Diagnosis of Geographic Atrophy Via Imaging

Baruch D. Kuppermann, MD, PhD

Diagnosing geographic atrophy (GA) is usually straightforward, and a nuanced understanding of the strengths of each imaging modality commonly used in clinical settings will help providers leverage the technology to their advantage.

Color Fundus Photography

Color fundus photography (CFP) has a long tradition of use in research settings, including its use in clinical studies to classify dry age-related macular degeneration (AMD)¹ and to assess the natural history of GA.^2,3 A vast majority of clinical settings have CFP available on their imaging platforms of choice, and documentation of GA on CFP is straightforward (Figure 1, column A). The red-free nature of CFP allows image manipulation, which may be useful in some scenarios. Still, early GA lesions are difficult to detect on CFP, and providers have not yet found prognostic value in the images CFP produces. This means that although CFP allows fast assessments to a wide number of providers, many clinicians may feel that CFP an insufficient modality in the age of GA therapy.

Fundus Autofluorescence Imaging

The use of fundus autofluorescence (FAF) as a means of quantifying and evaluating the progress of GA lesions has been documented extensively in the literature.^4,5 Since 2011, it has been considered the standard modality for assessing GA lesion enlargement.⁵ FAF allows providers to quickly and accurately diagnose GA, and the ability for providers to supply a prognosis based on FAF has made it useful in clinical settings (Figure 1, column B). Although FAF imaging is neither as widely available as CFP imaging nor as easy to capture as CFP, more providers have gained access to FAF imaging, which has led to a closing gap between those who use and understand this modality and those who rely on less reliable imaging means. It should be noted that, in my experience, patients report discomfort after FAF imaging and typically prefer sitting for other imaging modalities.

FAF depictions of GA lesions can be categorized based on size, shape, and pattern, and our prognostications about GA are in large part based on these categories. Jordi Monés, MD, PhD, will explore these prognostic patterns in detail in the next article.

En Face or Near Infrared Reflectance Imaging

Among the modalities we are discussing here, en face or near infrared (NIR) reflectance is the least widely available modality (Figure 1, column C). Still, NIR allows depiction of drusen as “well-defined, disseminated, spotted areas of increased reflectivity,” and can also depict reticular pseudodrusen (RPD).⁶

Much of the discussion of GA diagnosis and prognostication focuses on the characterization of GA lesions, but providers would be remiss to overlook the role of imaging and documenting drusen and RPD. Drusen themselves are considered by some to be an early manifestation of GA.⁷ The presence of RPD and progression of GA has been extensively documented^8-10; indeed, eyes with GA and RPD may be up to 4.9 times more likely to progress than eyes without RPD.¹¹

Optical Coherence Tomography

Imaging of retinal layers in GA patients could be an efficient method of characterizing GA in many clinics. The ability of optical coherence tomography (OCT) to depict morphologic changes in GA are well documented (Figure 1, column D).^12-14 OCT depictions of ellipsoid zone (EZ) loss and hypertransmission defects have been assessed in pivotal clinical trials for GA treatments.¹⁵ Further, there is prognostic value to OCT imaging. The separation between the retinal pigment epithelium (RPE) and Bruch membrane, which is correlates with rapid disease growth, can be depicted clearly on OCT.¹³

The Classification of Atrophy Meeting (CAM) study group analyzed OCT findings in GA patients and proposed a nomenclature that may be useful for some providers.¹⁶ Patients with incomplete RPE and outer retinal atrophy (iRORA) may show evidence of hypertransmission, RPE attenuation, or photoreceptor degeneration, and cannot have signs of scrolled RPE or an RPE tear; still, the extend of these anatomic characteristics have not yet advanced far enough. We consider iRORA patients to be early or nascent GA patients who are not yet good candidates for intervention. However, when patients demonstrate complete RPE and outer retinal atrophy (cRORA), they may be good candidates for treatment. The criteria for cRORA include a zone of hypertransmission of at least 250 µm, a zone of RPE attenuation of disruption of at least 250 µm, evidence of overlying photoreceptor degeneration, and no signs of scrolled RPE or RPE tear. A detailed comparison of iRORA and cRORA can be examined in Figure 2.

Given that OCT is a fast, widely available modality that is comfortable for patients to undergo, providers in busy clinics who feel comfortable interpreting OCT scans may consider embracing this modality in real-world settings. Still, providers should feel comfortable with image interpretation before widely adopting OCT for GA, as a nuanced understanding of GA’s manifestations on OCT is required.

