Age-related Macular Degeneration (AMD) is a significant cause of blindness in the elderly. AMD is characterised by progressive central vision loss, which is the part of vision critical to distinguishing fine detail. Loss of this vision restricts activities such as reading, driving, and facial recognition. AMD is a debilitating condition, which can lead to other problems such as an increased risk of falls, loss of independence, and the associated social and economic implications.
Understanding the pathogenesis of AMD has led to new, more targeted developments for treatment. AMD starts as a malfunction in the retinal pigment epithelium (RPE), which is the layer of epithelial cells between the retina and blood vessels. Normally the RPE allows nutrients and oxygen to pass from the blood to the retina, and allows waste products from the retina to be eliminated in the blood. When the RPE is not functioning properly, waste products collect and form deposits (drusen) under the RPE. This can cause the RPE cells to die, leading to loss of vision via two different mechanisms, categorised as either dry or wet AMD.
Dry AMD occurs when the death of RPE cells causes retina cells above that area to die, resulting in a missing section of the retina. Wet AMD occurs when the death of RPE cells allows blood vessels to grow into the retina, and blood leaks from vessels into the retina. The growth of these blood vessels into the retina is known as choroidal neovascularization (CNV). CNV is categorised as subfoveal, juxtafoveal or extrafoveal, depending on its distance from the fovea (central part of the macula). The protein primarily responsible for allowing blood to leak into the retina is vascular endothelial growth factor (VEGF).
There is currently no treatment for dry AMD, therefore the focus of this article is treatments for wet AMD. It is important to note that treatment options for wet AMD are not curative. Treatment can slow progression of the disease and maintain vision for longer. Hence, the earlier the disease is diagnosed, the better the outcome. Medication is the mainstay treatment for wet AMD, with the most commonly used treatments being anti-VEGF medications. These inhibit VEGF, and thus prevent blood leaking into the retina.
There are two anti-VEGF medications approved by the TGA; ranibizumab (Lucentis®) and aflibercept (Eylea®). Bevacizumab (Avastin®) and pegaptanib (Macugen®) are anti-VEGF medications which are not registered by the Therapeutic Goods Administration for the treatment of AMD, however they have been used off-label. Ranibizumab was shown to be statistically superior to placebo in two trials; 90-92% of patients treated with ranibizumab maintained vision at 24 months compared to 53% of patients treated with placebo. Vision maintenence is defined as a loss of less than 15 letters in visual acuity.
Aflibercept was compared to ranibizumab in a head-to-head trial, and was shown to be as effective as ranibizumab for the treatment of wet AMD. Post-marketing studies for both will be needed to determine benefit beyond 24 months.
Based on data from the clinical trials, the most common adverse effects were ocular effects, such as;
- Intraocular inflammation, vitritis, blepharitis
- Retinal or conjunctival haemorrhage, visual disturbance/floaters
- Eye pain, foreign body sensation in eyes
- Increased lacrimation or dry eye, eye pruritus
- Increased ocular pressure
- Vitreous detachment, and
- Headache (ranibizumab).
Both ranibizumab and aflibercept are administered intravitreally, so systemic absorption is minimal. After injection of a standard dose of aflibercept, the plasma concentration is estimated to be more than 50-fold less than the concentration needed to have a substantial systemic effect.
Similarly, the systemic concentration of ranibizumab after intravitreal administration is much lower than the concentration required to inhibit the biological activity of VEGF.
The recommended dose of ranibizumab is 0.5mg or 0.3mg given via a single monthly intravitreal injection. The efficacy and adverse effects were comparable for the 0.5mg group and the 0.3mg group in clinical trials. The recommended dose of aflibercept is one 2mg intravitreal injection monthly for three months, then one injection every two months. Both ranibizumab and aflibercept are listed on the Pharmaceutical Benefits Scheme (PBS) for the treatment of subfoveal CNV due to AMD, as the sole PBS-subsidised therapy.
