TREATMENTS AND RESEARCH
Dry AMD
Although several new drugs are being investigated and approved by regulatory agencies around the world for the treatment of the exudative (wet) type of AMD, aside from cessation of smoking and a healthy diet of dark green leafy vegetables and fruits supplemented by zinc and anti-oxidant vitamins (Vitamins E, C, and beta carotene), very little is currently available to help patients with "dry" AMD to prevent progression to more serious stages of debilitating disease.
However, this is an area which has ignited research interest, and the longer term future may be somewhat brighter for those with dry AMD.
Several companies are conducting research to explore how, or why, early, dry AMD converts to wet AMD or progresses to the late stages of the dry form - usually referred to as "geographic atrophy". A few different pathways such as inflammation, and/or oxidative damage have been considered, mostly involving drusen. Small drusen usually appear early in AMD and may not result in vision loss. However, the numbers and size of the drusen may increase along with concomitant other changes such as RPE cell pathology, causing AMD to progress with resulting vision loss. Linkage of these events to the appearance of wet AMD or progression to geographic atrophy is a key question and yet under investigation. One possibility is that the drusen debris buildup leads to a diminished blood supply to the RPE and photoreceptor cells, resulting in a diminished oxygen supply (hypoxia). In an attempt to compensate for this imbalance, new, abnormal blood vessels (neovascularization) could be formed, leading to wet AMD. Continuing research may lead to more effective antioxidants, anti-inflammatory agents, etc. which could halt or even reverse the progression of early, dry AMD to the more severe wet form or to the end stage dry form.
Researchers are also very interested in genetics as a link to AMD and as a factor in progression from dry to wet AMD. Researchers have now located particular genes whose mutations are associated with an increased risk for AMD. For example, one of these genes, known as Factor H, codes for a protein (complement factor H) which is a powerful inhibitor of inflammation. People who possess an alternate version of the gene produce an aberrant complement factor H, which fails to provide adequate suppression of the complement pathway of inflammation. This means that people with the defective gene are more vulnerable to certain inflammatory processes which can lead to the development of AMD.
NUTRITIONAL SUPPLEMENTATION
The Age-Related Eye Disease Study (AREDS) group is hoping to demonstrate
that modifications to the original vitamin formulation, shown to reduce the risk of
advanced age-related macular degeneration (AMD) by 25% over seven years,
will further reduce the risk of progression in patients at high risk for developing
advanced disease.
The vitamin formulation used in the original AREDS protocol consisted of:
- 500 mg of vitamin C;
- 400 IU of vitamin E;
- 15 mg of beta-carotene (smokers excepted);
- 80 mg of zinc, and
- 2 mg of cupric oxide.
In AREDS2, patients with either bilateral large drusen or large drusen in one eye and advanced AMD in the other will be given either high doses of lutein and zeaxanthin, both carotenoids, or omega-3 fatty acids or both, plus the original AREDS formulation for a total of six years.
The AREDS2 investigation will also compare the original AREDS formulation by comparing low zinc (25 mg) vs. high zinc (80 mg), and will also compare formulations with and without beta-carotene. As investigators note, the rational for adding lutein and zeaxanthin to the new formulation was based on observations that subjects in the original AREDS trial were less likely to progress to advanced AMD when they had high dietary levels of the two carotenoids.
Those who consumed at least two servings of fish a week in the original study were less likely to develop advanced AMD as well. Omega-3 fatty acids in the AREDS2 formulation will include both DHA and EPA, naturally found in fish oils.
LASERING OF DRUSEN
Prophylactic laser treatment of drusen does not apparently affect the rate of
vision loss over a five-year interval according to recently reported findings from the
Complications of Age-Related Macular Degeneration Prevention Trial (CAPT). CAPT
was designed to assess the safety and effectiveness of low-intensity laser treatment
in preventing vision loss in patients with at least 10 large drusen in both eyes at
study entry. During the study, patients received treatment in one eye only, the
other eye was not treated. At the end of five years, 20.5 percent of both treated
and observed eyes had visual acuity scores three lines worse than at study entry.
Another study (Laser to Drusen trial) confirmed that prophylactic laser of the
fellow eye of patients with neovascular AMD is not beneficial.
As a result of these findings, vitamin supplementation remains essentially the
only prevention therapy for either atrophic or neovascular AMD.
Nevertheless, 90 percent of all AMD is dry AMD, not wet, and novel approaches
aimed at inhibiting destructive processes within the eye that give rise to dry AMD
are now under exploration.