Artificial intelligence (AI) programs may mitigate any concerns about the ability of human graders to assess OCT images. A 2022 study found that use of AI-driven automated OCT image analysis can quantify photoreceptor loss in GA patients.¹⁷ The study authors suggested use of such a platform for both research and clinical settings.

Multimodal Imaging of Geographic Atrophy

Many providers opt to image diagnosed or suspected GA with more than a single modality. The literature backs up this strategy. The use of FAF and CFP together has been suggested by Khanifar, as he noted that while CFP is useful at measuring GA lesion area, FAF allows more reproducible assessments.¹⁸ Simultaneous use of FAF and OCT may be appropriate given that they have a good agreement rate in GA lesion assessment.¹⁹ It should be noted that in patients with neovascular AMD, OCT is more sensitive than FAF for identifying GA lesions.²⁰

Individual providers must decide for themselves which imaging options are best for their workflow, their goals, and their comfort level. Given the number of options available for GA imaging, they should be able to find a good fit for their clinics. 

1. Seddon JM, Sharma S, Adelman RA. Evaluation of the clinical age-related maculopathy staging system. Ophthalmology. 2006;113(2):260-266.

2. Sunness JS, Margalit E, Srikumaran D, et al. The long-term natural history of geographic atrophy from age-related macular degeneration : enlargement of atrophy and implications for interventional clinical trials. Ophthalmology. 2007;114(2):271-277.

3. Sunness JS, Bressler NM, Tian Y, Alexander J, Applegate CA. Measuring geographic atrophy in advanced age-related macular degeneration. Invest Ophthalmol Vis Sci. 1999;40(8):1761-1769.

4. Schmitz-Valckenberg S, Fleckenstein M, Göbel AP, et al. Evaluation of autofluorescence imaging with the scanning laser ophthalmoscope and the fundus camera in age-related geographic atrophy. Am J Ophthalmol. 2008;146(2):183-192.

5. Göbel AP, Fleckenstein M, Schmitz-Valckenberg S, Brinkmann CK, Holz FG. Imaging geographic atrophy in age-related macular degeneration. Ophthalmologica. 2011;226(4):182-190.46.

6. Sukkarieh G, Lejoyeux R, LeMer Y, Bonnin S, Tadayoni R. The role of near-infrared reflectance imaging in retinal disease: A systematic review. Surv Ophthalmol. 2023;68(3):313-331.

7. 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.

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. 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.

10. Kovach JL, Schwartz SG, Agarwal A, et al. The relationship between reticular pseudodrusen and severity of AMD. Ophthalmology. 2016;123(4):921-923.

11. 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.

12. Fleckenstein M, Schmitz-Valckenberg S, Adrion C, et al. Tracking progression with spectral-domain optical coherence tomography in geographic atrophy caused by age-related macular degeneration. Invest Ophthalmol Vis Sci. 2010;51(8):3846-3852.

13. 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.

14. Nunes RP, Gregori G, Yehoshua Z, et al. Predicting the progression of geographic atrophy in age-related macular degeneration with SD-OCT en face imaging of the outer retina. Ophthalmic Surg Lasers Imaging Retina. 2013;44(4):344-359.

15. Ehlers JP. Hypertransmission Defects and Ellipsoid Zone Integrity Dynamics in the GATHER Clinical Trials. Presentation from a Large Multi-Center Study. Paper presented at: Angiogenesis, Exudation, and Degeneration; February 3, 2024; Virtual.

16. 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.

17. Riedl S, Vogl WD, Mai J, et al. The effect of pegcetacoplan treatment on photoreceptor maintenance in geographic atrophy monitored by artificial intelligence-based OCT analysis. Ophthalmol Retina. 2022;6(11):1009-1018. 

18. 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.

19. 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.

20. Massamba N, Sellam A, Butel N, Skondra, Caillaux V, Bodaghi B. Use of fundus autofluorescence combined with optical coherence tomography for diagnose of geographic atrophy in age-related macular degeneration. Med Hypothesis Discov Innov Ophthalmol. 2019;8(4):298-305.

Prognosticating Progression of GA and Deciding When to Treat Patients

Jordi Monés, MD, PhD

When assessing a patient’s suitability for geographic therapy (GA) therapy, ophthalmologists must prognosticate the rate of disease progression. Disease that is likely to progress quickly is distinct from that which might progress slowly—indeed, the differences are so great that mere diagnosis of “GA” in a patient is so vague that it confers few useful details, whereas the diagnosis/prognosis of “GA that is likely to rapidly progress” is more precise, and better informs the provider and care team of the patient’s specific disease dynamics.

