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The eyes have it: Macular degeneration and the challenge of drug therapy
By Leslie A. Davis, Pharm. D. Candidate, Auburn (AL) University Harrison School of Pharmacy
It is projected that by 2025 the population of people in the United States over the age of 65 will be six times higher than it was in 1990. This is because of both the "baby boomer" population aging and overall life expectancy increasing. As patients age they may begin to experience a loss of vision via macular degeneration.
Macular degeneration is the leading cause of blindness in patients over the age of 65 and it is predicted that almost three million people will have symptoms associated with age-related macular degeneration (AMD) by the year 2020. Macular degeneration affects a part of the retina known as the macula, which is responsible for central vision and therefore patients experience problems performing daily tasks such as driving, reading, or writing. Severe cases may cause a decrease in mobility, poor orientation, and the patient may become unable to recognize faces of family and friends. Due to these manifestations, quality of life can be affected to the point at which it causes depression.1,2,5
A specific cause for macular degeneration is not known, but there are several risk factors. Age plays an important role in the development of the disease, and AMD also appears to be more prevalent in Caucasian females as well as patients with a family history of the disease. Studies indicate that smoking may also be a factor in the development of this disease and therefore it is deemed as the most modifiable risk factor associated with the disorder. There are other indefinite risk factors that may be associated with AMD, which include hypertension, obesity, light eye color, and overexposure to sunlight, but these have not been proven in clinical studies. The toxic effects of the antipsychotic drug class phenothiazines and the anti-malaria drug chloroquine also have the potential to induce macular degeneration.1,2,3,6
AMD is divided into two subsets known as "dry" or non-neovascular form and "wet" or neovascular form. Dry macular degeneration is usually characterized by yellow deposits, known as drusen, which accumulate around the area of the macula. This is the mildest and most common form of the disease, and loss of vision occurs slowly. It is possible for the dry form of AMD to progress into the wet form.1,2
Wet AMD is characterized by the growth of new blood vessels beneath the retina. These new blood vessels that grow are not as stable as the original blood vessels and leak fluid and blood. This leakage causes the cells in the retina to die and this eventually leads to scarring and vision loss. Wet AMD can be further classified into two types known as classical or occult. Classical is associated with a more severe loss of vision. There is less leaking associated with the occult form of wet AMD and therefore there is less severe vision loss. With the wet form, vision loss usually occurs suddenly.1,2
While there is no cure, recently there has been increasing research centered on drugs to slow the progression of this devastating disease. Currently there are no therapies that are FDA approved for the treatment of dry AMD. Certain vitamins and nutrients have been implicated in protecting against the development of the disease or slowing its progression once a patient experiences AMD. These include antioxidants, omega-3 fatty acids, leutein, zinc, zeaxanthin, and vitamins A, C, and E.1
Studies are currently underway to research these benefits. The age-related eye disease study was conducted in 2001 and involved 3,600 subjects. This study supported that vitamins C, E, zinc, and beta-carotene reduced patients risks of progressing to more advanced stages of dry AMD by about 28%. The patients who experienced these decreases were the ones who had high amounts of intermediate to large size drusen; patients with smaller drusen did not experience the same benefits. Due to study weaknesses, there is some controversy about the true effectiveness of these therapies among physicians, and therefore more studies need to be conducted in order to prove or disprove what is now considered to be a theory.1
Visudyne® (verteporfin) was the first drug that was FDA approved for the treatment of wet macular degeneration in the year 2000. Visudyne is administered intravenously over ten minutes, and is then activated by a laser being projected into the eye. Once Visudyne is activated, pathological blood vessels are destroyed by oxidative processes that cause vessel occlusion. It is indicated only for patients who have the classical form of wet AMD. The latest drug therapy that has been the focus of research are the vascular endothelial growth factor inhibitors. There are currently three on the market that are being used to treat AMD, two of which are FDA approved. The first was approved in December 2004 and is a murine monoclonal antibody known as pegaptanib sodium (Macugen®). Pegaptanib specifically targets the VEGF-165 isoform, and is administered as an intravitreal injection into the eye every six weeks for up to two years. The other two VEGF inhibitors are recombinant humanized monoclonal antibody fragments that act on all isoforms of VEGF. The clinical significance of the difference between binding capacity for VEGF between pegaptanib and the humanized monoclonal antibodies is unknown at this time. Animal studies have shown that these monoclonal antibodies are able to penetrate the membrane of the eye and enter into the retinal space.
In June of this year, ranibizumab (Lucentis®) was approved by the FDA for the treatment of AMD. It is dosed as an intravitreal injection monthly but if for some reason this is not feasible, the patient can receive injections every three months. Bevacizumab (Avastin®) is another monoclonal antibody with promising results for the treatment of AMD. It is FDA approved for the treatment of metastatic colorectal cancer and has recently been used to treat AMD as an "off label" use. There is some debate between physicians about which of these drugs should be first line for AMD patients since there are no competitive trials available comparing these medications. Avastin is the less expensive of the two drugs but since it is not approved for the treatment of AMD, insurance companies do not reimburse for its use. Medicare Part D does reimburse for the use of Lucentis but Avastin still may be more cost efficient even with the reimbursement. Both drugs are manufactured by Genentech, and they argue that Lucentis was specifically designed with smaller particles to penetrate the retina more efficiently than Avastin. Genentech has no plans of conducting trials on the use of Avastin as an AMD treatment because of their large financial investment in Lucentis; therefore, the government is currently conducting studies to determine Avastin's safety and efficacy compared with Lucentis. It is believed that this debate will be resolved once these trials have been completed and it is predicted that this may be as early as 2009.1,4,5
The treatment of AMD has recently become a hot topic in research and there are several new therapies currently being studied for both the dry and wet forms of the disease. Discovering treatment options for the dry form is important since it can progress to the more serious wet form. Another VEGF inhibitor called the "VEGF Trap" is being studied in addition to drugs and procedures that have other mechanisms such as a blood filtering system and implantable devices. With the aging population, more research will continue on the diseases and conditions that affect the elderly such as AMD. The elderly are a vital part of society and by preserving their sight, the patient will have a better quality of life and be able to serve their community more productively well into their retirement years.1