**3.1 Vitamin supplementation for AMD**

Lifestyle modifications are thought to delay progression of AMD. The American Academy of Ophthalmology recommends smoking cessation, an antioxidant-rich diet with healthy unsaturated fats or omega-3 supplements, management of other medical conditions, routine exercise, and regular eye examinations for all AMD patients [44]. Additionally, antioxidant vitamins and minerals have been demonstrated to slow progression to advanced AMD according to the AREDS [45]. The original formulation consisted of: 500 mg vitamin C, 400 international units (IU) vitamin E, 15 mg beta carotene, 80 mg of zinc (zinc oxide), and 2 mg of copper (cupric oxide) [45]. Copper was added to the formulation as zinc supplementation can cause copper-deficiency anemia. Smoking cessation is specifically recommended because the high dose of beta-carotene supplementation is subject to a small increased risk of lung cancer [46]. The subsequent AREDS 2 investigation evaluated adding lutein + zeaxanthin and DHA + eicosapentaenoic acid [EPA], or lutein + zeaxanthin + DHA + EPA to the original AREDS preparation. It also explored removal of beta carotene and decreased the original dose of zinc. It adapted the formula to include: 10 mg of lutein and 2 mg of zeaxanthin, 350 mg DHA and 650 mg EPA, no beta-carotene, and 25 mg zinc [47]. They found that lutein + zeaxanthin or DHA/EPA did not further halt the progression of AMD; however, removal of beta-carotene from the lutein + zeaxanthin formulation proved to be protective against AMD and better for patients due to the decreased risk of lung cancer in patients using the beta carotene poor formulation. Additionally, the decreased quantity of zinc was deemed less protective than the higher doses administered in AREDS. In short, AREDS 2 concluded administration of 500 mg vitamin C, 400 IU vitamin E, 10 mg of lutein and 2 mg of zeaxanthin, 80 mg of zinc (zinc oxide), and 2 mg of copper (cupric oxide), without beta carotene was beneficial in decreasing the progression to advanced AMD in patients with intermediate and advanced AMD in at least once eye [47].

## **3.2 Past therapeutics for AMD**

Past therapies for AMD include photodynamic therapy, photocoagulation, low vision rehabilitation, and radiation therapy [44, 46]. First introduced in the 1990's, photodynamic therapy (PDT) involved injecting verteporfin (Visudyne) into an arm vein. The injected medication collects in pathologic neovascular membranes in the central macula. The verteporfin is light activated by using a 690 nm laser over the affected area, causing the formation of ROS. Unfortunately, new models of the PDT laser are no longer available for sale in the United States, although a single model is available in Europe. PDT has become obsolete for AMD treatment with the rise of anti-VEGF therapeutics, although it is still used for other retinal conditions [46]. A second method, photocoagulation treatment, uses a laser to accomplish the same goal. This may also require retreatment; however, the laser can produce scarring, which can cause blind spots. For this reason, it is no longer used to treat pathology within the macula. Moreover, increased damage to the macula lowers the success rate of treatment.

Studies in the 1980s examined the use of photocoagulative therapies in minimizing the progression of disease due to CNV lesions. These assessed laser therapy of the extrafoveal, juxtafoveal, and subfoveal neovascular membranes [46]. It was determined that laser therapy of extrafoveal or juxtafoveal sites was more effective than subfoveal sites. Subfoveal photocoagulation was associated with increased risk of vision loss [46]. However, with increased anti-VEGF therapies, the use of photocoagulation is also declining [46]. A third treatment is low vision rehabilitation, which is used as supplemental therapy to accommodate the central vision changes that may ensue from AMD. This can include implementation of reading glasses, magnifiers, additional lighting, among others [44]. New advances in wearable technology use individualized deficit mapping and artificial intelligence to assist users in navigating their environment and common activities of daily living. The fourth form, radiotherapy, has been used to inhibit neovascularization, but the effectiveness of this method is unclear [46].

### **3.3 Current therapeutics for AMD**

Although there is no current treatment to delay the onset of non-exudative AMD, once the disease progresses to the exudative form, there are treatments to delay its progression, preserve remaining vision, and sometimes recover lost vision [44]. Most of these therapies target the neovascularization and associated fluid leakage and hemorrhage. These drugs inhibit VEGF, the main proangiogenic factor that contributes to neovascularization. Current treatments include bevacizumab (Avastin, Genetech), ranibizumab (Lucentis, Genentech), aflibercept (Eylea, Regeneron Pharmaceuticals), and brolucizumab (Beovu, Novartis).

Pegaptanib (Macugen, Pfizer) was the first anti-VEGF therapy approved by the FDA in 2004 and is an oligonucleic aptamer specifically targeting VEGF-165. Ranibizumab is a monoclonal antibody fragment to all VEGF-A that was approved by the FDA in 2006 based on the results of the phase III MARINA and ANCHOR trials [48, 49]. Aflibercept is a receptor-antibody fusion protein of VEGF receptors 1 and 2 fused to the Fc portion of IgG1 that blocks VEGF-A and B. Aflibercept was approved by the FDA in 2011 based on the VIEW-1 and 2 phase III trials [18, 46]. Brolucizumab is a single-chain antibody fragment approved by the FDA in October 2019 based on the phase III HAWK and HARRIER trials [46, 50]. Ranibizumab, aflibercept, and brolucizumab were created specifically for the treatment of exudative AMD, while bevacizumab was approved for colon cancer and is used off-label.

*An Overview of Age-Related Macular Degeneration: Clinical, Pre-Clinical Animal Models… DOI: http://dx.doi.org/10.5772/intechopen.96601*

Bevacizumab is considerably less expensive at an average of \$50 per treatment versus \$1,800 or \$2,000 for the other three available treatments and has been shown to be equally efficacious in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) studies [51].

In any of the treatment trials that are evaluating the efficacy of the anti-VEGF family of therapies, patients are monitored for exudation and treatment response using optical coherence tomography after intravitreal injection [45]. Frequency of injections varies, but most patients require multiple doses and repeat treatments. Brolucizumab is groundbreaking as it is the first anti-VEFG therapy that has demonstrated similar efficacy from a single injection, 4 times a year [46]. Unfortunately, adoption of Brolucizumab has been limited by intraocular inflammation, vasculitis, and vascular occlusion causing visual decline that was seen in 4.6% of trial participants [52]. Potential adverse effects of anti-VEGF therapies include conjunctival hemorrhage, vitreous hemorrhage, increased intraocular pressure, cataract progression, and, rarely, retinal detachment, infection, and intraocular inflammation [44].