Wet AMD
Essentially, persons with macular degeneration have, at present, three possible treatment options: thermal (heat laser); Photodynamic Therapy; or anti-VEFG drugs. Information on each of these is shown below. Further information about experimental therapies is covered in our section on Clinical Trials.
Anti-VEGF treatment
An anti-VEGF treatment called Lucentis is now broadly available in the developed world and is considered to be the best treatment currently available for wet AMD. Lucentis is a medical breakthrough because it is the first and only treatment clinically proven to restore vision in patients with wet AMD. In scientifically-sound, randomized clinical trials, approximately forty per cent of Lucentis-treated patients experienced a clinically significant sustained improvement in vision Š enough to resume driving. Ninety-five per cent of Lucentis-treated wet AMD patients maintain their vision. Delivered by intravitreal injection into the eye, Lucentis works to halt the proliferation of leaky blood vessels in the macula. Anti-VEGF drugs work by targeting VEGF (Vascular endothelial growth factor), a protein involved in causing new blood vessel formation. In the case of AMD these new blood vessels are unstable and tend to leak fluid and blood under the retina, causing loss of central vision. The anti-VEGF drugs work by inhibiting the growth of new blood vessels.
Retina experts say that they expect treatment will turn out to be highly individualized based on each patientÕs unique biology. It is essential that treatment decisions be made in consultation with your own retinal specialist, who is in the best position to provide expert medical advice for your unique eyes. In general, the recommended treatment schedule for Lucentis in patients with neovascular AMD, according to a panel of experienced retina specialists (David M. Brown, Philip Rosenfeld, Nancy Holecamp, and Tom S. Chang), is a monthly injection for three consecutive months and, in general, treatment afterwards that is dependent on the recurrence of fluid (e.g., diffuse edema, intra-retinal cysts, sub-retinal fluid, sub-RPE fluid) as shown by optical coherence tomography (OCT).
Another anti-VEGF treatment is Macugen (pegaptanib sodium), and it is also widely approved for use in the developed world. Randomized clinical trials of Macugen demonstrated that the drug reduced vision loss in 70 per cent of clinical trial patients. Macugen is effective in reducing vision loss for all sub-types of wet AMD.
Avastin (bevacizumab)
Because there was no other treatment available at that time, in early 2004, Philip Rosenfeld, MD, PhD, and colleagues at the Bascom Palmer Eye Institute in Miami, began treating AMD patients with the anti-VEGF cancer drug Avastin. Avastin is currently approved by the USA Food and Drug Administration (FDA) as an intravenous therapy for metastatic colorectal cancer patients. Although they are not the same molecule, Avastin is thought to work by a similar principle as another anti-VEGF treatment called Lucentis, namely by blocking the production of VEGF. VEGF, which is also produced by cancer cells, prompts the abnormal growth of blood vessels, also known as angiogenesis. Anti-VEGF drugs bind together with VEGF and interfere with its ability to stimulate blood vessel growth.
The first study of Avastin for AMD treatment was conducted by Dr. Roseneld, and was called Systemic Avastin for Neovascular AMD (SANA). In this and subsequent clinical case studies, which consisted of intravitreal injections of Avastin, individuals who were clinically followed reported improvements in visual acuity comparable to Lucentis with no serious adverse events. It is important to note that these clinical studies were not conducted as randomized clinical trials. Based on these results, the use of Avastin for the treatment of AMD appears to have been broadly accepted by retinal specialists around the world.
The use of Avastin in the eyes, an indication for which it is not approved, is called off-label use. The off-label use of drugs is legal in North America, Europe, and Asia, and is a practice that is accepted by physicians, healthcare providers and institutions, and some insurers. There is growing anecdotal evidence about the efficacy of the off-label use of Avastin. However, at this time, published reports on Avastin are limited to a number of human clinical case series in and a few animal studies on intravitreal injection.
There have been no randomized controlled clinical trials, nor are there any broad, scientifically-accepted published reports in this regard. In fact, due to the fact that Avastin is a full-length antibody, some researchers assert that it will not be as effective in the long term because it cannot penetrate all layers of the eye as well as the fragment antibody Lucentis.
