Medical Care
Antiangiogenic Agents
VEGF inhibitors
Animal and clinical studies have established vascular endothelial growth factor (VEGF) as a key mediator in ocular angiogenesis. [62, 63] In clinical trials, particular attention has focused on the development of pharmaceutical agents to block or neutralize VEGF expression.
Pegaptanib sodium
Pegaptanib sodium (Macugen; OSI Pharmaceuticals and Pfizer) is an anti-VEGF pegylated aptamer that demonstrated both safety and efficacy in clinical trials compared with placebo. This intravitreally administered polyethylene glycol (PEG)–conjugated oligonucleotide was specifically designed to bind and neutralize VEGF165, hypothesized to be the predominant VEGF isomer associated with CNV in humans.
The VEGF Inhibition Study in Ocular Neovascularization (VISION) Study was composed of 2 phase II-III multicenter, randomized, placebo-controlled trials. Enrollment of 1186 subjects was completed in July 2002. The 12-month data for all types of CNV showed that 70% of participants receiving a 0.3-mg intravitreous injection every 6 weeks lost fewer than three lines of vision versus 55% of control subjects receiving sham injection (P< 0.001). [64] This was a similar efficacy to PDT, the standard treatment at that point.
The FDA accepted a new drug application (NDA) for wet age-related macular degeneration (AMD) in August 2004, as did the European Medicines Agency (EMA) in September 2004. [65] On December 17, 2004, the FDA approved the drug, which became available for consumer use in the United States in January 2005. [66]
Ranibizumab
Ranibizumab (Lucentis; Genentech and Novartis Ophthalmics), an intravitreally injected, recombinant, humanized, monoclonal antibody fragment designed to actively bind and inhibit all isoforms of VEGF, has become an FDA-approved common treatment for exudative AMD.
The Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab (formerly, RhuFab) in the Treatment of Neovascular AMD (MARINA) was a phase III randomized, prospective, double-blind, placebo-controlled comparison of ranibizumab against sham controls. Investigators enrolled 716 patients to receive 24 monthly intravitreal injections (0.3 mg or 0.5 mg) or sham injections. At 12-month follow-up, 95% of those treated with monthly ranibizumab injections had improved or stable vision versus 62% of control subjects receiving sham treatment (P< 0.001). More importantly, 34% of participants receiving the 0.5-mg dose experienced at least a 15-letter improvement that was maintained over 2 years, whereas 26% of participants receiving the 0.3 mg dose and 4% of the sham injection group achieved this level of improvement (P< 0.001). [60] This was the first treatment for AMD that had demonstrated significant visual gains.
The Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) trial was another prospective, randomized, multicenter, double-blind phase III trial designed to compare ranibizumab versus verteporfin in 423 subjects with predominantly classic exudative AMD. Similar to MARINA, 96% of subjects receiving 0.5 mg monthly of ranibizumab had improved or stable vision versus 64% receiving verteporfin (P< 0.001). Visual acuity improved in 40% of subjects receiving the 0.5-mg dose versus 6% in the verteporfin group (P< 0.001). [67]
These trials altered the treatment paradigm of exudative AMD from a condition in which vision loss could only be slowed or stabilized to one in which visual acuity improvement was a real possibility. Clinicians are now attempting to maximize visual acuity while minimizing the number of retreatments to eyes with exudative AMD. The PIER trial gave 3 monthly injections of ranibizumab followed by quarterly injections over a 24-month interval. The 3-month results mirrored MARINA and ANCHOR; however, visual acuity gains declined once quarterly dosing began. The PIER data suggest that quarterly injections are less effective than monthly dosing. [68]
The HORIZON extension study, including patients from MARINA, ANCHOR, and FOCUS, documented adverse events and visual acuity results in patients treated with ranibizumab over 4 or more years. Rates of adverse events, including stroke and myocardial infarction continued to be low with long-term treatment. Some visual acuity gains achieved with monthly treatment during the initial phases of the studies were lost as patients were followed and treated less frequently during the latter years of the HORIZON study. [69]
The EXCITE trial measured the response to quarterly dosing and again confirmed that the regimen is less effective than monthly dosing. [70] In clinical practice, most ophthalmologists and retina specialists, use an induction phase, usually with 3 monthly injections, followed by an as-needed (prn) phase based on visual response, clinical examination, and imaging results. Several studies have attempted to compare this as-needed approach to the results found in MARINA and ANCHOR.
