Eye care providers managing patients with advanced age-related macular degeneration (AMD) have dealt with a frustrating reality: although various treatments have been shown to be safe and effective for patients with neovascular AMD (wet AMD), no treatments have been approved by regulatory bodies for the treatment of geographic atrophy (GA). This means that we are able to simultaneously provide sight-saving care for a substantial number of our wet AMD patient population, while remaining unable to treat a meaningful number of patients with GA.

Decades of research may soon yield options that are safe and effective to prevent the progression of GA, and there is reason for optimism: as of December 2022, the FDA has accepted filing for review for two therapies intended for the treatment of GA. Given this context, a detailed discussion about AMD, in general, and GA, in particular, is essential to ensure all clinicians are able to identify GA on multiple imaging modalities.

Programs that engage audiences and allow dialogue are among the most productive types of discourse in science. With that in mind, the program we participated in prompted audience members to submit questions. We have selected a pair of those Q&A submissions as sidebars in this piece.

Each speaker at this live event was tasked with covering a particular subject, and their presentations have been adapted here. You’ll also see a section covering real-world patient cases, which shows how patients with GA have experienced disease progression.

—Yasha S. Modi, MD, and SriniVas Sadda, MD, Program Co-Chairs

AMD and GA:Background, Prevalence, and Burden

Yasha S. Modi, MD

Age-related macular degeneration (AMD) is, as the name suggests, a process related to aging. As the population in the United States and the globe ages, we can expect to see increased prevalence of AMD. Current estimates place the prevalence of AMD between 11 and 19 million in the United States and 170 million globally.^1,2 By 2050, prevalence rates are estimated to increase to 22 million and 288 million, respectively, for the US and global populations.^3,4

AMD is categorized into four stages based on fundoscopic clinical features (Figure 1).⁵ The first stage (Category 1) is characterized by small drusen or drupelets (≤ 63 µm). As patients progress to early AMD, they may manifest many small or few medium-sized drusen (Category 2). Category 3, or intermediate AMD, is defined as many medium-sized drusen or one large drusen (> 125 µm). As patients progress through the intermediate stages of AMD, they may develop pigmentary changes, which portends a poor prognosis for progression to advanced disease. Finally, advanced, or Category 4 AMD, is defined as foveal-involving geographic atrophy (GA) or exudative AMD.

GA is a progressive disease that is defined as an abrupt and well-delineated loss of the retinal pigment epithelium (RPE) and choriocapillaris.⁶ Approximately 85% to 95% of patients with AMD manifest dry AMD, with about 30% progressing to GA.^4,7,8 Fundus autofluorescence (FAF) imaging clearly depicts GA as a hypoautofluorescent area corresponding to loss of the RPE (and associated lipofuscin that the camera is designed to detect; Figure 2). The utility of FAF and other imaging modalities is discussed later in this piece.

Similar to how rates of AMD are forecast to increase with an aging population, so too are GA prevalence rates. GA in the United States was estimated to be 1.75 million in 2004, and grew to nearly 3 million in 2020.⁹

Several environmental or lifestyle factors contribute to the development of AMD, and some factors have been linked to GA, in particular. Diet has been linked to AMD development, with Western diets correlated with increased risk of AMD compared with non-Western diets.¹⁰ Obesity and hypertension have been linked with an increasing risk of AMD.¹¹ Exposure to ultraviolet light is also a potential risk factor for developing AMD.¹²

One of the strongest and preventable risk factors is smoking. A smoking history can be used to predict vison loss secondary to GA.¹³ Patients with more than a 40 pack-year history of cigarette smoking are nearly 3.5 more times likely to develop GA.¹⁴

Other risk factors associated with AMD and GA cannot be controlled by patients. Increased age, white race, and the presence of particular genetic risk alleles increase the likelihood of developing AMD.^14-17 A 2020 estimate of the British population concluded that 1.3% of patients between the ages of 65 and 69 had GA.¹⁸ This increased to nearly 12% in patients aged 85 to 90.¹⁸ As for understanding the simplified genetic risk markers, two alleles (CFH and ARMS2) have been identified as increasing risk for AMD development.¹⁵ Sepp et al identified the CFH variant Y402H as increasing the risk for GA development.¹³ While understanding genetics is helpful for understanding pathogenesis, there is no current clinical indication to conduct genetic testing in patients.

Women are at a higher risk for developing advanced AMD compared with men. Although the reasons for this remain unknown, some researchers have proposed theories involving differences in hormonal or cerebrovascular dynamics.^19,20 Patients who are hyperopic²¹ or have lighter colored irises²² are also at increased risk of developing AMD.

