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New treatments for age-related macular degeneration
1 Bristol Eye Hospital, Lower Maudlin Street, Bristol, BS1 2LX, UK
2 Bristol Eye Hospital, Lower Maudlin Street, Bristol, BS1 2LX, UK
Address correspondence to: F. R. Imrie. Tel: 0117 928 4653 Fax: 0117 928 4653. Email: fraser.imrie{at}ubht.nhs.uk
Age-related macular degeneration (AMD) is the most common cause of visual disability and blindness in Europe and North erica. On the basis of clinical appearance, AMD is classified as dry (non-neovascular) or wet (neovascular). Features of dry AMD include drusen, hyperplasia of the retinal pigment epithelium and geographic atrophy. The hallmark of wet AMD is choroidal neovascularisation (CNV), a pathological process whereby abnormal new vessels arising from the choroidal capillaries grow through the membrane separating the choroid and the retina (Bruch's membrane) and spread under the retina. The majority of patients who develop CNV will also have features of dry AMD in the affected or contralateral eye. CNV is visualised by fluorescein angiography and is categorised into two main lesion types termed ‘classic’ (well defined) and ‘occult’ (poorly defined), or combinations of these. The position of the CNV in relation to the fovea (the centre of the macula) is also used to classify lesions into subfoveal, juxtafoveal (extending to within 1–199µm of the fovea) and extrafoveal (extending no closer than 200µm from the fovea).
There is no specific treatment for dry AMD, but patients should be offered advice on cessation of smoking, the importance of a healthy diet including plenty of fruits and vegetables, the avoidance of ultraviolet and blue light and the potential value of nutritional supplements for prevention of progression to advanced AMD. The Age-Related Eye Disease Study (AREDS) demonstrated that 5 years of supplementation with high doses of antioxidant vitamins (A, C and E) and zinc reduced the risk of developing advanced AMD by about 25% in the contralateral eye of subjects with pre-existing moderate to advanced dry or wet AMD in one (the study) eye [1].
Wet AMD (CNV) represents only 10% of the overall disease prevalence, but is responsible for 90% of the cases for severe visual loss [2]. Treatment for CNV will therefore have maximum impact on reducing the burden of severe visual loss due to this condition. There have been significant advances in the treatment opportunities for wet AMD recently, some of which have attracted considerable media interest. Studies on treatments for CNV have reported their findings using logMAR visual acuity charts, which have five letters on each line and three lines representing a doubling of the visual angle. In other words, the difference between 6/6 and 6/12 Snellen acuity (and 6/12 and 6/24, etc.) is three lines of logMAR acuity or 15 letters. Moderate and severe visual loss is described as the loss of three and six lines of logMAR acuity, respectively.
Argon laser photocoagulation has been used since the 1970s to treat CNV. The aim is to destroy the neovascular membrane by coagulation, but such treatment also destroys the overlying retina, with a resultant scotoma. For this reason, subfoveal and juxtafoveal CNV are rarely treated by laser photocoagulation, as there is usually an immediate post-treatment reduction in central vision. Well defined, extrafoveal CNV can be treated by photocoagulation, with reduction in severe visual loss; however, such lesions represent only 8% of all CNV at presentation [3], and long-term results are limited by high recurrence rates (54% at 5 years) [4].
Photodynamic therapy (PDT) was the next development in the treatment of neovascular AMD, which has been approved in the United States since 2000. PDT utilises a 10-min intravenous infusion of verteporfin (a benzoporphyrin derived photosensitising drug) followed by application of diode laser (689 nm) treatment to the affected area in the retina. Light is absorbed by the verteporfin molecules, which causes an oxidation process in lipid membranes and proteins. Pre-clinical studies in animals showed that light-activated verteporfin could selectively occlude active CNV, with minimal effects on the overlying retina and underlying choroid. It can therefore be used to treat subfoveal and juxtafoveal CNV. In two controlled clinical trials, PDT was shown to be effective in limiting vision loss in patients with predominantly classic (but not minimally classic) subfoveal CNV [5, 6]. Two-year follow-up data for predominantly classic lesions showed that 59% of the treated eyes lost less than 15 letters of visual acuity compared to 31% of the eyes in the placebo group. Patients require follow-up at 3-monthly intervals and re-treatment if the CNV remains active (the mean number of treatments is 5 over 2 years). PDT has only a moderate effect in preventing vision loss and the majority of patients continue to lose vision. At 2 years, the average number of letters lost for visual acuity was 13.4 in the treated group and 19.6 in the placebo group [6]. This treatment is recommended in the United Kingdom for only predominantly classic subfoveal CNV (about 26% of all CNV at presentation [3]).