The Prospective OCT Imaging of Patients with Neovascular AMD Treated with Intra-Ocular Lucentis (PrONTO) Study was a small, uncontrolled open-label study, that treated patients with 3 monthly ranibizumab injections followed by monthly follow-up and redosing on an as-needed basis. The visual acuity improvements remained near the level of MARINA and ANCHOR, but the average number of retreatments dropped to 5.6 over 12 months. [71] Another as-needed dosing study, the SUSTAIN study, tested 3 monthly injections followed by an as-needed treatment regimen. During the as-needed phase, injections were given if there was a vision loss of 5 letters or an increase of 100 microns in central retinal thickness on OCT. The best improvement in vision occurred after the first 3 monthly injections, but dropped slightly when the as-needed regimen was initiated. [72]
Other clinicians are adopting the "treat and extend" approach, where patients are treated with 3 serial monthly ranibizumab injections followed by gradually extending the interval between subsequent injections until fluid reaccumulates. If a time pattern of recurrence develops, tailored treatments can be adopted. [73, 74] Two studies have demonstrated results similar to MARINA and ANCHOR with this approach. [75, 76]
The long-term safety of intravitreal ranibizumab 0.5-mg injections in neovascular AMD was examined in the SECURE study, a 24-month, open-label, multicenter trial involving 234 patients previously treated with ranibizumab for 12 months in the EXCITE/SUSTAIN study. Ranibizumab administered as per a visual acuity-guided flexible dosing regimen was well tolerated during the 2-year study, and no new safety signals were identified in patients who were treated with ranibizumab for up to 3 years. On average, patients lost best-corrected visual acuity from baseline, probably because of either disease progression or undertreatment. [77]
Aflibercept
Aflibercept (Eylea; Regeneron Pharmaceuticals) was approved in November 2011 for intravitreal injection for ocular indications. It is a newer therapeutic agent that improves visual outcomes while requiring less frequent injections. Aflibercept is a fusion protein designed to bind to all forms of VEGF-A. Two phase 3 studies, VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW 1 and 2) trials compared aflibercept to ranibizumab. VIEW 1 and 2 demonstrated safety and tolerability with visual results proving noninferior to the active control, ranibizumab. [78]
In VIEW 1 (n=1217), conducted in the United States, and VIEW 2 (n=1240), conducted in Europe, all regimens of the drug, including 2 mg dosed every 2 months (after 3 monthly loading doses), successfully met the primary endpoint of statistical noninferiority compared with monthly intravitreal ranibizumab, which was then the most potent FDA-approved treatment option for wet AMD.
The proportions of patients who maintained or improved vision over the course of 52 weeks in VIEW 1 were 96%, 95%, and 95% of patients receiving aflibercept 0.5 mg monthly, 2 mg monthly, and 2 mg every 2 months, respectively. This compared with 94% of patients receiving the standard 0.5-mg monthly dose of ranibizumab.
For the secondary endpoint, visual acuity, the new drug was better. Patients receiving 2 mg monthly had a greater mean improvement in visual acuity at Week 52, with a gain of 10.9 letters compared with 8.1 letters with ranibizumab (P< .01). All other dose groups were not significantly different from ranibizumab with respect to this secondary endpoint. [79]
Results from the CLEAR-IT 2 study, a phase 2 study of as-needed dosing with VEGF-trap, demonstrated that good visual results obtained after a fixed dosing regimen were maintained with a subsequent as-needed dosing schedule. After an initial 3 monthly injections, the 159 patients were treated on an as-needed basis for the remainder of the year. On average, patients needed two further injections to maintain the visual results. [80, 81]
In August 2018, the FDA approved an extended dosing frequency for aflibercept of every 12 weeks after 1 year of effective therapy, although it is not as effective as the recommended every-8-week dosing regimen. Approval was based on the VIEW-1 and VIEW-2 clinical extension trials. [82]
Brolucizumab
Brolucizumab (Beovu; Novartis Pharmaceuticals) was approved by the FDA in October 2019 for the treatment of neovascular (wet) age-related macular degeneration (nAMD). Approval was based on two phase III trials (n=1817) that compared intravitreal brolucizumab with aflibercept for nAMD. At 48 weeks, brolucizumab was demonstrated as noninferior to aflibercept in mean best-corrected visual acuity (BCVA). At Week 16, after identical treatment exposure, fewer eyes treated with brolucizumab 6 mg had disease activity compared with aflibercept in HAWK (24% vs 34.5%; P = 0.001) and HARRIER (22.7% vs 32.2%; P = 0.002). [83]
Faricimab
Faricimab is the first bispecific antibody for treatment of adults with neovascular (wet) age-related macular degeneration (AMD). Faricimab targets two distinct pathways – angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A). By inhibiting VEGF-A, faricimab suppresses endothelial cell proliferation, neovascularization and vascular permeability. By inhibiting Ang-2, faricimab promotes vascular stability and desensitize blood vessels to the effects of VEGF-A.