When considering progression to AMD, there are some high-risk ocular features. The presence of subretinal drusenoid deposits (SDDs) has been linked with progression of GA,²³ with Finger et al finding that SDDs were an independent risk factor for developing GA in eyes without advanced AMD among patients with unilateral wet AMD.²⁴ In the following pages, Dr. Sadda will explore risk factors linked to disease progression among eyes with GA lesions that are depicted on FAF and OCT.

Advanced AMD and GA may severely reduce quality of life (QOL) and may exacerbate or contribute to depression. Activities such as reading, shopping, meal preparation, and self-care are significantly hindered by AMD.²⁵ Depression rates are higher among patients with AMD compared with patients who do not have AMD.²⁶ Among patients with any AMD, those with wet AMD have reported more optimistic expectations about their future and those with GA (a condition without an approved treatment) are saddened by “profound loss.”²⁷

Even extrafoveal GA can disrupt QOL and hamper independence. One major manifestation of this is through loss of comfort with driving. The majority of patients with GA do not feel comfortable driving during the day (52%) or night (88%), regardless of the location of GA lesions.²⁸ Chakravarthy et al have determined that 67% of UK patients with bilateral GA were ineligible to drive at mean 1.6 years following their diagnosis.²⁹

MEASURING VISUAL DISRUPTION IN GA PATIENTS

Given the foveal-sparing nature of some GA, conventional measurements of BCVA may inadequately characterize a patient’s “true” quality of vision.^30,31 Alternative assessments of visual function, such as low-luminance visual acuity (LLVA), reading speed, questionnaires, and microperimetry have been used by some researchers and clinicians to better assess these deficits.

Patients with GA often have difficulty seeing in dimly lit environments. LLVA evaluations, which require patients to read letters from an ETDRS chart viewed through a neutral density filter, may demonstrate poorer testing relative to BCVA alone. Additionally, greater discrepancies between LLVA and BCVA testing may predict progression of GA.^32,33 Reading speed, too, has been an effective tool at predicting vision loss in GA patients with good baseline BCVA. This method assesses whether the “central visual field is preserved enough to read entire words or sentences” compared with individual letters as seen on a typical BCVA evaluation.³⁰ The National Eye Institute Visual Function Questionnaire 25 (NEI VFQ-25) has been found to be a “reliable and valid cross-sectional measure of the impact of GA on patient visual function and vision-related quality of life,” but real-world clinical usage remains unknown.³⁴

Microperimetry testing allows clinicians to identify areas of scotoma and measure functional GA progression.³² During microperimetry testing, specific areas of retinal tissue are stimulated with light and patients acknowledge perception by pressing a button. Microperimetry has been shown to correlate with progression of GA lesion area.³⁵

PATHOPHYSIOLOGY AND THE COMPLEMENT SYSTEM

The exact pathophysiology of GA remains unknown. There is a plethora of hypotheses that all favor a multifactorial approach involving environmental factors, genetic factors, and oxidative stress. This may result in complement deposition between the RPE and Bruch membrane, loss of complement regulation, localized inflammation, and a breakdown of the blood-retina barrier.^36,37

Drusen are the hallmark clinical feature of AMD. A close examination of the composition of drusen reveal some compelling findings that have informed potential therapeutic strategies for GA. Drusen are lipid- and protein-rich extracellular debris found beneath the RPE.³⁶ Wang et al determined that 40% of drusen are lipid, and that RPE secretions are a major source of drusen.³⁸ Complement factors C1q, C3, C5, and C5b to C9 have been found in drusen, implicating the complement system in the formation of drusen.³⁶

The complement system is part of the innate immune system, a system that protects the body from foreign pathogens and does not adapt as we age. There are three pathways in the complement system (ie, the classical, lectin, and alternative pathways), each of which is activated via distinct mechanisms. Specifics areas of focus for the purposes of this discussion include complement component 3 (C3), where the three complement pathways first converge; complement component 5 (C5), which is further downstream from C3 and is activated following the cleavage of C3; and the membrane attack complex (MAC), the creation of which ultimately results in cell death, is assembled following cleavage of C5 (Figure 3).³⁹

1. 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.

2. Rein DB, Wittenborn JS, Burke-Conte Z, et al. Prevalence of age-related macular degeneration in the US in 2019 [published online ahead of print November 3, 2022]. JAMA Ophthalmol.