Scientifically proven answers to questions about Avastin will only be known following the completion of clinical trials and publication of the results. Clinical trials comparing Avastin and Lucentis are currently ongoing in the United States and England. The American CATT (Comparison of Age-Related Macular Degeneration Treatments Trials: Lucentis-Avastin Trial) is currently enrolling clinical trial participants in 56 locations across the USA. This study started enrolling participants in February 2008, with preliminary results expected in February 2011. A study, called the IVAN trial is also ongoing in England. For more information about the USA trial, click here and for the British trial click here
While we await the clinical trial results, our position is that individuals must make an informed decision about treatment in consultation with their own retinal specialist. According to the American Medical Association, informed consent refers to significantly more than the process of signing a 'consent to treat' form. Rather, informed consent refers to the communication that takes place between individuals and their physician, with the patient understanding the information conveyed. You may also wish to look at the Macular Disease Patient Charter (link) which provides an outline of what you, as a person with macular disease, have a right to expect! The process of arriving at an informed decision includes questions such as: 1. What is my exact diagnosis? 2. What is the typical progression for an individual with my eye condition? 3. What treatment options and/or care do you recommend? 4. How will each of these treatments and/or care options help me? 5. What are the risks and side effects for my unique eye condition? 6. What are the proven and unproven benefits of treatment for my unique eye condition? 7. Are the differences in the evidence gathered through randomized clinical trials versus clinical studies significant for me? 8. Regardless of cost or coverage by my insurance, what are some alternative treatments? 9. Where can I access other supports such as low vision rehabilitation or counseling?
Triple Therapy for AMD? Bevacizumab + PDT + Steroids
There is widespread agreement that data for any form of combination therapy is currently insufficient and that additional studies are needed before recommendations can be made for treatment. The theory behind triple therapy is that abnormal blood vessel growth in AMD is caused by various mechanisms, only one of which would be impacted by anti-angiogenesis (anti-VEGF) therapies such as ranibizumab (Lucentis) and bevacizumab (Avastin). Researchers are looking for an "ideal therapy" that would eradicate existing choroidal neovascularization (CNV), reduce inflammation, and reduce the concentration of VEGF in the retinal milieu. This would combine photodynamic therapy, intravitreal steroid injections of dexamethasone, and bevacizumab.
A study of 104 patients who received one cycle of triple therapy showed a significant increase in visual acuity and a significant decrease in retinal thickness for as long as 56 weeks post-treatment. (Only five patients required a second round of triple therapy due to ongoing CNV activity.) The researchers concluded that triple therapy may offer a sustained benefit and may be preferred to anti-VEGF therapy alone, which requires more frequent injections. For details regarding the triple therapy procedure, see Augustin AJ, et al., Triple therapy for choroidal neovascularization due to age-related macular degeneration: verteporfin PDT, bevacizumab, and dexamethasone. Retina 2007;27:133-40.
A quad therapy has also been proposed that would add vitrectomy to the above series. Yet another adds beta radiation to the quad therapy. However, as mentioned above, there is widespread agreement that data for any form of combination therapy is currently insufficient and that additional studies are needed before recommendations can be made for treatment.
Photo Dynamic Therapy (PDT)
Photodynamic Therapy (PDT) (trade name Visudyne) uses a non-thermal (or cold) laser with an intravenous light-sensitive drug to seal and halt or slow the progression of abnormal retina blood vessels. This treatment does not produce a blind spot on the retina. The light is shone directly at the targeted tissue and the drug accumulates in these cells. It therefore reduces damage to normal surrounding tissue and allows the treatment to be given again as needed. However, early diagnosis of AMD is key, because once vision is lost due to of the growth of abnormal blood vessels, it cannot be reclaimed by either treatment.
Laser Photocoagulation
Laser photocoagulation is a surgical procedure involving the application of a hot laser to seal and halt or slow the progression of abnormal blood vessels. In the 1990's laser treatment was the only therapy available for AMD.Through the use of a high-energy light that turns to heat when it hits the parts of the retina to be treated, laser photocoagulation seals the choroidal neovascularization (CNV) and inhibits the leaky blood vessels growth, preventing further vision deterioration. A scar forms as a result of the treatment, and this scar creates a permanent blind spot in the field of vision. Vision does not usually improve after laser treatment and may even be somewhat worse. However, loss of vision following laser treatment, though immediate, is generally less severe than the eventual loss of vision that usually occurs if laser treatment is not done. In many cases, some visual distortion will disappear after laser treatment.
What's happening in AMD? An answer from AMD Alliance International based on recent medical developments.
For the latest report on what's happening in AMD you might also wish to access our report on medical presentations at the annual congress of the American Academy of Ophthalmology. download file