Approval was based on the phase 3 TENAYA and LUCERNE studies (271 worldwide trial sites). The studies randomly assigned patients with wet AMD (TENAYA, n=334 faricimab; n=337 aflibercept) and (LUCERNE, n=331 faricimab; n=327 aflibercept) to determine noninferiority. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline. BCVA with faricimab was noninferior to aflibercept in both studies and ocular adverse events were comparable between faricimab and aflibercept. [84]
Bevacizumab
Prior to the commercial availability of ranibizumab, bevacizumab (Avastin; Genentech) was attempted as an off-label VEGF inhibitor to control exudative AMD. Bevacizumab is a full-length humanized monoclonal antibody against human VEGF, whereas ranibizumab is a fragmented humanized monoclonal antibody against human VEGF, with a molecular weight of about one third that of bevacizumab. The FDA approved bevacizumab for the treatment of metastatic colorectal cancer on February 26, 2004. [85]
Researchers initiated the Systemic Avastin for Neovascular ARMD (SANA) Study, an open-label uncontrolled pilot study of nine participants with subfoveal CNV, to evaluate the efficacy of systemic intravenous bevacizumab. Patients were infused with 5 mg/kg bevacizumab every 2 weeks for two to three treatments. Follow-up through 12 weeks revealed significant improvements in mean visual acuity (P = 0.008) and central retinal thickness (P = 0.001) over baseline with a marked reduction in leakage on FA. [86]
To allay concerns about systemic morbidity, an intravitreal injection route was detailed in a case report in 2005 that demonstrated marked reduction of subretinal fluid and stable visual acuity. [87] Numerous small studies have subsequently supported the use of intravitreal bevacizumab by demonstrating decreased retinal thickness and improved visual acuity over baseline. [88, 89, 90, 91, 92]
Because ranibizumab ($1950/dose) and bevacizumab ($50-$75/dose) have an enormous price differential, and many retina physicians have felt they have comparable effectiveness, a good portion of patients are treated with bevacizumab, which has not been FDA approved for ocular indications. The National Eye Institute funded a large randomized controlled trial to directly compare the safety and efficacy of bevacizumab and ranibizumab in the Comparison of Age-Related Macular Degeneration Treatment Trial (CATT).
The study, whose findings were printed in The New England Journal of Medicine (May 19, 2011), showed that ranibizumab and bevacizumab have equivalent effects on visual acuity after 1 year. [93] These results were maintained after 2 years. Patients treated on an as-needed basis had slightly less visual acuity gain than those who continued on the monthly treatment regimen, but they received, on average, 10 fewer injections during the 2-year study period. No significant differences were noted in the number of significant adverse events associated with each drug. [94]
Intravitreal injections carry a small risk for endophthalmitis, with reported risk of 0.009% to 0.541%. [95, 96, 97, 98, 99] A meta-analysis of endophthalmitis cases following intravitreal injection revealed multiple cases secondary to Streptococcus species, in addition to the usual Staphylococcus species. [100] This led the authors to hypothesize that aerosolized oral flora may be responsible. Wen et al investigated the amount of bacterial dispersal associated with speech by having volunteers read over a blood agar plate with and without a face mask. [101] They found significant growth of Streptococcal bacterial colonies associated with uncovered speech and suggested wearing a face mask or minimizing speech during the procedure.
The FDA issued a safety alert regarding repackaged intravitreal injections of bevacizumab (Avastin), an anti-VEGF antibody. Serious eye infections caused by Streptococcus endophthalmitis have been reported in 12 patients who received the injections. The infections were the result of contamination that occurred during the repackaging of bevacizumab from 100 mg/4 mL single-use, preservative-free vials into individual 1-mL syringes for off-label use to treat wet macular degeneration. [102]
Complement Inhibitors
Pegcetacoplan intravitreal (Syfovre) binds to complement protein C3 and its activation fragment C3b, thereby regulating cleavage of C3 and the generation of downstream effectors of complement activation. It is Indicated for geographic atrophy (GA) secondary to age-related macular degeneration.
