Geographic Atrophy: Best Practices for Diagnosis and Referral

Advanced age-related macular degeneration (AMD) is subtyped into exudative (also called “wet AMD”) and non-exudative (also called “dry AMD”) disease.¹ The prevalence of wet and dry AMD is estimated to be 11 million in the United States and 170 million globally.² Approximately 85% to 90% of patients with AMD have dry AMD.³

Historically, patients with advanced dry AMD present with geographic atrophy (GA) upon examination. GA was classically described as “a discrete area of retinal depigmentation at least 175 μm in diameter with a sharp border and visible choroidal vessels.”⁴ With advanced imaging modalities in 2021, however, GA can be detected earlier than when these classic findings show up on examination. GA may lead to central scotomas and loss of visual acuity,⁵ and it has been shown that 31% of eyes with GA lose 3 lines of vision within 2 years, and that 53% of eyes lose 3 lines within 4 years.⁶ The estimated prevalence of AMD in the United States was nearly 3 million for 2020.⁷

There is no treatment approved by the US FDA that halts or reverses GA and its effects. Drugs in the pipeline that are designed to address GA progression show some promise, but as of mid-2021, no complete set of pivotal trial data have found that any treatment is safe and effective for the treatment of GA. Eye care providers should stay abreast of the latest developments in GA therapy so that, if and when treatments are approved by regulatory agencies, they can knowledgably refer their patients to the proper channels to receive the latest care.

— Roger Goldberg, MD, MBA, Moderator

THE STATE OF GA IN 2021

Q|Roger Goldberg, MD, MBA: It is estimated that 3 million Americans have AMD, which is a significant increase from the 1.75 million Americans who were estimated to have it in 2004.⁷ A partnership between optometrists and general ophthalmologists (who are most likely to detect evidence of GA in patients during routine and symptom-based eye exams) and retina specialists (who will be tasked with administering therapy to patients if and whe n such therapies are found safe and effective) will be key to ensuring that patients are properly referred and cared for. I’m curious to hear about the panel’s experience with real-world GA patients. Do the prevalence numbers above match your perceptions?

David Lally, MD: I roughly see 15 to 20 patients every day with the presence of GA in at least one eye. Many of those eyes have concomitant neovascular disease. However, many are referred to my practice for consideration of a GA clinical trial. These high patient volumes underscore the prevalence of GA in the population that I treat.

Mary Beth Yackey, OD: Optometrists and general ophthalmologists see a large portion of the population with
GA, perhaps because retina specialists have been inundated with patients seeking therapy for wet AMD, which has FDA-approved treatments. As of 2020, 26% of patients with bilateral GA were under the management of an optometrist or a general ophthalmologist.⁸ 

Dr. Goldberg: As a clinician, can you get a sense of how GA affects patients’ lives?

Dr. Yackey: GA can have an immense effect on a patient’s independence. Daily tasks such driving, meal preparation, reading, computer use, and shopping are all negatively affected by GA.⁹ The literature has shown that depression rates are significantly higher in patients with GA compared with patients who do not have it, which should be cause for concern.¹⁰

Diana Shechtman, OD, FAAO: As someone who practices in South Florida, I see many older patients whose ability to drive has been affected by GA. It should be noted that society shares the burdens of GA in this way, too, as unsafe driving affects people beyond the patient. GA is responsible for approximately 20% of all cases of legal blindness,¹¹ which greatly affects the patient’s activities of daily living. 

As eye care provides become better equipped to detect—and potentially treat, in the future—GA, patient education remains key. In many cases, my patients are not aware of the early symptoms associated with GA. They have 20/20 BCVA and yet trouble with contrast sensitivity, which may affect their daily activities. Most may not feel a need to get an evaluation for minor visual disturbance and wait until there is apparent visual impairment. Unfortunately, that level of visual impairment is often associated with more advanced stages of disease.

Dr. Goldberg: I am regularly surprised by the disconnect between measured visual acuity and real-world functional vision in patients with GA. Patients might present with 20/20 BCVA, such as those described by Dr. Shechtman, but complain of reading difficulty or challenges when emerging from a tunnel while driving. In those patients, I look for evidence of GA. Other patients, however, are reluctant to tell me about changes to their functional vision. They chalk it up to having “old eyes.” Detecting GA based on symptomatology alone, therefore, can be a challenge. The BCVA that we measure in a dark room with black letters on a white wall doesn’t tell the full story, and we need to remember that when examining our patients.

Carlos Medina, MD: The foveal-sparing nature of early GA likely explains why some patients experience reduced visual function but normal Snellen BCVA measurements in our clinics. Indeed, real-world data have shown that patients with extrafovealGA lesions have better vision than patients with foveal-involving GA lesions.⁸ Still, it has been shown that BCVA and lesion enlargement are not necessarily correlated. These data illustrate the unique dynamic between anatomy and function in patients with GA.¹² In that sense, BCVA testing in inadequate.

