Advances in the Treatment of Dry Age-Related Macular Degeneration

By Rishi P. Singh, MD

Macular degeneration is currently the leading cause of visual impairment in the U.S. Breakthrough treatment with anti-VEGF eye injections such as Avastin® (bevacizumab, Genentech), Lucentis® (ranibizumab, Genentech) and Eylea® (aflibercept, Regeneron) has almost arrested the progression of the wet form of the disease.

However, almost 80 percent of people diagnosed with age-related macular degeneration (AMD) have the non-neovascular (dry) or atrophic subtypes. The American Academy of Ophthalmology notes that the most advanced form of non-neovascular AMD, known as geographic atrophy (GA), can occur as early as in intermediate AMD or (more typically) in advanced AMD. Estimates predict advanced AMD will impact as many as 3 million people in at least one eye by 2020. The growing number of aging Americans underscores the need for treatments that can prevent progression of and/or treat advanced AMD.

Trials underway for treatment of GA

Surprisingly, no treatments are currently available for the prevention of GA. Evidence from the Age-Related Eye Disease Study (AREDS) suggests antioxidant vitamin and mineral supplementation may help prevent the progression to neovascular AMD, but the study failed to show that vitamin supplementation decreased progression to geographic atrophy. Even in AREDS2, when beta-carotene was replaced with lutein/zeaxanthin to decrease the risk of lung cancer, the new formulation also failed to show decreased progression to GA.

Clinical studies are underway at Cole Eye to further elucidate and understand the mechanisms of dry AMD and to evaluate new therapeutics directed at slowing the progression. We are fortunate to have two large phase 3 trials underway for the treatment of GA. The FILLY study assesses the safety, tolerability and evidence of activity of multiple intravitreal (IVT) injections of APL-2 (Apellis Pharmaceuticals) for patients with GA. The second is a multicenter, randomized, double-masked, sham-controlled study to investigate IVT injections of lampalizumab in patients with GA.

The complement cascade: several compounds under investigation

The discovery of complement byproducts in drusen led to associations between complement dysregulation and AMD. Thus, several researchers are evaluating the complement cascade as a clinical therapeutic target for non-neovascular AMD. Factor D is considered a critical early component of the alternative pathway that involves complement factor H. Factor D is an upstream of factor B and other AMD-associated proteins, making it a potential powerful target for treatment. Anti-inflammatory agents under development include lampalizumab, fluocinolone, glatiramer acetate, sirolimus, eculizumab and ARC-1905.

These are but the tip of the iceberg of compounds under development for advanced AMD or GA. Visual cycle inhibitors are among those in latter-stage development and include fenretinide, ACU-4429 and ALK-001. These compounds down-regulate the visual cycle to decrease the accumulation of the toxic waste products of retinal metabolism. Amyloid-beta has been found in drusen, and RN6G and GSK933776 are in development to regulate amyloid-beta accumulation.

Neuroprotective drugs are also under development, including UF-021, ciliary neurotrophic factor and brimonidine tartrate intravitreal implant. Topical agents such as MC-1101 are attempting to slow AMD by increasing choroidal perfusion. Stem cell therapies including HuCNS-SC and MA09-hRPE are also under investigation as potential treatments for GA. At this point, it is too early to tell which — if any — of these treatments will become a standard of care.

Dr. Singh is Medical Director of the Clinical Systems Office and staff in Cole Eye Institute.