Photodynamic therapy (PDT) with verteporfin (Visudyne®) is another treatment option for wet AMD. Verteporfin is a photosensitiser with treatment consisting of two steps; firstly verteporfin is administered via an intravenous infusion, and then laser light is used to activate it within the affected area of the eye. Activated verteporfin causes damage to the neovascular endothelium leading to blood vessel occlusion. Damaged epithelium also releases procoagulant factors, resulting in platelet aggregation. The activated drug specifically targets rapidly dividing cells, as seen with CNV, due to the specific receptor mediated uptake mechanism. This limits damage to the surrounding tissue.
In one clinical trial, PDT with verteporfin was found to be superior to placebo, with vision maintained in 59% of patients (versus 31% with placebo) at 24 months. Anti-VEGF medications are usually used in preference, however, because vision is maintained from treatment initiation, whereas vision continues to deteriorate for six months before stabilising with PDT/verteporfin. One trial found ranibizumab was superior to PDT with verteporfin; vision was maintained in 90% of patients treated with ranibizumab, versus 66% treated with PDT with verteporfin, at 24 months.
Anecortave acetate (Retaane®) is a synthetic analogue of cortisol which has no glucocorticoid activity. It inhibits angiogenesis (the growth of blood vessels) in the eye, through several mechanisms which may include suppression of certain extracellular proteinases, inhibition of VEGF and blocking proliferation of retinal endothelial cells. It is administered as a posterior juxtascleral depot injection, 15mg every six months. Clinical trials show anecortave acetate is superior to placebo in inhibiting vision loss, and vision is maintained in approximately 73% of patients at 24 months versus 47% for placebo. In one clinical trial, anecortave acetate was found to be less effective than PDT with verteporfin, however there are no head-to-head trials against the newer treatments.
Laser photocoagulation was the first treatment for AMD. A thin beam of high energy thermal light is directed at the retina, sealing and destroying leaking blood vessels. Although it has shown benefit in certain specific circumstances, it is generally not recommended due to an increased risk of vision loss immediately following the procedure. In addition, only 10-20% of patients with neovascular AMD have the specific circumstances necessary to benefit from laser coagulation.
AMD is a debilitating progressive disease which results in vision loss. Although there is currently no treatment for dry AMD, treatment for wet AMD has improved enormously in recent years. The anti-VEGF medications ranibizumab and aflibercept are now the mainstay treatments for wet AMD. They have demonstrated good efficacy, with minimal side effects or systemic absorption. As a result, wet AMD now has less of a negative impact on the quality of life of patients with this disease.
- Eylea (aflibercept) Australian approved product information. Pymble: Bayer Australia Ltd. Approved 7 March 2012, amended 7 November 2013.
- Kaiser PK. Comparison of recent AMD clinical trials: an evidence-based approach to treating AMD patients. Medscape Ophthalmol 2005; 6(1): 503094.
- Lucentis (ranibizumab) Australian approved product information. North Ryde: Novartis Pharmaceuticals Australia Pty Ltd. Approved 27 February 2007, amended 22 October 2013.
- Macular Disease Foundation Australia. Treatment for Macular Degeneration. Sydney: Macular Disease Foundation Australia; 2014. Available from: www.mdfoundation.com.au/treatments.aspx. Accessed 27 March 14.
- Macular Disease Foundation Australia. What is Macular Degeneration? Sydney: Macular Disease Foundation Australia; 2014. Available from www.mdfoundation.com.au/page122150.aspx. Accessed 27 March 2014.
- Retaane (anecortave acetate) Australian approved product information. Frenchs Forest: Alcon Laboratories (Australia) Pty Ltd. Approved 9 December 2005.
- Soubrane G, Bressler NM. Treatment of subfoveal choroidal neovascularisation in age related macular degeneration: focus on clinical application of verteporfin photodynamic therapy. Br J Ophthalmol 2001; 85(4): 483-95.
- Therapeutic Goods Administration (TGA). Extract from the Clinical Evaluation Report for bevacizumab. Woden: TGA; 2012.
- Virgili G, Bini A. Laser photocoagulation for neovascular age-related macular degeneration. Cochrane Db Syst Rev 2007; 3: CD004763.
- Visudyne (verteporfin) Australian approved product information. North Ryde: Novartis Pharmaceuticals Australia Pty Ltd. Approved 1 August 2007, amended 24 September 2013.