Dr. Shechtman: Some of the patients who have been referred to our clinic with GA come with a note from the referring clinician in which they express concern about the patient’s declining BCVA. Educating our referral network is critical. We may be able do more for a patient with 20/20 BCVA and early signs of GA than we can for a GA patient whose disease has already progressed. This will be especially crucial as new therapeutic treatment options become available, which can decrease progression of the disease.

Dr. Medina: Tests that evaluate functional vision rather than BCVA may prove useful in detecting and monitoring disease. Low luminance visual acuity (LLVA) testing may be more appropriate in patients with GA and good BCVA. It has been observed that LLVA is a more sensitive measurement than BCVA for assessing risk of visual decline.¹³ Reading speed, which has been shown to correlate with GA lesion size, is useful for assessing a patient’s ability to read full sentences rather than a single letter in the center of the visual field.¹⁴ Patient questionnaires are also useful in this population, as they provide insight into how GA affects a patient’s quality of life.¹⁵ One such questionnaire, which was developed specifically for patients with GA, has been endorsed by the European Medicines Agency for use in clinical trials.¹⁵ Like reading speed rates, scores on these questionnaires have been shown to correlate with GA lesion size.¹⁶ Whether these tests fit in the workflow of a busy clinic is a different question, of course. In many instances, they do not.

Dr. Yackey: Dr. Medina is correct to note that some of these tests are too cumbersome for real-world high-volume clinics. Part of the benefit of such testing is that it can objectively show the patient that their visual function is declining even while their BCVA remains good. I have found that imaging reports work as an effective educational tool. By sharing the results of a fundus autofluorescence (FAF) scan, I can show a patient (and any family who has joined them) the presence of an extrafoveal macular lesion and explain how it will negatively affect their vision as the lesion progresses. Some patients understandably struggle to reconcile their good BCVA measurements with a prognosis of visual decline. After the patient sees an image of the macular lesion in their own eye, however, they begin to understand how progression of the disease will affect their vision.

Dr. Goldberg: Fitting GA examinations—and particularly some of these other functional tests such as LLVA and reading speed—into our workflow in an efficient way is key to maximizing the care we provide for our patient populations. Walk me through an appointment for a GA referral. (See sidebar “The Value of Multimodal Imaging in Detecting New Geographic Atrophy” for a case depicting a new GA patient.)

Dr. Medina: Every patient who comes into our clinic, regardless of the disease they are referred for, receives an OCT evaluation. Patients who are GA suspects also receive FAF imaging by our technicians at this point in the visit. By the time I see that patient, I have reviewed their OCT and FAF scans and am prepared for a thorough examination.

Dr. Shechtman: I follow a protocol similar to the one described by Dr. Medina. I find that FAF is a highly sensitive test, as it helps visualize the entire GA lesion area. It should be noted that increased areas of hyperfluorescence on FAF are associated with lipofuscin accumulation, which precedes development of GA. In the literature, FAF has been called the gold standard for imaging GA patients.¹⁷

Q| Dr. Goldberg: Large optometric clinics with greater resources may have access to imaging platforms such as FAF and OCT, but smaller clinics may not have them. Still, these practices will see patients with possible GA. How should they proceed with an examination?

Dr. Shechtman: In my experience, many optometrists in South Florida do not have OCT imaging. The chief reasons are twofold: the up-front cost of an OCT platform is high, and vision insurance plans do not reimburse for OCT imaging. Most of these practices do, however, have access to color fundus photography (CFP), which has been used in a number of studies to visualize GA lesions.^18,19 Although CFP is not as sensitive as OCT or FAF in detecting GA lesions, it can help eye care providers detect structural alternations that could indicate the presence of GA.

Dr. Lally: I see value in CFP, and patients who visit my practice receive CFP in addition to spectral-domain OCT (SD-OCT) and FAF during their visit with the technician. All of these images serve as a baseline against which we can refer later. On SD-OCT, I usually look for the double-layer sign (DLS). Instances in which I see a DLS lead me to investigate for macular neovascularization, which can be observed in greater detail using OCT angiography (OCT-A). Patients with extrafoveal GA lesions and a subfoveal DLS undergo OCT-A imaging so that I can understand the degree of neovascularization occurring near the DLS and, from there, understand the likely prognosis of their disease.

Dr. Shechtman: We can’t ignore the value of OCT when it comes to visualizing changes in the outer retina and retinal pigment epithelium (RPE) in GA patients. OCT of patients with GA often shows overall thinning on the retinal thickness map, with variable retinal alterations. A key finding is increased signal transmission below the RPE, associated with loss of the overlying retinal layers.

