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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 � 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 patient�s 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.

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.

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Statement on Bevacizumab
Position Statement Released by AMD Alliance International, April 28, 2006

The role, efficacy, and safety of anti-vascular endothelial growth factor (VEGF) therapies for use in the treatment of age-related macular degeneration (AMD) were first established by clinical trials of pegaptanib sodium, (Macugen, [OSI] Eyetech/Pfizer) and later by clinical trials for ranibizumab (Lucentis, Genentech, Inc.).

PEGAPTANIB SODIUM
Phase 3 clinical trials for pegaptanib sodium demonstrated that after 1 year of treatment, individuals who were treated with 0.3 mg and 1 mg pegaptanib sodium experienced less vision loss than those who were treated with a placebo. Individuals who were treated with pegaptanib sodium experienced lasting results for 2 years. The most common side effect (occurring in approximately 1.3% of cases) was endophthalmitis, which was caused by the injection. 1

RANIBIZUMAB
Phase 3 clinical trials for ranibizumab demonstrated superior results after 1 year of treatment, and showed that the majority of individuals who were treated with ranibizumab improved or maintained vision 2 years later. The improvement in visual acuity endpoints in the ranibizumab-treated groups (0.3 mg and 0.5 mg) was maintained at year 2, while individuals in the control group continued to experience vision deterioration. At 2 years, at least 90% of individuals who were treated with ranibizumab maintained or improved vision compared to approximately 53% of individuals who were treated with sham injections. Treatment side effects were mild to moderate, affected less than 3% of individuals, and included conjunctival hemorrhage, increased IOP, vitreous floaters, and endophthalmitis.2

BROADENING THE ANTI-VEGF THEORY
Ranibizumab was developed by Genentech, Inc. The company had previously developed bevacizumab (Avastin, Genentech, Inc.) an anti-VEGF drug that is currently approved by the Food and Drug Administration (FDA) as an intravenous therapy for metastatic colorectal cancer patients. Bevacizumab for use in cancer therapy is currently being investigated. Ranibizumab is a molecular fragment of an antibody, and bevacizumab is a full-length antibody. They are both thought to work by a similar principle - the drug blocks the production of VEGF. VEGF, which is also produced by cancer cells, prompts the abnormal growth of blood vessels, also known as angiogenesis. Bevacizumab binds with VEGF and interferes with its ability to stimulate blood vessel growth.
In early 2004, Philip Rosenfeld, MD, PhD, and colleagues at the Bascom Palmer Eye Institute in Miami, Fla, initiated the use of bevacizumab in the treatment of AMD. Their first study was called Systemic Avastin for Neovascular AMD (SANA). In this and subsequent studies, which consisted of intravitreal injections of bevacizumab, individuals who were clinically followed reported improvements in visual acuity comparable to ranibizumab with no serious adverse events.3 It is important to note that these clinical studies were not conducted as randomized clinical trials.4,5 Based on these results, the use of bevacizumab for the treatment of AMD appears to have been broadly accepted by retinal specialists around the world.
The use of bevacizumab in the eyes, an indication for which it is not approved, is called off-label use. It is reasoned conjecture on the part of the AMD Alliance International that the off-label use of bevacizumab was first suggested for reasons of economy and availability in the face of a significant unmet need. Treatment with ranibizumab is not yet available unless an individual is registered in a clinical trial, or, as is possible in some European countries, receives the treatment on what is called a 'named-patient' basis. The FDA is expected to respond to Genentech's application for the approval of ranibizumab in the United States by June 30, 2006.

SAFETY AND EFFICACY OF BEVACIZUMAB
There is growing anecdotal evidence about the efficacy of the off-label use of bevacizumab. However, at this time, published reports on bevacizumab are limited to a number of human clinical case series in and a few animal studies on intravitreal injection. Most notable among the animal studies is one conducted by Anat Lowenstein, MD, who reported no safety issues in rabbit testing.6 Published human research on the safety and efficacy of bevacizumab is limited to the previously mentioned small human study at Bascom Palmer Eye Institute.
There have, however, been reports of serious life-threatening adverse events that can be attributed to bevacizumab when it is used in clinical trials on cancer patients. Most notably, a 4.4% risk of thromboembolic events has been referenced. It is noted that when used as a cancer treatment, bevacizumab is administered systemically rather than locally.

OUR POSITION ON BEVACIZUMAB
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. As stated earlier, there is growing anecdotal evidence about the efficacy of the off-label use of bevacizumab. However, 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 bevacizumab 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 ranibizumab. Answers to all of the questions about bevacizumab will only be known following the completion of clinical trials and publication of the results. Genentech, Inc., has stated that it is not planning to conduct any clinical trials involving the medication.
On April 20, 2006, the American Academy of Ophthalmology (AAO) issued a statement declaring their support for Medicare reimbursement consideration for the cost of bevacizumab usage in cases where individuals who are deemed by their treating physician to have failed FDA-approved therapies and/or are likely to have greater benefit from the use of intravitreal bevacizumab.
Individuals also have access to a clinical trial of ranibizumab, sponsored by Genentech, Inc., the makers of bevacizumab. The trial, known as Safety Assessment of Intravitreal Lucentis for AMD (SAILOR), is a 1-year, phase 3b study that is designed to evaluate the safety of ranibizumab, the VEGF inhibitor, which, as discussed above, has not yet been approved by the FDA. The trial provides access to the drug for eligible individuals in advance of the FDA's response and is open to individuals with all subtypes of new or recurrent active subfoveal wet AMD. For more information, see www.clinicaltrials.gov or www.amdalliance.org. Eligible patients are not able access these clinical trials outside the United States.

Meanwhile, until options such as ranibizumab become widely available, individuals are desperately seeking options and answers. 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.7

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?4
8. Regardless of cost or coverage by my insurance, what are some alternative treatments?

Our website, www.amdalliance.org is continually updated. Please check back frequently for updated details as developments occur in future. This report was last updated on April 28, 2006.