3. BrightFocus Foundation. Sources for Macular Degeneration: Facts & Figures. Available at: https://www.brightfocus.org/sources-macular-degeneration-facts-figures. Updated July 14, 2020. Accessed December 6, 2022.

4. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106-116.

5. Ferris FL 3rd, Wilkinson CP, Bird A, et al. Clinical classification of age-related macular degeneration. Ophthalmology. 2013;120(4):844-851.

6. Coleman HR, Chan C, Ferris FL 3rd, Chew EY. Age-related macular degeneration. Lancet. 2018;372(9652):1835-1845.

7. 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.

8. Lindblad AS, Lloyd PC, Clemons TE, et al. Change in area of geographic atrophy in the Age-Related Eye Disease Study: AREDS report number 26. Arch Ophthalmol. 2009;127(9):1168-1174.

9. 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.

10. Chapman NA, Jacobs RJ, Braakhuis AJ. Role of diet and food intake in age-related macular degeneration: a systematic review. Clin Exp Ophthalmol. 2019;47(1):106-127.

11. 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. Updated January 11, 2021. Accessed December 6, 2022.

12. Delcourt C, Cougnard-Grégoire A, Boniol M, et al. Lifetime exposure to ambient ultraviolet radiation and the risk for cataract extraction and age-related macular degeneration: the Alienor Study. Invest Ophthalmol Vis Sci. 2014;55(11):7619-7627.

13. 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.

14. Nowak JZ. AMD--the retinal disease with an unprecised etiopathogenesis: in search of effective therapeutics. Acta Pol Pharm. 2014;71(6):900-916.

15. 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.

16. Klein R, Klein BEK, Knudtson MD, et al. Prevalence of age-related macular degeneration in four racial/ethnic groups in the Multi-Ethnic Study of Atherosclerosis. Ophthalmology. 2006;113:373–380.

17. 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.

18. Wilde C, Poostchi A, Mehta RL, et al. Prevalence of age-related macular degeneration in an elderly UK Caucasian population-The Bridlington Eye Assessment Project: a cross-sectional study. Eye (Lond). 2017;31(7):1042-1050.

19. Cho BJ, Heo JW, Kim TW, Ahn J, Chung H. Prevalence and risk factors of age-related macular degeneration in Korea: the Korea National Health and Nutrition Examination Survey 2010-2011. Invest Ophthalmol Vis Sci. 2014;55(2):1101-1108.

20. Rudnicka AR, Jarrar Z, Wormald R, et al. Age and gender variations in age-related macular degeneration prevalence in populations of European ancestry: a meta-analysis. Ophthalmology. 2012; 119: 571–580.

21. Michael G. Quigley, John V. Lovasik; Is the higher incidence of ARMD in hyperopia versus myopia associated with higher intensity light at the retina? Invest Ophthalmol Vis Sci. 2011;52(14):1837.

22. Frank RN, Puklin JE, Stock C, Canter LA. Race, iris color, and age-related macular degeneration. Trans Am Ophthalmol Soc. 2000;98:109-15; discussion 115-7.

23. 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.

24. 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.

25. 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.

26. 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.

27. McCloud C, Khadka J, Gilhotra JS et al. Divergence in the lived experience of people with macular degeneration. Optom Vis Sci. 2014;91:966–974.

28. Patel PJ, Ziemssen F, Ng E, et a. Burden of illness in geographic atrophy: a study of vision-related quality of life and health care resource use. Clin Ophthalmol. 2020;14:15-28.

29. Chakravarthy U, Bailey CC, Johnston RL, et al. Characterizing disease burden and progression of geographic atrophy secondary to age-related macular degeneration. Ophthalmology. 2018;125(6):842-849.

30. Fleckenstein M, Mitchell P, Freund KB, et al. The progression of geographic atrophy secondary to age-related macular degeneration. Ophthalmology. 2018;125(3):369-390.

31. Sunness JS, Rubin GS, Zuckerbrod A, Applegate CA. Foveal-sparing scotomas in advanced dry age-related macular degeneration. J Vis Impair Blind. 2008;102(10):600-610.

32. 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.

33. Sunness JS, Rubin GS, Broman A, Applegate CA, Bressler NM, Hawkins BS. Low luminance visual dysfunction as a predictor of subsequent visual acuity loss from geographic atrophy in age-related macular degeneration. Ophthalmology. 2008;115(9):1480-1488, 1488.e1-2.

34. Sivaprasad S, Tschosik E, Kapre A, et al. Reliability and Construct validity of the NEI VFQ-25 in a subset of patients with geographic atrophy from the phase 2 Mahalo study. Am J Ophthalmol. 2018;190:1-8.