Dr. Goldberg: I agree with that wholeheartedly. Loss of the RPE overlying Bruch’s membrane, with secondary increased penetration into the choroid, is the hall mark finding of GA on OCT.²⁰ This can sometimes cause a “striping” on OCT that is easy for clinicians to recognize. This can also be useful for detecting the earliest forms of atrophy. Sadda et al determined that incomplete RPE and outer retinal atrophy (iRORA) and complete RORA (cRORA) are two nascent forms of GA, with iRORA progressing to cRORA.²¹ Using their paradigm could allow disease detection in patients with very early GA—who are, to the point Dr. Shechtman made earlier, the patients we will most be able to help whenever the FDA approves a treatment for GA.

Research has found that GA lesions detected on FAF can be categorized based on their shape, pattern, and/or hyperautofluorescence at the lesion border (Figure 1). Bindewald et al found that small lesions and unifocal lesions progress slower than large or multifocal lesions,²² and Hu et al have found that patients with banded lesions (ie, those with a hyperautofluorescent band surrounding the lesion margin) and autofluorescence changes beyond the lesion border are most likely to experience disease progression.²³ These categorizations are useful for clinicians, but I wonder how much utility they have for explaining likely disease progression to patients.

Figure 1. GA lesions as detected on FAF may be classified as focal, patchy, banded, diffuse, diffuse-trickling, or as having no pattern. Banded and diffuse lesions are the most likely lesions to progress.

Dr. Medina: I don’t go into much detail regarding focality or lesion band patterns during my discussion with patients. I might speak in general terms, such as telling the patient that bigger lesions grow more quickly. And if I have baseline images against which to compare their most recent image, I may use that to illustrate lesion growth. Anything beyond that, though, functions only to confuse or depress the patient about their eventual visual decline.

The only circumstances in which I get into details about the relationship between focality/lesion type and disease progression is if I’m talking to a patient about enrolling in a clinical trial or if I’m preparing for a discussion about risk factor modification, such as smoking cessation or diet adjustments.

Dr. Lally: For the most part, patients with GA know that they have a visual problem. Until we have an FDA-approved treatment for GA, one of the most helpful discussions we can have with these patients is to prepare them for activities of daily living which may need adjusted in the coming years. Conversations with patients about their specific visual needs are key. Are they currently driving? Do they take care of an aging spouse? Do they read or cook or use a checkbook? When we have answers to these types of questions along with an understanding of disease progression based on the lesion characteristics, then we can provide guidance for patients about how the visual changes they may experience in the forthcoming year will affect the most important aspects of their lives.

Dr. Goldberg: Whenever we do get an FDA-approved therapy for GA, the conversation around lesion location and types will be different. At that point, we can use those data to gauge which patients are best suited for therapy. Until that occurs, however, we chiefly use these images to determine the rate of progression.

Dr. Yackey: Discussing the promise of the GA pipeline with some patients is appropriate, as long as it is done ethically. For patients who present with lesions that are less likely to rapidly progress—that is, smaller lesions, nonbanded lesions, and unifocal lesions—we consider telling them that some drugs are under investigation to treat their disease. We need to balance educating our patients against inspiring false hope. 

Dr. Shechtman: If clinical findings and ancillary imaging tests suggest that the patients is likely to progress slowly, my follow-up regimen of 6 to 12 months. If, however, there is evidence that the patient may progress quickly, I tend to follow that patient closely, and consider asking them to return within 3 to 6 months.

Dr. Medina: My practice pattern is similar. Sometimes these patients are good candidates for a clinical trial, or are just on the cusp of the enrollment criteria. In those cases, I ask the patient to return sooner than they normally might. In other instances,
if I sense that a patient might soon develop a DSL or advance to foveal-involving disease, I ask them to return in a 3-to-6-month window. I also ask patients to return in an earlier window if I observe reticular pseudodrusen (RPD) on examination. Multiple studies have linked the presence of RPD to the progression of GA,^24-28 with one study showing that the risk of progression was nearly 5 times higher for patients with RPD.²⁴

Q| Dr. Goldberg: When it comes to optometry and general ophthalmology, some clinicians may not see a value in referring to a retina specialist because there is no FDA-approved therapy. Do you feel there is value in a patient seeing a retina specialist despite the fact that there is little we can do to treat their condition at the moment?

