The relative risk of vision loss of three or more lines was reduced by 19%. The AREDS did not show a statistically signiÞcant beneÞt of the vitamin formulation for either the development of new GA or for involvement of the fovea in eyes with pre-existing atrophy [4]. In part, this result may be due to the paucity of patients with GA in the study.

Other studies of oral vitamin supplementation have demonstrated an increased risk of lung cancer in smokers who take beta-carotene [5]. For this reason, it is recommended that smokers should be offered a form of AREDS vitamin supplementation without beta-car- otene. The AREDS-2 is underway to determine the effect of other vitamin supplements, such as lutein, zeaxanthin, and omega-3 fatty acids, on the progression of intermediate or advanced AMD.

Cigarette smoking confers an approximately twoto three-fold increased risk of developing AMD [6]. In addition, an increased risk for AMD has been associated with a higher total fat intake, and a lower risk for AMD has been associated with the consumption of Þsh, nuts, and dark green leafy vegetables [7].

While antiangiogenic therapies such as ranibizumab (LUCENTIS, Genentech/Roche) and bevacizumab (AVASTIN, Genentech/Roche) have revolutionized the care of patients with neovascular AMD, there is no evidence to suggest that these antiangiogenic drugs have any beneÞcial or detrimental effect on the underlying degenerative process known as dry AMD. Even under the best of circumstances when eyes with wet AMD are treated and converted back to dry AMD, the dry AMD will most likely progress over time to central GA and vision loss.

Currently, there is no proven drug treatment for dry AMD; however, the cessation of smoking and treatments based on AREDS formula vitamin supplementation combined with a healthy diet are considered the only options for slowing disease progression.

17.3Targeting the Cause of AMD

The cause of AMD is multifactorial resulting from a combination of genetic and environmental risk factors. It is believed that these factors are responsible for the pathological alterations in the choroid, retinal pigment epithelium, and retina that presumably come about as a result of oxidative damage, inßammation, and/or the accumulation of toxic metabolites. This process leads

to a cascade of events resulting in the loss of central vision secondary to the loss of the choriocapillaris, the RPE, and the outer retina. Cellular dysfunction and apoptosis probably play a key role in understanding the pathogenesis of AMD [8].

The overall goal of treating dry AMD is to target the underlying cause of the disease and prevent, or at least slow, the loss of vision, which requires the preservation of the choroid, RPE, and photoreceptors. This approach has been hampered by two major issues. First, there are no reliable in vitro systems for testing the efÞcacy of any drug for dry AMD, and no true animal model exists for AMD. A well-developed macula is only found in primates and birds, and while numerous attempts have been made to develop nonprimate models for AMD and these models highlight various pathological features of human AMD, none of these animal models truly replicates the disease process seen in humans. The only model that may be useful for potential drug testing is the naturally occurring monkey colonies that have been found to develop drusen [9]. The second issue that has hampered drug development is the uncertainty surrounding the best molecular pathway to target for the treatment of dry AMD.

17.4Preclinical and Phase I Drugs in Development for Dry AMD

Over the past few years, treatment options have focused on slowing the progression of dry AMD and several clinical trial endpoints have been considered to test the different treatment strategies. These strategies include:

¥Preservation of photoreceptors and the RPE (neuroprotection)

¥Prevention of oxidative damage and damage from micronutrient deprivation

¥Suppression of inßammation (complement inhibitors, glucocorticoids, and other immunosuppressive agents)

17.4.1 Clinical Trial Endpoints in Dry AMD

The most obvious study endpoint for dry AMD therapies would be the preservation of visual acuity; however, studies using visual acuity as an endpoint would take many years to complete due to the slow progression

of the disease. To decrease the time required to show a beneÞt from a drug, surrogate endpoints have been developed that might indicate a positive outcome without waiting the years required to show visual acuity beneÞt. These surrogate endpoints include slowing or eliminating the progression of dry AMD to wet AMD, reducing the treatment interval and burden for patients with wet AMD undergoing anti-VEGF therapy, eliminating or reducing the drusen burden in the macula, and slowing the enlargement rate of GA. The surrogate endpoint of preventing the progression from dry to wet AMD was Þrst used in a study investigating anecortave acetate (RETAANE, Alcon Research Ltd., Fort Worth, TX) for the treatment of dry AMD. While the drug failed to prevent the progression of dry to wet AMD, the study demonstrated the feasibility of this clinical trial endpoint. Another strategy is to assume that a treatment for dry AMD might also affect the underlying stimulus for neovascularization in wet AMD. If true, then a potential endpoint might be to demonstrate that a drug for dry AMD is able to decrease the need for retreatment with antiangiogenic therapy in wet AMD or improve the visual acuity outcome. This study design has not been tested. The area of drusen in the macula can be measured using color fundus photography and has already been used as an endpoint in the laser-to-drusen trials. These trials failed to show that the decrease in the drusen areas were associated with a decrease in disease progression [10]. However, these studies were ßawed by selecting eyes with drusen outside the central macula and selecting drusen based on size rather than other physical properties such as volume and autoßuorescence characteristics. The change in drusen autoßuorescence characteristics in response to pharmacotherapy is a novel clinical trial endpoint that has not been explored previously. Another clinical trial endpoint would incorporate spectral-domain optical coherence tomography (OCT) as a way to reliably and reproducibly identify drusen in the macula and provide truly automated volume and area quantiÞcation. This strategy is currently being tested in clinical trials. However, based on a symposium held in Washington, DC, and sponsored by the National Eye Institute and the Food and Drug Administration, the most likely surrogate clinical trial endpoint is to assess a drugÕs effects on the growth of GA, since GA is a feature of dry AMD that would affect vision by being associated with the loss of photoreceptors, the RPE, and the choriocapillaris [11].

No one knows the best clinical trial endpoint for studying any of the emerging treatments; however, slowing the growth rate of GA has become the most appealing option. Since GA represents the loss of photoreceptors, it is considered an acceptable surrogate for the loss of vision, and several imaging modalities exist for accurate detection of GA. These modalities include color fundus photography, ßuorescein angiography, fundus autoßuorescence, and spectral domain OCT. The next most attractive endpoint involves the quantitative assessment of drusen, which are best identiÞed using color fundus photography and spectral domain OCT.

17.4.2Drugs to Promote Survival

of Photoreceptors and the RPE

17.4.2.1Drugs to Improve Choroidal Circulation and Protect Against

Ischemia

Trimetazidine

Trimetazidine is a drug currently used for the treatment of angina pectoris. Trimetazidine improves myocardial glucose utilization by stopping fatty acid metabolism, and it is considered to have cytoprotective effects in ischemic conditions. An ongoing multicenter, randomized, placebo-controlled study in Europe is investigating the off label use of trimetazidine (Vastarel MR, 35 mg tablet) and the primary goal of this study is to slow the conversion of dry AMD to wet AMD. Other uses for this drug include the treatment of vertigo, tinnitus, and vision loss and visual Þeld loss due to vascular causes (Table 17.1).

MC-1101

MacuCLEAR, Inc. (Plano, TX), has developed a topical agent (MC-1101) that has been shown to increase mean choroidal blood ßow and also possesses antiinßammatory and antioxidative properties. MC-1101 aims to maintain the integrity of BruchÕs membrane by restoring choroidal blood ßow, controlling inßammation, and restoring RPE function through its antioxidative effects. The active ingredient of MC-1101 is approved for use as an oral antihypertensive drug and its safety and tolerability proÞle is well characterized. A phase I/proof of concept, open-label, placebocontrolled study, in which healthy volunteers and patients with early dry AMD self-administered