35. Meleth AD, et al. Changes in retinal sensitivity in geographic atrophy progression as measured by microperimetry. Invest Ophthalmol Vis Sci. 2011;52:1119–1126

36. Ambati J, Atkinson JP, Gelfand BD. Immunology of age-related macular degeneration. Nat Rev Immunol. 2013;13(6):438-451.

37. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2011;119(10):1417-1436. Erratum in: Arch Ophthalmol. 2008;126(9):1251.

38. Wang L, Clark ME, Crossman DK, et al. Abundant lipid and protein components of drusen. PLoS One. 2010;5(4):e10329.

39. Wu J, Sun X. Complement system and age-related macular degeneration: drugs and challenges. Drug Des Devel Ther. 2019;13:2413-2425.

Imaging in the Diagnosis and Prognostication of GA

SriniVas Sadda, MD

A variety of imaging modalities may be used to assess geographic atrophy (GA). These include color fundus photography (CFP), confocal fundus autofluorescence (FAF), and OCT. The benefits and drawbacks of these various modalities, some of which I will describe herein, have been explored in the literature.¹

CFP has been the gold standard modality for diagnosis of GA. In their evaluation of various imaging modalities for use in GA, the Classification of Atrophy Meeting (CAM) Group noted that the classical definition of GA as imaged on CFP requires sharply demarked borders, a hypopigmented or depigmented appearance, and visibility of choroidal vessels in an atrophic area (Figure 1).¹

Although this definition is useful in many cases, insufficient border contrast, particularly in the setting of media opacity or poor stereopsis, sometimes complicates diagnosis or characterization of GA on CFP alone. Use of FAF may provide more consistent and clear depiction of the atrophic region, which is represented on the FAF image as an area of decreased autofluorescence (Figure 2). FAF allows clinicians to better quantify GA lesion area, and has been called the “gold standard for evaluating progressive GA enlargement.”² For this reason, FAF has been used in clinical trials evaluating the safety and efficacy of potential GA therapies. Still, FAF is uncomfortable for patients and may not be as widely available in ophthalmic and optometric clinical practices as OCT.

OCT imaging remains an important part of the imaging framework for GA, in part because of its ubiquity in offices, the degree of patient comfort it allows, and its ability to provide cross-sectional assessment of all of the tissues impacted by the atrophy process, including the neurosensory retina, retinal pigment epithelium (RPE), and inner choroid. Areas of choroidal hypertransmission as seen on B scan serve as a feature to rapidly screen for regions of potential atrophy (Figure 3), and use of en face OCT images can be used to depict and quantify atrophy from a fundus perspective (Figure 4).

FAF and OCT measures of atrophy have shown a high degree of agreement, although it should be noted that these two modalities may not be measuring the same thing despite their high correlation.³ Also, OCT may not be specific enough for all cases. Hypertransmission may indicate total cell loss, but it may also merely indicate loss of pigment in the RPE. In addition, the extent of injury and loss to the overlying neurosensory retina may vary within regions of hypertransmission.

In an effort to classify and reliably define atrophy, the CAM consensus program was convened; I was fortunate enough to be a part of that event. My colleagues and I concluded that there was no previously accepted definition of atrophy as seen on OCT, and the features associated with atrophy or risk for progression to atrophy were not well defined. We examined cases of patients whose multimodal imaging did not, at first, suggest the presence of GA, but whose GA evolved over the course of several visits. By assessing the OCT images of these patients, we aimed to identify which characteristics appeared to define the definite presence of atrophy on OCT.

• One of the terms we defined is complete RPE and outer retinal atrophy (cRORA).⁴ Patients have cRORA if the following criteria are met:
• A zone of hypertransmission that is at least 250 µm in diameter
• A zone of attenuation or disruption of the RPE–basal lamina complex that is at least 250 µm in diameter
• Degeneration of the overlying photoreceptors with outer nuclear layer thinning, external limiting membrane loss, and ellipsoid zone loss
• No evidence of scrolled RPE or other signs of RPE tear

Many clinicians focus on identifying hypertransmission on OCT for good reason: it may be the most obvious and important finding and, in busy clinics, it can be quickly identified. Still, confirmation that hypertransmission is linked with the features of atrophy is needed, and using evidence of overlying RPE and photoreceptor degeneration validates any suspicions that hypertransmission is indeed the result of GA. The CAM also determined that, in order for areas of hypertransmission and RPE defect to be measured in a reproducible manner, a threshold of 250 µm was appropriate (Figure 5).⁴

PROGNOSTICATION OF GA LESION GROWTH

If and when treatments for GA are approved by regulatory bodies, eye care providers may be tasked with identifying patients who stand to benefit the most from therapy by detecting which patients are at risk for the most rapid progression of GA lesions. Use of imaging data, particularly from FAF and OCT findings, will be key in these efforts.