Dr. Lally: Getting GA patients on the radar of retina specialists is going to be important to ensuring that treatment—if and when it becomes available—can be administered promptly. I encourage the optometrists and general ophthalmologists with whom I collaborate to have a low threshold for referral. If any GA lesions are detected, I think referral is appropriate. Keep in mind that some patients progress very quickly. Functional vision could deteriorate in the period between semiannual or annual eye examinations, so the sooner a retina specialist sees these patients, the better.

PATHOGENESIS OF GA AND THE ROLE OF THE COMPLEMENT SYSTEM

Q Dr. Goldberg: Controllable and uncontrollable nonophthalmic factors contribute to GA risk. What are some of the risk factors that are linked to GA development or progression that you often consider?

Dr. Yackey: As might be expected with an age-based disease, age is a major risk factor for the development of GA. The Beaver Dam Eye Study, a population-based cohort study, found that 3.2% of patients who were at least 75 years old had GA, compared with 0.0% of patients who were under 54 years old.²⁹ A family history of AMD is also a risk factor for the development of GA.³⁰

Genetics also play a role in a patient’s risk for developing GA. Patients who have both risk alleles CFH and ARMS2 are at increased risk for developing AMD.³¹ Specific to GA development, the presence of CFH variant Y402H increases a patient’s risk of developing GA independent of smoking status.³²

Dr. Medina: Diet, lifestyle, and smoking all play a role in development of GA,^30,33 and I encourage patients to address these controllable factors whenever possible. Current smoking status in particular is a major factor, as risk of developing advanced AMD has been linked to current smoking status.³¹ But for many of our patients, treatments will likely have a more profound effect than adjusting the above factors. Luckily, data from several clinical trials give us hope that a treatment may soon be approved by regulatory bodies.

Dr. Goldberg: Our knowledge of the pathology of GA has improved as research has become more robust in the past several years, leading researchers to conclude that compliment disruption might be linked to the development of GA. Indeed, data such as that published by Ambati et al found that drusen in GA patients contains complement components C1q, C3, C5, and C3b-9, implicating the complement cascade in the pathogenesis of GA.³⁴

Let’s break down the complement system and the complement cascade so that we can further understand the biologic mechanisms behind GA development and growth.

Dr. Lally: The complement system is part of the innate immune system. It contains three main pathways: the classical pathway, the lectin pathway, and the alternative pathway.³⁵ The activation of each pathway ultimately can result in cell death. When functioning properly, such cell death is directed at foreign bodies. However, in the case of GA, complement disruption may lead to the death of cells in the retina itself.

All three pathways converge on complement component 3, often simply called C3 (Figure 2). In the alternative pathway, C3 cleaves into C3a and C3b, which contributes to cell death and C5 activation.³⁵ The alternative pathway is activated in part by complement factor D (CFD).³⁷ Further down the cascade, C5 convertase cleaves C5, leading to the creation of C5b, which combines with C6, C7, C8, and C9 to create membrane attack complex (MAC),³⁸ a protein complex that attacks cells.

Given the multiple points at which we could intervene in the complement cascade and the findings that the drusen deposits contain complement components, complement inhibition has been the main focus of pipeline development.

Figure 2. The classical, alternative, and lectin complement pathways all converge on C3. The cleavage of C3 results in the formation of C3b, which in turn leads to the activation of C5. When C5 is cleaved, C5b is formed, which combines with C6, C7, C8, and C9 to form MAC.

Dr. Goldberg: A return to this level of basic science may surprise some clinicians, but it’s important to have a working understanding of the biologic mechanisms that may be activating this devastating disease. Plus, when we understand the complement system’s role in disease activity, we can better understand mechanisms of action of potential therapies targeting the complement cascade.

THE GA PIPELINE

Dr. Goldberg: A number of drug candidates have been evaluated for the treatment of GA, several of which leverage the opportunities presented by the complement cascade. Let’s review some of the top-line data from some of the most important trials in GA therapy.

Dr. Lally: Earlier, I explained that CFD activated the alternative pathway.³⁷ Lampalizumab is a CFD inhibitor that was evaluated in the phase 3 Chroma and Spectri trials.³⁹ Researchers enrolled patients with bilateral GA and randomly assigned them to receive 10 mg lampalizumab every 4 or 6 weeks, or sham every 4 to 6 weeks. The study’s primary endpoint was mean change of GA lesion area from baseline at week 48. It was determined that patients in the treatment arms did not demonstrate a reduction in GA enlargement compared with patients in the sham groups.

Dr. Goldberg: The inability of lampalizumab to significantly reduce GA lesion growth area was discouraging news for the eye care community—particularly among those who envisioned the complement cascade as a viable target for complement inhibition—but other drugs have seen success in phase 2 and phase 3.

Dr. Lally: The two drugs to which Dr. Goldberg is referring—pegcetacoplan and avacincaptad pegol—are PEGylated. PEGylation may increase retention and slow down metabolism, which could give these drugs some advantages over lampalizumab,which was not PEGylated.