Fortunately, modern retina practice allows providers to reliably assess the risk of GA progression based on imaging biomarkers. Fundus autofluorescence (FAF) and optical coherence tomography (OCT) imaging, in particular, have been proven useful in estimating a prognosis.

Fundus Autofluorescence Imaging

Factors on FAF imaging that providers use in prognosticating disease progression include lesion size, configuration, and location. Large and multifocal lesions have been found to progress faster than smaller and unifocal lesions (Figure 1).^1,2 Similarly, extrafoveal lesions have been shown to progress faster than foveal lesions.² We should note that foveal lesions may lead to significant vision disruption irrespective of size given the fovea’s role in central vision.

Lesions with a hyperautofluorescent band at the margin of the lesion, or with extensive autofluorescence change at the margin or beyond the lesion itself, also progress rapidly.³ In general, these characteristics depict active disease activity. Larger lesions with hyperautofluorescent bands may progress quicker in some patients because they have a larger perimeter from which to grow.

GA lesions on FAF can be classified into specific categories based on shape, pattern, and/or autofluorescence (Figure 2).⁴ Patients who have no evidence of abnormal autofluorescence but still show an area of atrophic tissue on FAF are unlikely to progress quickly³; in fact, they may not even have GA, and further examination may be warranted. Focal lesions show limited autofluorescence activity, and these, too, grow slowly.³

In addition to banded lesions, diffuse lesions grow quickly (Figure 3). Diffuse-trickling patterns—which have been variously described as grayish and lobular⁴—present a unique threat to vision, as these lesions progress at rapid rates. Diffuse-trickling patterns often coincide with large reticular pseudodrusen (RPD).

Optical Coherence Tomography

The presence of RPD can be used to assess risk of GA lesion growth. As outlined above, the presence of RPD in a GA patient may confer a nearly five-times risk of rapid progression compared to GA patients without RPD.⁵ RPD (which are sometimes called subretinal drusenoid deposits) are well characterized on OCT imaging (Figure 4, top).

Choroidal thinning, which his linked with diffuse-trickling patterns, can also be assessed on OCT (Figure 4, bottom).⁶ Thinner choroids have been shown to correlate with faster disease progression in GA patients.⁷

Drusen themselves are a risk factor for progressing from intermediate age-related macular degeneration (AMD) to advanced AMD (ie, GA or neovascular AMD). In a 2023 meta-analysis of OCT data, Trinh et al found that in patients with intermediate AMD, both large drusen and RPD, as well as hyporeflective drusen cores, were predictive of conversion to advanced AMD.⁸

Use of multimodal imaging to help predict rates of GA progression allows providers to assess GA from different perspectives, thereby illustrating a more complete image of disease. We should remember that the manifestations of GA we observe on imaging (eg, RPD, hyperautofluorescence, etc.) best inform prognostication when used in concert with each other. Forecasting growth in a patient with multifocal lesions on FAF, for example, may be less accurate than forecasting growth for the same patient knowing that they also have RPD.

When Should We Treat GA?

Researchers have articulated several figures that can guide, in a broad sense, our understanding of GA’s mean rates of growth. The median rate of GA progression is 1.78 mm² annually.^9,10 The AREDS study found that mean time to foveal encroachment for extrafoveal lesions was 2.5 years,¹¹ and the AREDS2 study found that the 4-year risk of eyes with noncentral GA developing central GA was 57%.¹²

These figures are best used when applied to a high-level understanding of GA progression, and may undercut the assumption by some providers that GA progression occurs as a slow and steady rate. But we must remember that these figures are means, and that we must, as providers, assess the risk of the patient in our chair based on unique examination results.

My decision to treat a patient is in large part based on the rate at which his or her disease will advance. I do not consider patients who see well and have little evidence of rapidly advancing disease good candidates for treatment, as the burden and risk of intravitreal injections outweighs potential benefit. Therefore, in large part, my decision to treat is based on prognosis, in addition to other factors such as lesion location and size, and nonimaging risk factors.

If a patient’s longitudinal growth rate indicates likely rapid growth, I typically initiate treatment. If longitudinal growth rate data are unavailable, I then consider the location and size of the patient’s GA lesions. Patients with extrafoveal lesions, given their tendency to advance faster than foveal lesions, are often good candidates for treatment.

Consideration of phenotypic characteristics comes next. Does the patient show a high amount of autofluorescent activity? Are RPD present? How thick is the choroid? These questions help determine treatment. Our field is still learning about other markers of disease progression risk, such as the photoreceptor/RPE ratio.¹³ I expect these metrics to be used in the near future as we refine our treatment algorithms.