Classification of lesion size and pattern can be used to estimate the rate of GA progression (Figure 6). Large lesions or those with multifocal patterns progress faster than small or unifocal lesions.⁵ This may be in part because GA lesions tend to expand from their borders, and the total perimeter of large and/or multifocal lesions are greater than those of small and/or unifocal lesions.

Lesions can be typed based on their location and degree of autofluorescence at their edges. A pattern of hyperautofluorescence that appears to surround the lesion along its margin is termed a “banded” pattern, and has been shown to be associated with more rapid enlargement of the GA lesion.⁶ In addition, lesions with hyperautofluorescence not only at the lesion margin but also in surrounding regions are deemed to have a “diffuse” pattern, which is also associated with faster GA growth.^6-9 Some GA lesions with diffuse patterns have a grayish (rather than black) hypoautofluorescence that may be a sign of a “diffuse-trickling” pattern, which is particularly suspectable to rapid growth.^6-9

In practical terms, I do not think that clinicians will be obliged to extensively characterize the lesions of patients with GA as having particular sizes or as having specific patterns or autofluorescence features. Rather, eye care providers who are aware of the relationship between size, shape, and autofluorescence patterns can use such information to broadly assess the risk of rapid disease progression, thereby triaging which patients are best suited for immediate intervention. This, of course, assumes that a treatment will soon be approved.

OCT imaging, too, may be used to assess the risk for more rapid progression. For example, reticular pseudodrusen (RPD), also called subretinal drusenoid deposits (SDD), are drusen that accumulate above the RPE (rather than below the RPE, as drusen do). RPD appear to confer an increased risk of progression from AMD to GA and for progression of GA.¹⁰

1. Holz FG, Sadda SR, Staurenghi G, et al; CAM group. Imaging protocols in clinical studies in advanced age-related macular degeneration: recommendations from classification of atrophy consensus meetings. Ophthalmology. 2017;124(4):464-478.

2. 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.

3. Velaga SB, Nittala MG, Hariri A, Sadda SR. Correlation between Fundus Autofluorescence and En Face OCT Measurements of Geographic Atrophy. Ophthalmol Retina. 2022:S2468-6530(22)00132-00134.

4. 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. Ophthalmology. 2018;125(4):537-548.

5. Fleckenstein M, Mitchell P, Freund KB, et al. The progression of geographic atrophy secondary to age-related macular degeneration. Ophthalmology. 2018;125(3):369-390.

6. 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.

7. 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.

8. 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. 

9. Holz FG, Bindewald-Wittich A, Fleckenstein M, et al. Progression of geographic atrophy and impact of fundus autofluorescence patterns in age-related macular degeneration. Am J Ophthalmol. 2007;143;463-472.

10. 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.

Latest Update on the GA Pipeline

Caroline R. Baumal, MD, FASRS

Multiple therapeutic agents are being explored to treat or prevent the progression of geographic atrophy (GA). Many of these potential treatments target the complement pathway, while a handful of others attempt to address GA via other routes. I will review some selected therapies here.

FIRST GENERATION OF COMPLEMENT INHIBITORS

Several early complement inhibitors were examined for the treatment of GA, all of which failed to show sufficient efficacy in phase 2 or phase 3 studies. The C5 inhibitor eculizumab was assessed in the phase 2 COMPLETE study, a prospective, double-masked, randomized clinical trial.¹ Eculizumab was administered via an intravenous route. At 26 weeks, eculizumab therapy did not reduce GA lesion growth rate.¹ The C5 inhibitor tesidolumab, which was delivered via intravitreal injection, failed to demonstrate a reduction in GA lesion growth.² The complement D inhibitor lampalizumab was assessed for the treatment of GA in the phase 3 Spectri and Chroma studies.³ Patients who received intravitreal lampalizumab every 4 or 6 weeks failed to demonstrate a reduction in GA enlargement compared with patients who received sham therapy every 4 or 6 weeks.³

MORE RECENT GENERATION OF COMPLEMENT INHIBITORS

The inability of the preliminary complement inhibitors to reduce the growth rate of GA lesions did not discourage other groups from assessing the safety and efficacy of other complement inhibitors. Two complement inhibitors—pegcetacoplan and avacincaptad pegol—have submitted filings with the FDA for the treatment of GA. Several others are in earlier stages of clinical development.