Dr. Goldberg: Let’s talk about those two drugs now. Dr. Shechtman, before I review pegcetacoplan, can you update us on the status of avacincaptad pegol?

Dr. Shechtman: Avacincaptad pegol is a C5 inhibitor that aims to disrupt the formation of MAC.^40,41 The study’s two pivotal trials are titled GATHER1 and GATHER2. In the GATHER1 study, researchers enrolled patients with GA secondary to dry AMD and randomly assigned them to receive monthly 2 mg or 4 mg of intravitreal avacincaptad pegol or sham. Patients in both treatment arms demonstrated a significantly improved reduction in the mean rate of GA growth area at 1 year, with reductions of 27.4% (P = .007) and 27.8% (P = .005) in the 2-mg and 4-mg groups, respectively.

The GATHER2 study is expected to complete its enrollment of 400 patients by the end of July 2021.⁴² In that study, patients will be randomly assigned to monthly treatment or sham, and the mean rate of change of GA growth during a 12-month period will remain the primary endpoint.⁴³ At month 12, patients in the treatment arm will be randomly assigned to receive monthly or every-other-month (EOM) treatment, with final data readouts occurring at the end of year 2.⁴³

Dr. Goldberg: Pegcetacoplan is a C3 inhibitor, which targets a mechanism further upstream in the complement cascade. C3 is the convergence point of the three complement pathways, and inhibition of C3 may prevent the cascade that allows C5 and other downstream elements to activate. Pegcetacoplan is also designed to bind to C3b, which leads both to cell death and the activation of C5.

In the phase 2 FILLY study, researchers enrolled patients with GA secondary to AMD and randomly assigned them to receive 15 mg intravitreal pegcetacoplan monthly or EOM or sham monthly or EOM.44 A 29% and 20% reduction in the rate of GA lesion growth was observed at month 12 in patients who received monthly and EOM treatment, respectively.⁴⁴ Both of these reductions were considered statistically significant.⁴⁵ The phase 3 DERBY and OAKS studies will evaluate the safety and efficacy of pegcetacoplan in pivotal trials. Topline data from those studies are expected in the third quarter of 2021.⁴⁶ Dr. Medina: A post-hoc analysis of the FILLY study assessed patients on FAF imaging. Patients with iRORA were 39% less likely to advance to cRORA,⁴⁷ which could mean that pegcetacoplan is appropriate for early intervention of patients with GA. Further studies on this topic are needed.

Dr. Lally: As long as we’re talking about the complement pathway, we should mention the phase 2 HORIZON54 and EXPLORE55 trials, which are assessing the upregulation of complement factor I (CFI) for the treatment of GA secondary to dry AMD via the drug GT005 (Gyroscope Therapeutics). The studies have a novel approach insofar that they are grouping patients in the study by genotype. In fact, patients in the EXPLORE study will all have rare CFI gene variants.

Q| Dr. Goldberg: A number of therapies have targeted biological mechanisms other than the complement cascade. Have we seen success or momentum with any of those therapies?

Dr. Medina: Attempts to decrease toxic metabolic byproducts associated with retinal tissue function have not shown much success and have been associated with delayed dark adaption. Such failures are not isolated in the GA pipeline. The C5 inhibitors eculizumab⁴⁸ (Solaris, Alexion Pharmaceuticals) and tesidolumab^49,50 (LFG316, Novartis) did not demonstrate reductions in GA lesion growth. That said, current clinical trials have shown some degree of promise, so we shouldn’t be too certain that past failures will dictate future ones.

Dr. Yackey: The Cincinnati Eye Institute recently participated in a phase 1/2a study that explored the safety and efficacy of the subretinal transplantation of human embryonic stem cell–derived RPE cells for the treatment of GA.⁵¹ The procedure was well tolerated, and encouraging structural and clinical changes were observed. As this is an early-stage study, I expect further research in this area.

Part of our job as eye care providers is to ensure that patients understand that clinical trials are never patient-funded ventures, and that any patient who is paying for cell therapy for GA should do so with extreme caution. In a 2019 study, Nirwan et al found a number of direct-to-consumer marketing campaigns that advertised cell therapy for GA,⁵² leading Parke II to point out that the out-of-pocket nature of payment for these procedures occurred despite language such as “clinical trial” and “research” appearing in the marketing materials.⁵³ 

Dr. Goldberg: That is such an important point. We need to ensure the safety of our patients, and part of our job is to caution patients that, if they seek second opinions, they must do so with legitimate, ethical clinics. If a supposed clinical trial is patient-funded, it is likely not a clinical trial at all. We all hope that a therapy for GA will be approved in the near future, which will finally allow eye care providers to direct patients toward relief for their condition. Until that day comes, we must stay prepared and educated so that we can hit the ground running as soon as we are able to treat patients with GA. 