Vascular endothelial growth factor (VEGF) has been identified as having a pivotal role in the development of CNV [7]. Three treatments are now available that inhibit VEGF—all are delivered by a trans-scleral injection into the vitreous cavity. Pegaptanib (Macugen) is a selective anti-VEGF oligonucleotide conjugated with polyethylene glycol that binds VEGFA165. Bevacizumab (Avastin) is a full-length recombinant humanised monoclonal antibody (rhuMAb) that binds all isoforms of VEGFA. It is a large molecule (148 kD) and initial studies in monkeys found that it did not penetrate the retina easily [8]. Ranibizumab (Lucentis) is a humanised monoclonal antibody fragment (rhuFAb) that also binds all isoforms of VEGFA, but it penetrates all layers of the retina because of its smaller size (48 kD). Pegaptanib and ranibizumab have undergone randomised controlled clinical trials assessing safety and efficacy for intravitreal use, whereas bevacizumab has not. Pegaptanib and ranibizumab have both been approved for intraocular use in the United States in 2005 and 2006, respectively. Pegaptanib was approved in the United Kingdom in May 2006 and ranibizumab is likely to get approval by early 2007. Bevacizumab is approved for intravenous use in colorectal cancer and is used in an off-label basis by an alternative (intravitreal) route to treat neovascular AMD.
Two randomised controlled clinical trials of 6-weekly intravitreal injections of pegaptanib have shown that it is an effective therapy for all forms of CNV [9]. At 1 year, 70% of the pegaptanib group had lost fewer than 15 letters of visual acuity compared with 55% in the control group. The mean change in visual acuity at 1 year was a loss of 7 letters in the pegaptanib group and loss of 14 letters in the control group. Two separate randomised controlled clinical trials have assessed the safety and efficacy of monthly intravitreal injections of ranibizumab. The MARINA trial compared ranibizumab with placebo in minimally classic and occult CNV. The ANCHOR trial compared ranibizumab with PDT in predominantly classic CNV. The 1- and 2-year results of the MARINA trial, and the 1-year results of the ANCHOR trial have recently been published [10, 11]. At 1 year, 94% of the ranibizumab group lost fewer than 15 letters of visual acuity in each trial. This benefit was maintained at 2 years in the MARINA trial, with 92% of the ranibizumab group losing fewer than 15 letters. Ranibizumab is the first treatment to show an average gain in vision: 6.5 letters at 1 year and 5.4 letters at 2 years in the MARINA trial and 8.5 letters at 1 year in the ANCHOR trial. After the 1-year results of the MARINA trial were presented at international meetings, many ophthalmologists around the world started to use intravitreal injections of bevacizumab on an ‘off-label’ basis because ranibizumab was not available commercially at that time. Intravitreal bevacizumab appears to be similar in effect to ranibizumab [12] and has recently been shown to penetrate all layers of the retina of albino rabbits [13]. The long-term safety and optimal dosage of intravitreal bevacizumab is unknown, as no controlled trials of its intravitreal use have been performed. Bevacizumab is many times cheaper than both ranibizumab and pegaptanib because a single 4- or 16-ml vial of bevacizumab (designed for intravenous use) can be aliquotted into multiple smaller 0.05–0.1 ml doses for intravitreal use.
The great advantage of anti-VEGF therapies is that all types of CNV can now benefit from some form of treatment. Treatment with ranibizumab is the first to show an average improvement in vision. The main disadvantages of treatment are the need for repeated intravitreal injections (with a 0.1% risk of endophthalmitis per injection), high cost of the two approved therapies (pegaptanib and ranibizumab) and the requirement of treatment for 2 years or more [14]. In an attempt to address these issues, several studies are currently investigating whether a reduced frequency of dosing (either alone or in combination with PDT) can reduce side effects and cost while maintaining the excellent results of 4–6-weekly dosing.
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Conflicts of interest |
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Fraser Imrie and Clare Bailey are both investigators in ongoing commercially sponsored clinical trials of Macugen (manufactured by Pfizer) and Lucentis (manufactured by Novartis). Clare Bailey has received one-off honoraria for sitting on advisory panels to Pfizer and Novartis. Clare Bailey has received travel expenses to attend meetings from Pfizer and Novartis.
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