Pegcetacoplan, which binds to C3 and C3b, is delivered via intravitreal injection. The DERBY and OAKS studies are a pair of phase 3, 24-month, randomized, double-masked, sham-controlled trials that evaluated the safety and efficacy of pegcetacoplan to treat GA.⁴ The DERBY and OAKS studies were informed by the phase 2 FILLY study, which found that pegcetacoplan therapy reduced the rate of GA growth by 29% and 20% with monthly and every-other-month (EOM) dosing, respectively, at month 12; both rates were statistically significant.⁵ The effect was greater during the second 6 months of treatment during the first year.⁵

The phase 3 DERBY and OAKS studies randomly assigned patients to one of four arms: pegcetacoplan 15 mg/0.1 mL (monthly or EOM) or sham (monthly or EOM). In these large studies, more than 800 patients were in the pegcetacoplan treatment groups. The primary endpoint was the change in total area of GA lesions based on fundus autofluorescence (FAF) imaging at month 12. A series of endpoints (at month 24) assessing function and subjective patient responses will be reviewed. The GALE extension study will assess patients for an additional 3 years.⁴ Note that inclusion criteria for the DERBY and OAKS trials allowed patients with foveal and extrafoveal lesions to enroll in the study, which makes it distinct from some other studies in GA that only enrolled patients with extrafoveal GA lesions.

In OAKS, a statistically significant reduction in GA lesion growth was observed in the monthly (22% reduction) and EOM (16% reduction) arms compared with pooled sham patients.⁴ Among patients with extrafoveal lesions, the reduction rates of GA growth in the monthly and EOM arms were 25% and 21%, respectively, and both were statistically significant.⁴ DERBY barely missed the statistical primary endpoint at 12 months, which reduction rates on monthly and EOM arms at 12% and 11%, respectively.⁴

A prespecified analysis of the 12-month data combining the DERBY and OAKS studies found a reduction of GA lesion growth rate of 17% and 14% in monthly and EOM arms, respectively.⁴ When only looking at patients with extrafoveal lesions, the monthly and EOM GA lesion growth reduction rates were 26% and 23%, respectively.⁴

Researchers evaluated 18- and 24-month study results in DERBY and OAKS and found meaningful reductions in GA lesion growth rate observed in each study, with monthly/EOM reductions of 22%/16% in OAKS and 13%/12% in DERBY at 18 months (nominal P < .002).⁶ This continued at month 24, where reductions in GA lesion growth rate in monthly/EOM arms were 22%/18% in OAKS and 19%/16% in DERBY (nominal P < .003; Figure 1).⁷

Notably, the treatment effect of pegcetacoplan accelerated over time during the DERBY and OAKS studies, being the greatest at months 18 to 24 compared with earlier 6-month quartiles (Figure 2).⁷ In pooled study results, GA lesion growth reduction was similar among patients with foveal (34% monthly, 28% EOM) and extrafoveal (28% monthly, 28% EOM) lesions during months 18 to 24.⁷

Overall safety from intravitreal injection of pegcetacoplan was acceptable in DERBY and OAKS. Cases of intraocular inflammation were mild, and there were no instances of retinal vasculitis or retinal vein occlusion.⁴ A total of 6.0%, 4.1%, and 2.4% of patients in the combined monthly, EOM, and sham groups, respectively, experienced new-onset investigator-determined exudative AMD.⁴ The endophthalmitis rate was 0.47%.⁴

The new drug application (NDA) filing with the FDA for pegcetacoplan was amended to include this 24-month long-term data, with decision pending February 26, 2023.⁸

Avacincaptad pegol is a C5 inhibitor that was assessed in the GATHER1 study, where patients with nonfoveal GA were randomly assigned to receive monthly intravitreal avacincaptad pegol at 2-mg or 4-mg doses or sham.⁹ Patients in the 2-mg and 4-mg treatment arms, respectively, experienced reductions in GA lesion growth at month 12 of 27.4% and 27.8%; both reduction rates were statistically significant.⁹

The data from GATHER1 were used to inform the phase 3 GATHER2 study. In GATHER2, patients were randomly assigned to 2 mg monthly avacincaptad pegol or sham.¹⁰ The mean rate of change of GA growth at month 12 was the primary endpoint. Areas of GA lesion growth were measured with a square root transformation formula and with an observed rate of growth. The difference in mean rate of growth using square root transformation was 14.3%, which was statistically significant. The difference in observed rate of GA growth was 17.7%, and the GATHER2 met its primary endpoint.¹⁰ At month 12 in GATHER2, patients in the treatment arm were randomly assigned to monthly or EOM dosing regimens and will be assessed again at month 12.¹¹