THE VALUE OF MULTIMODAL IMAGING IN DETECTING NEW GEOGRAPHIC ATROPHY
By Roger Goldberg, MD, MBA

A 69-year-old white man presented to my clinic with complaints of difficult night driving and reduced contrast sensitivity. A clinical exam revealed 20/40 VA OU and trace nuclear sclerosis. Diffuse drusen were detected, but there was no evidence of geographic atrophy (GA) lesions on exam or on color fundus photography (CFP; Figure 1).

Figure 1. Bilateral CFP revealed evidence of drusen but no GA lesions.

The patient underwent fundus autofluorescence (FAF) and OCT imaging. On FAF, multifocal GA lesions were present OU (Figure 1). OCT imaging showed atrophy of the retinal pigment epithelium (RPE) that is characteristic of GA, with increased transmission into the choroid (Figure 2).

Figure 2. On FAF, multifocal GA lesions were observed in both eyes.

Figure 3. Atrophy of the RPE and increased transmission into the choroid were observed on OCT.

This case demonstrates that multimodal imaging of GA patients is valuable in the assessment of new patients. If this patient had only undergone routine examination and monomodal imaging (ie, CFP), no GA lesions would have been detected. Instead, lesions were detected, and cross-sectional imaging confirmed patterns of atrophy in the RPE. Although FAF may be gold standard platform for GA imaging, not all practices keep this modality in house. Practices that have access only to CFP should consider referring any GA suspects to a practice with multimodal imaging capacity. Clinicians with OCT may choose to rely on evidence of RPE atrophy by detecting increased transmission into choroid to diagnose GA.