Each provider will determine which clinical factors they weigh most when assessing suitability for GA therapy. Reliance on imaging data provides an objective dataset by which we can make decisions, and collation of images over time will empower providers to measure patient progress. 

1. Klein R, Meuer SM, Knudtson MD, Klein BE. The epidemiology of progression of pure geographic atrophy: the Beaver Dam Eye Study. Am J Ophthalmol. 2008;146(5):692-699.

2. 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.

3. 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.

4. 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. 

5. 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.

6. Lindner M, Bezatis A, Czauderna J, Becker E, Brinkmann CK, Schmitz-Valckenberg S, Fimmers R, Holz FG, Fleckenstein M. Choroidal thickness in geographic atrophy secondary to age-related macular degeneration. Invest Ophthalmol Vis Sci. 2015 Jan 13;56(2):875-882. 

7. Lee JY, Lee DH, Lee JY, Yoon YH. Correlation between subfoveal choroidal thickness and the severity or progression of nonexudative age-related macular degeneration. Invest Ophthalmol Vis Sci. 2013 Nov 21;54(12):7812-7818. 

8. Trinh M, Cheung R, Duong A, Nivison-Smith L, Ly A. OCT prognostic biomarkers for progression to late age-related macular degeneration: a systematic review and meta-analysis. Ophthalmol Retina. 2023:S2468-6530(23)00668-1.

9. Sunness JS, Margalit E, Srikumaran D, et al. The long-term natural history of geographic atrophy from age-related macular degeneration: enlargement of atrophy and implications for interventional clinical trials. Ophthalmology. 2007;114(2):271-277.

10. 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.

11. AREDS Report 26. AREDS Research Group. Arch Ophthalmol. 2009;127(9):1168-1174.

12. Keenan TD, Agron E, Domalpally A, et al. Progression of geographic atrophy in age-related macular degeneration: AREDS2 report number 16. Ophthalmology. 2018;125(12):1913-1928.

13. Schmidt-Erfurth U, et al. Presented at ARVO 2023; April 23-27, 2023; New Orleans, LA.

Pathogenesis

Baruch D. Kuppermann, MD, PhD

Two complement inhibitors—pegcetacoplan  and avacincaptad pegol—have been approved for the treatment of geographic atrophy (GA) by the FDA. To fully appreciate the mechanisms of action of these two drugs, let’s review the pathogenesis of GA.

Modifiable and Unmodifiable Risk Factors

Several unmodifiable and modifiable risk factors contribute to the risk of age-related macular degeneration (AMD) and GA development. Among the unmodifiable risk factors are age and genetic profile.

Aging is the leading unmodifiable risk factor for developing GA. The Beaver Dam Eye Study found GA incidence of 3.2% among patients who were at least 75 years old; no patients under 54 years had GA.¹ Age is also a risk factor for the development of any-stage AMD, with the AREDS study authors pointing to age as a consistent finding among patients with at least 15 drusen.²

Genotype plays a role in the risk of developing AMD and GA. Patients with alleles CFH and ARMS2 have a greater risk for developing early AMD, and patients with at least one of those alleles are at risk for developing advanced AMD or GA.³ The CFH variant Y402H has been linked with GA development, in particular, and appears to confer risk irrespective of other risk factors (eg, smoking status).⁴ CFH isn’t the only gene linked to the complement system that is implicated in AMD risk, as genes CFI, C9, and C3 have also been identified.^5,6

Modifiable risk factors for AMD and GA include smoking, Western diets,⁷ and low physical activity rates.⁸ Smoking, in particular, is cause for concern. Current smoking status is associated with advanced AMD.³ A 40 pack-years history increases risk of developing GA by a factor of 3.5,⁹ and predictive models have found that smoking history can be used to predict vision loss related to AMD and GA.⁴

The Complement System

The innate immune system includes the complement system, which is activated via the classical pathway, the lectin pathway, or the alternative pathway (Figure). Irrespective of which pathway starts the complement system, activation of the complement cascade results in the formation of membrane attack complex, commonly called MAC, which leads to cell lysis and death.¹⁰

All three initial pathways converge at C3, the cleavage of which is key to all downstream activity. Complement factor D, which activates the alternative pathway, contributes to the amplification of the classical and lectin pathways.¹¹ Further downstream, the cleavage of C5 leads to the formation of C5b, which combines with C6, C7, C8, and C9 to create MAC.¹²

Both treatments that are approved in the United States for GA are complement inhibitors, with pegcetacoplan inhibiting C3 and avacincaptad pegol inhibiting C5. These treatments are not approved by the European Medicines Agency.