Early deposition of complement components C3 and C5 in the retina, suggest a contributing role of complement in AMD. It is thought that activating the complement cascade results in potent inflammatory mediators that activate and recruit leukocytes to inflammatory sites, and that these mediators enhance the proinflammatory and proangiogenic environment in the retina of patients with AMD. [103]
Approval was supported by results from the phase 3 OAKS (n = 637) and DERBY (n = 621) studies. At 24 months, the treatment effects of pegcetacoplan were similar between the trials. Reductions in GA lesion growth from baseline were approximately 16-18% with every other month dosing and 19-22% with monthly dose of pegcetacoplan compared with placebo (p < 0.003 or less). [104]
Statins
Because of the association of serum lipid levels with AMD, using statins in an effort to prevent AMD has been considered. Some positive effects have been demonstrated in several studies, but overall, data are conflicting and sufficient evidence is lacking to support their use for AMD. [105, 106]
Laser treatments
Thermal laser photocoagulation
Until the advent of anti-VEGF agents, ophthalmologists traditionally used thermal laser destruction of CNV as the primary treatment of exudative AMD based on the results of the Macular Photocoagulation Study (MPS). This study, which was initiated in the 1980s and supported by the National Institutes of Health, demonstrated that laser photocoagulation of extrafoveal, juxtafoveal, and subfoveal CNV limited the risk for severe reductions in visual acuity compared with observation alone.
Patients were eligible for laser photocoagulation if they had classic CNV, as determined by FA. However, only 13-26% of all patients with exudative AMD presented with this inclusion pattern. Therefore, it was unclear whether laser photocoagulation was beneficial to a majority of patients with exudative AMD. [107, 108, 109, 110, 111, 112] Moreover, at least one half of the enrolled subjects had persistent or recurrent CNV within 2 years of treatment. [108, 109]
Today, thermal laser photocoagulation is usually reserved for CNV outside the fovea and for treatment of variants of exudative AMD, including retinal angiomatous proliferation (RAP) and polypoidal choroidal vasculopathy. [29, 113] Although data from the subfoveal CNV arm of the MPS suggested that laser photocoagulation was better than observation, most clinicians do not treat subfoveal CNV with thermal photocoagulation because of the induction of an immediate, iatrogenic, central scotoma. [109, 110] Researchers have searched for alternative methods of treating subfoveal CNV with laser, including feeder-vessel photocoagulation [114] and transpupillary thermotherapy [115] ; however, these methods are not widely used clinically.
Photodynamic therapy
To avoid creating a central blinding scotoma when treating subfoveal CNV with thermal laser, clinicians turned to PDT. After intravenous infusion of a photosensitizing dye and a sufficient delay to concentrate it into pathologic choroidal neovascular tissue, the photosensitizer is stimulated with a specific wavelength of light that is directed at the CNV. The dye reacts with water to create oxygen and hydroxyl free radicals, which, in turn, induce occlusion of the pathologic vasculature by means of massive platelet activation and thrombosis while preserving the normal choroidal vasculature and nonvascular tissue. [116, 117, 118]
Verteporfin therapy
In April 2000, the FDA approved PDT with verteporfin (Visudyne; QLT Therapeutics and Novartis Ophthalmics) for use in patients with predominantly classic, subfoveal CNV caused by AMD. Marketing approval was granted in Europe in July 2000, and the drug is commercially available in more than 70 countries for the treatment of predominantly classic CNV. [119]
Verteporfin is a modified porphyrin with an absorption peak near 689 nm that is delivered intravenously for 10 minutes. After a 5-minute delay, the CNV complex is irradiated through the pupil with a large-spot diode laser at 689 nm for 83 seconds. The laser energy activates the intravascular photosensitizer and stimulates the photodynamic action within the pathologic CNV. Verteporfin is cleared rapidly from the body, resulting in minimal skin photosensitivity by 5 days.