References
1. Elshatory YM. Age-related macular degeneration. American Academy of Ophthalmology Eye Wiki. Available at: eyewiki.aao.org/Age-related_macular_degeneration. Accessed January 27, 2021. Updated August 10, 2020.
2. Pennington KL, Deangelis MM. Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors. Eye Vis (Lond). 2016;3:34.
3. Bressler NM, Bressler SB, Fine SL. Chapter 61. Neovascular (Exudative) Age-Related Macular Degeneration. In: Retina, Volume II, 4th Edition. Elsevier, Mosby. 2006. Editor: Andrew SP. Schachat.
4. Coleman HR, Chan C, Ferris FL 3rd, Chew EY. Age-related macular degeneration. Lancet. 2018;372(9652):1835-1845.
5. Nielsen MK. Geographic atrophy. American Academy of Ophthalmology Eye Wiki. Available at: eyewiki.aao.org/Geographic_atrophy. Accessed January 26, 2021. Updated March 23, 2019.
6. Sunnes JS, Gonzalez-Baron J, Applegate CA, et al. Enlargement of atrophy and visual acuity loss in the geographic atrophy form of age-related macular degeneration. Ophthalmology. 1999; 106:1768-1779.
7. Friedman DS, O’Colmain BJ, Munoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004;122:564–572.
8. Rahimy E, Khan MA, Chao W, et al. Evaluation of Geographic Atrophy (GA) Secondary to AMD in Real-World Clinical Practice: Analysis of the AAO IRIS Registry. Paper presented at: AAO Annual Meeting; November 13-15, 2020; Virtual.
9. Taylor DJ, Hobby AE, Binns AM, Crabb DP. How does age-related macular degeneration affect real-world visual ability and quality of life? A systematic review. BMJ Open. 2016;6(12):e011504.
10. Dawson SR, Mallen CD, Gouldstone MB et al. The prevalence of anxiety and depression in people with age-related macular degenera­tion: a systematic review of observational study data. BMC Ophthalmol. 2014;14:78-78.
11. Holz FG, Strauss EC, Schmitz-Valckenberg S, et al. Geographic atrophy: clinical features and potential therapeutic approaches. Ophthalmology. 2014;121(5):1079-1091.
12. Schmitz-Valckenberg S, Sahel JA, Danis R, et al. Natural history of geographic atrophy progression secondary to age-related macular degeneration (geographic atrophy progression study). Ophthalmology. 2016;123(2):361-368.
13. Sadda SR, Chakravarthy U, Birch DG, Staurenghi G, Henry EC, Brittain C. Clinical endpoints for the study of geographic atrophy secondary to age-related macular degeneration. Retina. 2016;36(10):1806–1822
14. Sunness JS, Applegate CA, Haselwood D, Rubin GS. Fixation patterns and reading rates in eyes with central scotomas from advanced atrophic age-related macular degeneration and Stargardt disease. Ophthalmology. 1996;103(9):1458-1466.
15. Rasi G. Letter of support for reading speed and functional reading independence (FRI) index in geographic atrophy [press release]. January 25, 2015; European Medicines Agency.
16. Kimel M, Leidy NK, Tschosik E, et al. Functional Reading Independence (FRI) index: a new patient-reported outcome measure for patients with geographic atrophy. Invest Ophthalmol Vis Sci. 2016;57(14):6298-6304.
17. Göbel AP, Fleckenstein M, Schmitz-Valckenberg S, Brinkmann CK, Holz FG. Imaging geographic atrophy in age-related macular degenera­tion. Ophthalmologica. 2011;226(4):182-190.
18. Seddon JM, Sharma S, Adelman RA. Evaluation of the clinical age-related maculopathy staging system. Ophthalmology. 2006;113(2):260-266.
19. Khanifar AA, Lederer DE, Ghodasra JH, et al. Comparison of color fundus photographs and fundus autofluorescence images in measuring geographic atrophy area. Retina. 2012;32(9):1884-1891.
20. Moussa K, Lee JY, Stinnett SS, Jaffe GJ. Spectral domain optical coherence tomography-determined morphologic predictors of age-related macular degeneration-associated geographic atrophy progression. Retina. 2013;33(8):1590-1599.
21. Sadda SR, Guymer R, Holz FG, et al. Consensus definition for atrophy associated with age-related macular degeneration on OCT: clas­sification of atrophy report 3 [published correction appears in Ophthalmology. 2019;126(1):177]. Ophthalmology. 2018;125(4):537-548.
22. Bindewald A, Schmitz-Valckenberg S, Jorzik JJ, et al. Classification of abnormal fundus autofluorescence patterns in the junctional zone of geographic atrophy in patients with age related macular degeneration. Br J Ophthalmol. 2005;89(7):874-878.
23. Hu Z, Medioni GG, Hernandez M, Hariri A, Wu X, Sadda SR. Segmentation of the geographic atrophy in spectral-domain optical coherence tomography and fundus autofluorescence images. Invest Ophthalmol Vis Sci. 2013;54(13):8375-8383.
24. Marsiglia M, Boddu S, Bearelly S, et al. Association between geographic atrophy progression and reticular pseudodrusen in eyes with dry age-related macular degeneration. Invest Ophthalmol Vis Sci. 2013;54(12):7362-7369.
25. Fleckenstein M, Schmitz-Valckenberg S, Lindner M, et al; Fundus Autofluorescence in Age-Related Macular Degeneration Study Group. The “diffuse-trickling” fundus autofluorescence phenotype in geographic atrophy. Invest Ophthalmol Vis Sci. 2014;55(5):2911-2920.
26. Finger RP, Chong E, McGuinness MB, et al. Reticular pseudodrusen and their association with age-related macular degeneration: the Melbourne Collaborative Cohort Study. Ophthalmology. 2016;123(3):599-608.
27. Kovach JL, Schwartz SG, Agarwal A, et al. The relationship between reticular pseudodrusen and severity of AMD. Ophthalmol­ogy. 2016;123(4):921-923.
28. Finger RP, Wu Z, Luu CD, et al. Reticular pseudodrusen: a risk factor for geographic atrophy in fellow eyes of individuals with unilateral choroidal neovascularization. Ophthalmology. 2014;121(6):1252-1256.
