Age-related macular degeneration is the most common cause of blindness in the Western world and the leading cause of blindness in the United States in patients older than 65 years of age. AMD is a progressive degenerative disease of the retinal pigment epithelium, Bruch’s membrane, and choriocapillaris that is classified into two types:
- nonexudative or dry AMD (90%) characterized by drusen, pigment changes, and RPE atrophy
- exudative or wet AMD characterized by choroidal neovascularization (CNV) and disciform scarring (10%).
Risk factors include age, heredity, gender (female), race (Caucasian), smoking, nutrition, photic exposure, hypertension, light iris color, hyperopia. Symptoms are decreased vision, central scotoma, and metamorphopsia with a range of severity from minimal in mild cases of dry AMD to severe in advanced cases of dry AMD and in wet AMD. Although there have been numerous advances in the treatment of wet AMD over the past decade, current therapy for both forms of the disease still has significant limitations. Here is a closer look at the various modalities for treating this potentially devastating condition:
Medical treatment for dry AMD
Carefully monitoring of vision (home monitoring with Amsler grid, and eye exam every 6 to 12 months), oral supplements (vitamins C, E, A, zinc, and copper [AREDS]; or vitamins C, E, A, zinc, copper, omega-3 fatty acids, lutein, and zeaxanthin [AREDS2]), and low vision aids. Fenretinide (ReVision Therapeutics) is a new medication in development that may slow the progression of geographic atrophy and reduce the risk of developing CNV.
Surgical treatment for wet AMD
Laser: this was evaluated in the Macular Photocoagulation Study (MPS), which showed a treatment benefit for patients with well-demarcated extrafoveal or juxtafoveal CNV. After 5 years, more than 6 lines of visual loss occurred in 64% of untreated eyes as compared to 46% of treated eyes. However, the CNV recurrence rate was greater than 50%. Also, many patients do not qualify for laser treatment because of subfoveal and occult CNV lesions.
Photodynamic therapy (PDT) with verteporfin (Visudyne; QLT Ophthalmics): this was evaluated in both the Treatment of Age-Related Macular degeneration with Photodynamic Therapy (TAP) Trial and the Verteporfin in Photodynamic Therapy (VIP) Trial. The TAP study showed that this treatment is able to prevent vision loss in eyes with subfoveal, predominantly classic and occult, with no classic CNV. The VIP study also demonstrated efficacy with this treatment, which prevented vision loss in eyes with occult and no classic CNV.
Anti-VEGF agents: intravitreal injections of various drugs have proven to be an effective treatment and have revolutionized the treatment and prognosis of wet AMD.
- Pegaptanib (Macugen; EyeTech Inc.) was the first FDA-approved drug. It is an aptamer (i.e., a selective VEGF antagonist that binds to the 165 isoform of VEGF-A while sparing other isoforms) requiring injection every 6 weeks and was evaluated in the VISION Trial. It is not commonly used anymore.
- Ranibizumab (Lucentis; Genentech) was the next FDA-approved agent and is the most effective for all forms of CNV. It is a humanized, antigen-binding fragment (Fab) designed to bind and inhibit all vascular endothelial growth factor (VEGF) isoforms. It was evaluated in the MARINA and ANCHOR Trials, and requires intravitreal injection monthly.
- Bevacizumab (Avastin; Genentech) is similar to Lucentis but FDA-approved for colorectal cancer (used off-label for treating AMD). It is a full-length antibody that binds and inhibits all VEGF isoforms.
- Aflibercept (VEGF Trap Eye)is a fusion receptor decoy containing domain 2 from VEGF receptor 1 and domain 3 from VEGFR2 fused to human Fc fragment that blocks all isoforms of VEGF-A and placental growth factor (PLGF). It is injected in to the vitreous either monthly or every 2 months after a loading dose, and is being evaluated in the VIEW 1 and 2 Trials.
Although these anti-VEGF agents have improved our ability to treat wet AMD, there are safety concerns about their use because all of them can get into the systemic circulation thereby placing patients at risk for arteriothrombotic events such as hypertension, myocardial infarction, and stroke.
Combination therapy: this strategy is becoming more popular. Combining PDT and anti-VEGF agents has been shown to be safe with similar visual results and decreased injections. This was demonstrated in the DENALI and MT BLANC studies. Intravitreal Kenalog with or without PDT has also shown some efficacy in several studies.
Radiation therapy: this is currently the most promising new development in the treatment of CNV. Two approaches, internal and external, are being investigated in combination with anti-VEGF agents.
- NeoVista has developed epimacular brachytherapy utilizing strontium-90 as the radiation source. This is delivered internally after a pars plana vitrectomy is performed. The surgeon holds the strontium probe over the macula and the lesion is irradiated. This method is being evaluated in the company’s MERITAGE study in patients needing chronic anti-VEGF treatment. 1-year results from 53 patients in the study demonstrated stabilization of visual acuity in 79% as well as a reduction in the number of anti-VEGF injections required. Almost half the patients experienced an improvement in visual acuity, and 10% gained 3 or more lines of vision.
- Orayahas developed an external approach with low-dose x-ray radiation for CNV. Their IRay system precisely delivers the radiation via three inferior limbal sites. European studies are currently underway.
Surgery: this may also play a role in certain cases. Submacular surgery should be considered to remove CNV or displace hemorrhage in cases with large submacular hemorrhage. Macular translocation is another experimental technique that has been used. However, these techniques have not been promising with respect to visual potential.
Other treatments: these include transpupillary thermal therapy, modulating (feeder) vessel laser photocoagulation, and various combination therapies, all of which are being evaluated in clinical trials.