Avacincaptad pegol was well-tolerated across both studies, with no instances of endophthalmitis or ischemic optic neuropathy, and one instance of intraocular inflammation, which was considered transient and mild.¹⁰ In GATHER1, 9.0% and 2.7% of eyes in the 2-mg treatment arm and the sham arm had choroidal neovascularization (CNV); in GATHER2, those rates were 6.7% and 4.1%, respectively.¹⁰ The company completed its NDA filing with the FDA in December 2022.¹²

NGM621 is a C3 inhibitor assessed in the phase 2 CATALINA study, which randomly assigned 212 patients to NGM621 or sham every 4 or 8 weeks.¹³ The primary endpoint was the change from baseline in the GA lesion area at 48 weeks as measured on fundus autofluorescence. At week 52, the rates of change in GA lesion area were 6.3% and 6.5% in the 4-week and 8-week treatment arms. Neither rate was statistically significant.¹⁴

ANX007 is a C1q inhibitor that is under investigation in the phase 2 ARCHER study, topline data from which are expected in the first half of 2023.¹⁵ Results from a phase 1b study found that ANX007 was well-tolerated and that complete suppression of C1q target was achieved for at least 4 weeks at the highest dosing levels in patients with GA.¹⁵ The phase 2 study has completed enrollment and results are pending.

NONCOMPLEMENT THERAPIES IN THE PIPELINE

The use of stem cell therapy has been explored for the treatment of GA. Such treatment may be used to replace lost retinal pigment epithelium (RPE) cells or to support the survival of photoreceptor and RPE.¹⁶ An interim analysis of a phase 1/2a study exploring the use of a composite implant comprised of a stem cell-derived RPE in patients with nonneovascular age-related macular degeneration (NNAMD) found that no patients in the study lost vision and that 1 patient improved by 17 letters.¹⁶

Neuroprotective strategies to support photoreceptor and RPE survival, repair mitochondrial dysfunction, or treat oxidative stress have been evaluated. The neuroprotective agent elamipretide was evaluated in the phase 2 ReCLAIM-2 study, but failed to reach its primary endpoint.¹⁷

A photobiomodulation (PBM) platform was evaluated for the treatment of NNAMD in the phase 3 LIGHTSITE III study, in which patients were randomly assigned to receive PBM therapy or sham for 24 months.¹⁸ The study found that PBM treatment resulted in an increase of mean 5.5 letters from baseline at 13 months compared with sham treatment, which was statistically significant.¹⁸ No significant increase in drusen pathology was observed in the treatment arm, and numerical increases of drusen deposition were observed in the sham group.¹⁸

1. 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.

2. 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. 

3. 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.

4. Apellis announces top-line results from phase 3 DERBY and OAKS studies in geographic atrophy (GA) and plans to submit NDA to FDA in the first half of 2022 [press release]. Apellis Pharmaceuticals; Waltham, MA; September 9, 2021.

5. 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.

6. Apellis announces pegcetacoplan showed continuous and clinically meaningful effects at month 18 in phase 3 DERBY and OAKS studies for geographic atrophy [press release]. Apellis Pharmaceuticals; Waltham, MA; March 16, 2022.

7. Apellis Announces 24-Month Results Showing Increased Effects Over Time with Pegcetacoplan in Phase 3 DERBY and OAKS Studies in Geographic Atrophy (GA) [press release]. Apellis Pharmaceuticals; Waltham, MA; August 24, 2022.

8. Apellis Announces FDA Acceptance of NDA Amendment and New PDUFA Date of February 26, 2023, for Pegcetacoplan for Geographic Atrophy (GA) [press release]. Apellis Pharmaceuticals; Waltham, MA; November 18, 2022.

9. 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. 2021;128(4):576-586.

10. Iveric Bio Announces Positive Topline Data from Zimura® GATHER2 Phase 3 Clinical Trial in Geographic Atrophy [press release]. Iveric Bio; Parsippany, NJ; September 6, 2022.

11. 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

12. Iveric Bio Announces Completion of Rolling NDA Submission to FDA for Avacincaptad Pegol for the Treatment of Geographic Atrophy [press release]. Iveric Bio; Parsippany, NJ; December 12, 2022.