In 2001, the 2-year results of the Treatment of AMD with PDT (TAP) trial were published. The TAP trial consisted of 2 randomized, prospective, double-blind, placebo-controlled phase III trials with 609 participants. Second-year data showed that 59% of treated eyes lost fewer than 15 letters on a standardized eye chart compared with 31% in the control group when the lesion was predominantly classic. [32] The TAP trial was unmasked after 2 years of follow-up, and investigators continued with an open-label extension (to 36 months) in 124 of the 159 original TAP participants with predominantly classic CNV. Visual acuity remained nearly constant and the number of required repeat treatments decreased. [120]
Although standard PDT with verteporfin has shown promise in treating some forms of CNV, it is expensive, typically slows vision loss rather than improves it, and requires numerous repeat treatments. Therefore, other interventions to treat subfoveal CNV membranes were developed.
Combination therapies
Results from treatment with anti-VEGF agents have been promising, although there continues to be a subset of patients who have disappointing visual outcomes. In some cases, different forms of macular degeneration, such as polypoidal vasculopathy and retinal angiomatous proliferation, may respond dissimilarly to anti-VEGF agents. Other failures may be caused by the maturation of choroidal neovascular membranes that make them less susceptible to changes in VEGF levels. [4, 5, 6] Several clinical researchers have performed a variety of treatment combinations attempting to maximize visual acuity recovery while minimizing the number of retreatments in exudative AMD. [121, 122]
Because evidence can be found that PDT causes an increased expression of VEGF, there may be a theoretical advantage to various combinations of PDT and anti-VEGF treatments. [123] In 2 studies, the efficacy of reduced-fluence PDT combined with bevacizumab versus bevacizumab alone was tested. Both found that the number of injections needed in the combination groups was reduced by about half without significant differences in visual outcome. [124, 125] However, in another study using standard-fluence, visual acuity in the combination group was similar to monthly bevacizumab, but there was no drop in the number of bevacizumab injections required. [126]
Larger randomized clinical trials have addressed combination therapy. In the DENALI study, ranibizumab, as monotherapy or combined with verteporfin PDT, improved best-corrected visual acuity (BCVA) at Month 12, but did not demonstrate that combination regimens were noninferior to ranibizumab monotherapy. [127] In the MONT BLANC study, the combination of verteporfin PDT and ranibizumab was effective in achieving BCVA gain comparable with ranibizumab monotherapy, but combination therapy did not show benefits with respect to reducing the number of ranibizumab retreatment over 12 months. [128]
In a randomized, multicenter trial, Jackson et al found that a single dose of stereotactic radiotherapy (SRT) reduced the number of ranibizumab injections required for patients with neovascular AMD. The study evaluated 230 patients in whom neovascular AMD had developed within the previous 3 years; who had, within the preceding year, received at least 3 injections of ranibizumab or bevacizumab; and who required continuing treatment with either of these drugs. [129]
Randomly assigned to 4 groups, the patients received ranibizumab (on as as-needed basis), as well as, depending on the group, a single dose of 16 Gy SRT, sham 16 Gy SRT, 24 Gy SRT, or sham 24 Gy SRT. The investigators found that patients in the 16 and 24 Gy SRT groups received significantly less ranibizumab (mean 2.64 and 2.43 injections, respectively) than did patients in the sham SRT groups (mean 3.74 injections), but with comparable retention of visual acuity over the course of 1 year. [129]
Surgical Care
Vitreoretinal surgeons have attempted to remove CNVM with direct surgical excision of the CNV complex. In 1998, the National Eye Institute of the National Institutes of Health awarded funding to the Submacular Surgery Trial (SST). This study was a large randomized clinical trial comparing submacular CNVM removal versus observation. Patients were followed for 2 years and assessed for stabilization or deterioration of their visual acuity, a change in contrast sensitivity, cataract development, surgical complications, and quality of life. The trials did not demonstrate significant benefit of submacular surgery over observation. [130, 131]
Consultations
A neurologist should be consulted for patients with AMD who exhibit signs of cognitive dysfunction, since an association with Alzheimer disease has been found. [48]
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Age-related macular degeneration (AMD), exudative.
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Age-related macular degeneration (AMD), exudative.
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Color photograph of the fundus shows nonexudative age-related macular degeneration (AMD) with geographic atrophy of the retinal pigment epithelium (RPE) and drusen. Absolute atrophy of the RPE occupies the foveal region in this case of nonexudative AMD. The central atrophic region causes a corresponding central scotoma. Note the large choroidal vessels, which are visible through the RPE defect. Drusen surround the region of geographic atrophy. Photo by Tim Steffens.
