injection of humanized anti-sphingosine-1-phosphate (S1P) monoclonal antibody (Sonepcizumab), which is being tested in the management of AMD. Preclinical studies with this bioactive lipid have provided encouraging results in decreasing retinal and CNV and reducing macrophage influx.66 Anti-S1P antibody, iSONEP (Lpath Inc., San Diego, CA, USA) is being evaluated in Phase 2 clinical trial (the NEXUS study) for the management of neovascular AMD.67 Similarly, anti-platelet derived growth factor-BB pegylated aptamer (Fovista®, Ophthotech Corporation, New York, USA) is being evaluated in combination with anti-VEGF agents (RBZ, BCZ, and AFL) in a Phase 2a study for its safety in patients with neovascular AMD.68

Thus, it is likely that in future, a number of alternate or adjunctive therapies (in combination with anti-VEGF agents) may be become available to clinicians for the management of neovascular AMD, significantly improving treatment outcomes.

CONCLUSIONS

AMD continues to remain a leading cause of severe visual loss worldwide. In the past decade, a number of advances in pharmacotherapeutics have dramatically improved outcomes in these patients. VEGF inhibitors have become firmly established as the standard of care in the treatment of neovascular AMD. However, monthly or bi-monthly treatment regimens pose a high burden on both the patient and treating physician and the long-term systemic safety of these drugs also remain unclear. Results from large randomized controlled trials indicate that both BCZ and RBZ are equally efficacious for the treatment of neovascular AMD and can be safely administered without significantly increasing the risk of adverse systemic events for the first 2 years of therapy. The VIEW study has shown comparable efficacy and safety of AFL with extended treatment intervals due to its longer duration of action although the extent to which this translates into clinical practice remains to be seen in future studies.

The long-term effectiveness of multiple intravitreal injections of anti-VEGF agents on vision and risk of adverse ocular and nonocular events is still an unresolved issue. The results from novel experimental trials are expected to pave the way for improved visual outcomes and better quality of life in these patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.