13. NGM Bio Announces Initiation of Phase 2 CATALINA Study of NGM621 in Patients with Geographic Atrophy (GA) Secondary to Age-Related Macular Degeneration (AMD) [press release]. NGM Biopharmaceuticals; South San Francisco, CA; July 27, 2020

14. NGM Bio Announces Presentation of Post-hoc Analyses from CATALINA Phase 2 Trial of NGM621 in Patients with Geographic Atrophy (GA) Secondary to Age-Related Macular Degeneration (AMD) at The Retina Society Annual Scientific Meeting [press release]. NGM Biopharmaceuticals; South San Francisco, CA; November 3, 2022.

15. Annexon Biosciences Completes Enrollment in Archer Phase 2 Trial of Novel C1q Inhibitor, ANX007, in Patients with Geographic Atrophy [press release]. Annexon Biosciences; Brisbane, CA; April 7, 2022.

16. Kashani AH, Lebkowski JS, Rahhal FM, et al. A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration. Sci Transl Med. 2018;10(435):eaao4097.

17. Stealth BioTherapeutics Announces Data from the Phase 2 ReCLAIM-2 Study of Elamipretide in Geographic Atrophy at the Clinical Trials at the Summit Meeting 2022 [press release]. Stealth BioTherapeutics; Boston, MA; May 23, 2022.

18. LumiThera Presents US LIGHTSITE III Trial Data Showing Improvement in Vision in Intermediate Dry Age-Related Macular Degeneration [press release]. LumiThera; Seattle, WA; June 22, 2022.

REAL-WORLD PATIENT CASES

CASE 1: EXPANDING MULTIFOCAL LESIONS

SriniVas Sadda, MD: An 84-year-old woman with bilateral pseudophakia and advanced glaucoma in her right eye presented to the clinic in 2017 reporting increased difficulty driving through tunnels. Her BCVA is 20/25 in her left eye. Fundus autofluorescence (FAF) revealed multifocal lesions in the extrafoveal region, with hyperautofluorescence at the border of various lesions (Figure 1A).

Caroline R. Baumal, MD, FASRS: What does a conversation with this patient look like?

Dr. Sadda: I would be careful and honest with this patient, telling her that I see some features that suggest that her vision may worsen quickly, and that she needs close monitoring. I’d also tell this patient that, if a treatment becomes available, she is a good candidate for it. Atrophy has not progressed to the foveal center, which means we may be able to preserve vision if treatment can contain lesions to the extrafoveal region.

The patient returned 1 year later, with signs of progression (Figure 1B). Her BCVA was 20/30. Dr. Modi, what concerns you about this development?

Yasha S. Modi, MD: Two major elements of this patient’s progression are important to note. First, her lesions have grown in absolute size. Second, her lesions are growing toward the fovea. A patient like this would have been a great candidate for a clinical trial. If this patient presented to me today, I’d note that she is a good candidate for a treatment if and when the FDA approves a therapy.

Dr. Baumal: When this patient returned the following year, coalescence of lesions could be seen on FAF (Figure 1C). On OCT imaging, an area of hypertransmission larger than 250 µm corresponding with the lesion location and a zone of attenuation of the retinal pigment epithelium (RPE) larger than 250 µm can be seen (Figure 2). Given this imaging evidence, this patient fits the qualifications for complete RPE and outer retinal atrophy, or cRORA.

CASE 2: RAPID PROGRESSION NEAR THE FOVEA

Dr. Baumal: An 84-year-old woman was referred to a retina specialist for wet age-related macular degeneration (AMD) in her left eye. The patient has bilateral pseudophakia. Her left eye’s BCVA is 20/25. Anti-VEGF therapy was initiated. Upon examination, her right eye’s BCVA was 20/50. OCT imaging revealed evidence of geographic atrophy (GA; Figure 3) with a small focus near the fovea (Figure 4A).

Dr. Sadda: This patient’s OCT imaging clearly shows areas of hypertransmission. Although portions of the RPE are still intact, this patient is likely to experience disease progression.

Dr. Modi: By the following year, the patient’s BCVA was 20/100, and marked progression of GA was observed (Figure 4B). Two-and-a-half years after presentation, lesions had spread to the foveal center and BCVA was 20/150 (Figure 4C).

Dr. Baumal: If a therapy for GA is approved, patients with wet AMD in one eye and GA in the other may need to be treated with two different dosing regimens and agents. We will need to carefully plan how to proceed with treatment strategies for such patients.

NOTE: Both cases are courtesy of Roger Goldberg, MD, MBA.