Age-related macular degeneration (AMD) complications are the leading cause of severe vision loss among people aged 65 years and over in the United States1
and many western countries. AMD is grouped into two types, dry (nonexudative or nonneovascular) and wet (exudative or neovascular) macular degeneration. About 10%–20% of people with AMD have the wet type, but most (approximately 90%) of this vision loss is due to neovascular (or wet-type) AMD.2
The word ‘neovascular’ describes the development of new, abnormal blood vessels in the back of the eye. These new abnormal vessels are fragile, and often extravasate blood components, which occasionally becomes subretinal or vitreous bleeding resulting in sudden visual disturbance. Unfortunately, the majority of these new vessels were not amenable to treatment except by laser-photocoagulation including photodynamic therapy, which selectively destroys new abnormal vessels with verteporfin (Visudyne®
, a light-activated drug) and the use of a low-energy laser.
The Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) study group revealed that verteporfin therapy for predominantly classic choroidal neovascularization (CNV) subfoveal lesions had benefits for visual acuity without severe adverse effects.3
Before the advent of this treatment, treatment options for subfoveal or juxtafoveal CNV, including low-dose radiation therapy, were limited and ineffective. In 2000, the US Food and Drug Administration (FDA) approved Visudyne®
(new drug application number 21–119) therapy as the first drug treatment for predominantly classic wet-type AMD. Guidelines for verteporfin therapy for choroidal neovascularization secondary to AMD were published in 20024
and updated in 2005.5
These guidelines were based on trials and clinical experience in predominantly Caucasian populations. The prevalence of AMD is different among racial groups. For example, the leading cause of blindness among white Americans was AMD (54.4% of cases), while among black Americans, cataract and glaucoma accounted for more than 60% of blindness in the United States.1
The leading causes of blindness in a Japanese adult population were glaucoma and diabetic retinopathy. Oxidative damage-induced inflammation initiates AMD.6
Macular pigments, which work as antioxidants to prevent oxidative stress from lights, are one of the reasons for the differences in AMD prevalence among racial groups.7
More macular pigments are found in the retinas of Asians and blacks compared to retinas in whites. However, results from population-based studies show that the five-year incidence of AMD in Japan was close to those in western countries (Hisayama Study [0.8%],8
Beaver Dam Eye Study [0.9%],9
Blue Mountain Eye Study [1.1%]10
). Subsequently, the Japanese Age-Related Macular Degeneration Trial (JAT) was designed to evaluate photodynamic therapy for Japanese and found it to be efficacious and safe in Asian patients as well as in Caucasian patients.11
In 2004, verteporfin therapy was approved for Japanese patients with wet-type AMD.
The effectiveness of verteporfin therapy depends on the types of AMD in United States. Verteporfin therapy maintained visual acuity for patients with predominantly classic CNV. However, there is insufficient evidence in minimally classic CNV. In Japan, verteporfin therapy was able to maintain visual acuity for at least one year in patients with both types of CNV: predominantly classic and minimally classic lesions. Although this new laser therapy achieved some progress in the treatment for AMD, the effectiveness of this therapy is still limited; it maintained visual acuity, but did not improve it.
Vascular endothelial growth factor (VEGF) is a glycoprotein that stimulates the growth of new blood vessels. This broad term, ‘VEGF’, covers a number of proteins that result from alternate splicing of mRNA from a single 8- exon VEGF
gene. Alternate splicing of exon 6 and 7 alters their amino acid number (in humans: VEGF121
). Among them, VEGF121
are mainly expressing in the eye. The results of the VEGF Inhibition Study in Ocular Neovascularization (VISION) clinical trials in late 2004 marked a new era for the treatment of AMD. This trial tested the concept that targeting VEGF, a potent promoter of angiogenesis, could affect the formation of neovascular vessels in AMD and it was shown to be correct.12
They used pegaptanib (Macugen®
), a 28-base ribonucleic acid aptamer, which binds to the VEGF165
isoform with high specificity and affinity but does not bind to the other VEGF isoforms.13
This trial clinically proved that anti-VEGF therapy is a promising therapy for the patients with wet-type AMD. Ranibizumab (Lucentis®
) is an antibody fragment that binds and inhibits all identified VEGF isoforms.14
Ranibizumab was approved by the FDA in 2006 for the treatment of advanced or wet-type AMD. The approval was based on evidence from clinical trials showing that ranibizumab slows the rate of progression of vision loss from wet AMD.15
In addition to a low rate of developing vision loss, approximately one-third of patients treated in these trials had some improvement in vision at 24 months as measured on an eye chart.15
The Anti-VEGF Antibody for Treatment of Predominant Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR study group) trial revealed that ranibizumab was superior to verteporfin as an intravitreal treatment of predominantly classic CNV.16
In this study, ranibizumab improved visual acuity at one year on average.16
Bevacizumab ( Avastin™) is a drug closely related to ranibizumab. It was approved by the FDA in 2004 as an intravenous treatment for patients with advanced colorectal cancer and therefore has been available for what is called off-label use for other health conditions. It has been widely used to treat wet-type AMD. Bevacizumab is thought to remain in the eye longer than ranibizumab and therefore possibly allows for less frequent injections. No formal dose-ranging or dosing frequency studies have been performed. Almost all of the evidence comes from off-label usage in short-term uncontrolled clinical case series, but the results suggest that is associated with vision stabilization or improvement in most treated eyes.17
Anti-VEGF therapies were accepted for the treatment of AMD. The first anti-VEGF therapy, pegaptanib, was approved in Europe in 2006 and in Japan in 2008, respectively. This approval was shortly followed by the approval of ranibizumab for the treatment of neovascular AMD in Europe in 2007 and in Japan in 2009, respectively. The outcomes of these new treatments in these countries are forthcoming.