Treatments Being Investigated for Geographic Atrophy
Dry age-related macular degeneration (AMD) remains the most prevalent form of AMD. The Age-Related Eye Disease Study (AREDS) demonstrated that patients with extensive intermediate drusen, one large druse (defined as greater than or equal to 125 micrometers), or either wet AMD or geographic atrophy in one eye have a reduced risk of progression to wet AMD and a reduced risk of progression to severe vision loss if they take nutritional supplements containing 15,000 IU vitamin A, 400 IU vitamin E, 500 mg vitamin C, 80 mg zinc and 2 mg copper. Results of the AREDS2 trial suggest that two groups of patients may benefit from changes to the AREDS formulation.
First, patients who have smoked within the past seven years (and potentially even patients who have ever smoked) should avoid taking high doses of vitamin A as the latter may increase the risk of mortality due to lung cancer. For these patients, substituting lutein 10 mg/day and zeaxanthin 2 mg/day for vitamin A is recommended. Second, it is recommended that patients who tend to eat fewer than three servings of dark green leafy vegetables weekly take the AREDS2 formulation that contains lutein/zeaxanthin rather than vitamin A. Another important finding from the AREDS2 trial is that supplemental omega-3 fatty acids (1000mg) did not offer benefit above and beyond the AREDS formulation.
Often, family members of affected patients will ask what they can do to reduce the chance that they will develop AMD. I encourage them (as well as the affected patient) to stop smoking and to eat dark green leafy vegetables, such as broccoli, spinach and kale, at least three times a week. Although the AREDS2 trial did not find a benefit to supplemental omega-3 fatty acids in patients who have moderate to advanced AMD, numerous studies have found that patients who eat foods high in omega-3 fatty acids have a lower risk of developing AMD. As such, I encourage family members of patients with AMD to eat foods such as flax seed or fatty fish a few times a week. Maintaining normal body weight, as well as maintaining good cardiovascular fitness, also may reduce the risk of AMD.
There are currently no available treatments for geographic atrophy. However, there are a number of agents under investigation for the treatment of geographic atrophy and this article will provide an overview of a few of them.
Brimonidine, currently used as an intraocular pressure-lowering eye drop, has a neuroprotective effect that may offer some benefit to patients with geographic atrophy. In the phase IIb trial entitled "A Safety and Efficacy Study of Brimonidine Intravitreal Implant in Geographic Atrophy Secondary to Age-related Macular Degeneration (BEACON)," patients are given an intraocular injection of brimonidine that has been reformulated as an intravitreal implant that releases the drug over three months. It is injected into the eye with a device similar to that used to administer Ozurdex (Allergan, Inc). The BEACON trial is currently underway in multiple centers both in the United States as well as internationally. In the earlier phase 2 trial, one injection of brimonidine appeared to slow progression of geographic atrophy by approximately 20%.1
Doxycycline, a member of the tetracycline family, is an oral medication that may prevent photoreceptor and retinal pigment epithelium (RPE) degeneration through multiple mechanisms, including the prevention of complement activation and cytokine production, reducing reactive oxygen species, and inhibiting matrix metalloproteinases. In a trial currently underway, patients with geographic atrophy are given 40 mg of doxycycline daily, which is a lower dose than commonly prescribed to treat infections. One of the potential benefits of this drug is that it has been used for many years (for treatment of such conditions as acne, urinary tract infections, sexually transmitted diseases and rosacea) and has an excellent safety profile.
Of all the trials underway, none have captured public attention like cell-based therapies have. There are several different technologies currently under investigation.
Johnson & Johnson is sponsoring a trial investigating the role of suprachoroidal delivery of umbilical cells. These are not bioengineered cells; they are cells derived from the umbilical cord and they have a neurotrophic effect. Specifically, they protect photoreceptors and the RPE cells from degenerating. There were no safety signals (outside of the surgery itself) in the phase 1 trial.2 As it was a phase 1 trial, the focus was on safety; however, some patients experienced visual acuity improvement. A phase II trial looking at efficacy is currently underway.
In trials sponsored by Astellas Pharma (formerly Advanced Cell Technology/Ocata Therapeutics), embryonic stem cells are delivered through a transvitreal approach into the subretinal space. In the phase I trial, there were no safety signals such as unimpeded cell growth or evidence of teratoma.3 A phase II trial is underway.
Regenerative Patch Technologies is conducting a phase I/IIa clinical trial investigating a novel technique designed to grow human embryonic stem cell-derived RPE cells on a parylene membrane in patients with geographic atrophy. This “patch” is then implanted in the subretinal space.4
There are a number of companies investigating drugs that inhibit various parts of the complement cascade. The drug furthest along in development is lampalizumab (Genentech, Inc.), an agent that inhibits complement factor D. In a phase 2 trial, patients were randomized to monthly injections versus sham. At month 18, patients in the treatment arm had a 20.4% reduction in growth of geographic atrophy and, if patients were positive for complement factor I (a biomarker), there was a 44% reduction in growth of geographic atrophy.5 A phase 3 trial is currently enrolling. Ophthotech is sponsoring a phase 2/3 clinical trial evaluating the role of an intravitreal injection of an anti-C5 aptamer in eyes with geographic atrophy secondary to dry AMD.6 A recent trial using eculizumab did not slow the rate of geographic atrophy. AMD is a complicated disease with multiple mechanisms of action. Hopefully, the current trials using complement inhibition will permit a better understanding of the pathobiology of dry AMD.7
These are only a few of the very exciting treatments currently in development for patients with geographic atrophy. I recommend that patients with intermediate to more advanced AMD be encouraged to implement the lifestyle modifications discussed above, as well as to take the AREDS or AREDS2 vitamins. If geographic atrophy is present, a referral to a center that is conducting these trials may be of benefit both to the patients as well as to the larger community of patients with this disease.
1. Allergan, data on file.
2. A safety study of CNTO2476 in patients with age-related macular degeneration. Available at: https://clinicaltrials.gov/ct2/show/NCT01226628. Accessed July 5, 2016.
3. Schwartz SD, Regillo CD, Lam BL, et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet. 2015 Feb 7;385(9967):509-516.
4. Study of subretinal implantation of human embryonic stem cell-derived RPE cells in advanced dry AMD. Available at: https://clinicaltrials.gov/ct2/show/NCT02590692?term=amd+stemcell&recr=Open&no_unk=Y&rank=4. Accessed July 6, 2016.
5. Williams DF, Yaspan B, Zhengrong L, et al. Lampalizumab (anti-factor D) in geographic atrophy: the MAHALO phase II results; Presented at the 2013 American Society of Retina Specialists (ASRS) Meeting; August 27, 2013; Toronto, ON, Canada.
6. A phase 2/3 trial to assess the safety and efficacy of intravitreous administration of Zimura® (Anti-C5 Aptamer) in subjects with geographic atrophy secondary to dry age-related macular degeneration. Avialable at: https://clinicaltrials.gov/ct2/show/NCT02686658?term=amd+complement&rank=10. Accessed July 5, 2016.
7. Yehoshua Z, de Amorim Garcia Filho CA, Nunes RP, et al. Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the COMPLETE study. Ophthalmology. 2014;121(3):693-701.
About our author(s):
Sunir Garg, MD, FACS
Professor of Ophthalmology, The Retina Service of Wills Eye Hospital,
Thomas Jefferson University, Philadelphia