29. Klein R, Klein BE, Knudtson MD, Meuer SM, Swift M, Gangnon RE. Fifteen-year cumulative incidence of age-related macular degenera­tion: the Beaver Dam Eye Study. Ophthalmology. 2007;114(2):253-262.
30. Turbert D. Top 5 risk factors for AMD. American Academy of Ophthalmology. Available at: www.aao.org/eye-health/news/top-5-risk-factors-amd. Accessed January 27, 2021. Updated January 11, 2021.
31. Joachim N, Mitchell P, Burlutsky G, Kifley A, Wang JJ. The incidence and progression of age-related macular degeneration over 15 years: the Blue Mountains Eye Study. Ophthalmology. 2015;122(12):2482-2489. 32. Sepp T, Khan JC, Thurlby DA, et al. Complement factor H variant Y402H is a major risk determinant for geographic atrophy and choroidal neovascularization in smokers and nonsmokers. Invest Ophthalmol Vis Sci. 2006;47(2):536-540.
33. Nowak JZ. AMD--the retinal disease with an unprecised etiopathogenesis: in search of effective therapeutics. Acta Pol Pharm. 2014;71(6):900-916.
34. Ambati J, Atkinson JP, Gelfand BD. Immunology of age-related macular degeneration. Nat Rev Immunol. 2013;13(6):438-451.
35. Atkinson JP, Du Clos TW, Mold C, et al. 21 - The Human Complement System: Basic Concepts and Clinical Relevance. Clinical Immunology (Fifth Edition). Principles and Practice. 2019:299-317.
36. Wu J, Sun X. Complement system and age-related macular degeneration: drugs and challenges. Drug Des Devel Ther. 2019;13:2413-2425.
37. Katschke KJ Jr, Wu P, Ganesan R, et al. Inhibiting alternative pathway complement activation by targeting the factor D exosite. J Biol Chem. 2012;287(16):12886-12892.
38. Mullins RF, Warwick AN, Sohn EH, Lotery AJ. From compliment to insult: genetics of the complement system in physiology and disease in the human retina. Hum Mol Genet. 2017; 26(R1):R51-R57.
39. Holz FG, Sadda SR, Busbee B, et al; the Chroma and Spectri Study Investigators. Efficacy and safety of lampalizumab for geographic atrophy due to age-related macular degeneration: Chroma and Spectri phase 3 randomized clinical trials. JAMA Ophthalmol. 2018;136(6):666-677.
40. Jaffe GJ, Westby K, Csaky KG, et al. C5 inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a randomized pivotal phase 2/3 trial. Ophthalmology. 2020;S0161-6420(20)30845-9.
41. IVERIC bio’s Zimura, a novel complement c5 inhibitor, met its primary endpoint and reached statistical significance in a phase 2b randomized, controlled clinical trial in geographic atrophy secondary to dry age-related macular degeneration [press release]. IVERIC bio; October 28, 2019; New York, NY.
42. Iveric Bio to Present Zimura® GATHER2 Enrollment and Retention Updates and New GATHER1 Post-Hoc Analyses Today at its Dry Age- Related Macular Degeneration Virtual Symposium for Investors [press release]. IVERIC bio; June 18, 2021; New York, NY.
43. Iveric Bio Announces Publication of GATHER1 Phase 3 Clinical Trial Results for Zimura in Geographic Atrophy Secondary to Age-related Macular Degeneration, in Ophthalmology, the Journal of the American Academy of Ophthalmology [press release]. IVERIC bio; September 1, 2020; New York, NY.
44. Liao DS, Grossi FV, El Mehdi D, et al. Complement C3 inhibitor pegcetacoplan for geographic atrophy secondary to age-related macular degeneration: a randomized phase 2 trial. Ophthalmology. 2020;127(2):186-195.
45. Apellis Pharmaceuticals announces 18-month results of phase 2 study (FILLY) of APL-2 in geographic atrophy [press release]. Apellis Pharmaceuticals; Crestwood, KY, and Cambridge, MA; February 22, 2018.
46. Apellis Announces 18-Month Data from Phase 1b Study of Pegcetacoplan in Patients with Geographic Atrophy (GA) [press release]. Apellis Pharmaceuticals; Waltham, MA; October 19, 2020.
47. Sadda S. Impact of pegcetacoplan on progression of nascent atrophy in AMD. Paper presented at: EURETINA Annual Meeting; October 2-4, 2020; Virtual.
48. 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.
49. Nebbioso M, Lambiase A, Cerini A, Limoli PG, La Cava M, Greco A. Therapeutic approaches with intravitreal injections in geographic atrophy secondary to age-related macular degeneration: current drugs and potential molecules. Int J Mol Sci. 2019;20(7):1693.
50. Zamiri P. Complement C5 inhibition in AMD. Paper presented at the Angiogenesis meeting, February 6, 2016, Miami, FL.
51. Riemann CD, Banin E, Barak A, et al. Phase I/IIa clinical trial of human embryonic stem cell (hESC)-derived retinal pigmented epithelium (RPE, OpRegen) transplantation in advanced dry form age-related macular degeneration (AMD): interim results. Paper presented at: Association for Research in Vision and Ophthalmology Annual Conference; May 3-7, 2020; Virtual.
52. Nirwan RS, Albini TA, Sridhar J, et al. Assessing “cell therapy” clinics offering treatments of ocular conditions using direct-to-consumer marketing websites in the United States. Ophthalmology. 2019;126(10):1350-1355.
53. Parke DW 2nd. The cell therapy buffet. Ophthalmology. 2019;126(10):1356-1357.
54. HORIZON: A phase II study to evaluate the safety and efficacy of two doses of gt005. ClinTrials.gov Identifier: NCT04566445. Accessed January 28, 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT04566445.
55. EXPLORE: A phase II study to evaluate the safety and efficacy of two doses of GT005 (EXPLORE). ClinTrials.gov Identifier: NCT04437368. Accessed January 28, 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT04437368.