Future treatments adopting the approach of complement inhibition may seek to interact with one or more elements of the complement cascade, or may seek to include complement inhibition as part of a broader strategy of disease control. Although complement components C1q, C3, C5, and C3b-9 have been found in drusen of patients with GA,¹³ complement pathway targets beyond that list may be viable. 

1. 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.

2. Age-Related Eye Disease Study Research Group. Risk factors associated with age-related macular degeneration. A case-control study in the age-related eye disease study: Age-Related Eye Disease Study report number 3. Ophthalmology. 2000;107(12):2224-2232.

3. 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.

4. 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.

5. Fritsche LG, Igl W, Bailey JNC, et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet. 2016;48(2):134-143.

6. Boyer DS, Schmidt-Erfurth U, Campagne MVL, et al. The pathophysiology of geographic atrophy secondary to age-related macular degeneration and the complement pathway as a therapeutic target. Retina. 2017;37(5):819-835.

7. 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.

8. McGuinness MB, Le J, Mitchell P, Gopinath B, Cerin E, Saksens NTM, Schick T, Hoyng CB, Guymer RH, Finger RP. Physical Activity and Age-related Macular Degeneration: A Systematic Literature Review and Meta-analysis. Am J Ophthalmol. 2017;180:29-38.

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

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

11. 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.

12. 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. 

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

FDA-Approved Therapies

Jordi Monés, MD, PhD

Pegcetacoplan was approved the FDA in February 2023 and was granted an indication for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD) at a dosage of 15 mg delivered via intravitreal injection every 25 to 60 days.¹ This label allows providers to dose patients monthly or every other month (EOM). Approval was based on results from the pivotal DERBY and OAKS studies, which enrolled patients who had GA with or without subfoveal involvement and with or without choroidal neovascularization (CNV) in the fellow eye.²

In August 2023, the FDA approved avacincaptad pegol for the treatment of GA secondary to AMD at a dosage of 2 mg to be injected monthly for up to 12 months.³ The pivotal studies on which regulators relied, GATHER1 and GATHER2, enrolled patients with GA who had noncenter–involving lesions within 1500 µm from the foveal center and no fellow-eye CNV.⁴ A side-by-side comparison of the two drugs can be seen in Figure 1.

Pivotal Trial and Extension Study Data

Patients who received 2 mg avacincaptad pegol in GATHER1 and GATHER2 showed mean reductions of in GA lesion growth of 27.4% and 14.3%, respectively, at 12 months; both rates were statistically significant compared with sham (Figure 2).⁵ Researchers continued to follow patients out to 24 months in GATHER2, and found an increasing treatment effect differential between avacincaptad pegol 2 mg and sham at 18 months (Figure 3).⁶ As measured by observed difference in mean change in GA growth, the treatment effect at month 18 nearly doubled from month 12 (0.45 mm² at 12 months vs 0.83 mm² at 18 months; Figure 4).⁷

A post hoc analysis of the GATHER1 and GATHER2 data found that administration of avacincaptad pegol resulted in a 59% risk reduction in rate of vision loss (defined as a loss of ≥15 letters from baseline in two consecutive visits) compared with sham at 12 months.⁸

A widening treatment effect was also observed in the studies assessing the safety and efficacy of pegcetacoplan (ie, the pivotal DERBY and OAKS studies, and the GALE extension study). A pooled analysis found a 23% and 22% reduction, respectively among patients randomly assigned to monthly and EOM therapy at 24 months; reductions at month 36 for monthly and EOM therapy were 35% and 24%, respectively (Figure 5).⁹

In GALE, patients who had previously been randomly assigned to sham in DERBY and OAKS crossed over to pegcetacoplan therapy and experienced a 19% reduction in GA lesion growth rate over 12 months (P < .01).⁹ A pooled DERBY and OAKS analysis showed that patients who received pegcetacoplan had a mean change of -6.8 letters from baseline compared with mean change of -12.4 letters from baseline in the sham arm (difference of 5.6 letters) at month 24.¹⁰ At month 30 in GALE (ie, 6 months into the extension study), patients who had received pegcetacoplan had a mean change of -7.3 letters compared with mean change of -15.7 letters in the sham-to-crossover arm (difference of 8.4 letters).^11,12

Safety

In GATHER1 and GATHER2, avacincaptad pegol was generally well-tolerated.¹³ There was one case each of culture-positive endophthalmitis and ischemic optic neuropathy (ION), and no cases of intraocular inflammation (IOI) or retinal vasculitis associated with treatment. CNV rates were 11.9% and 11.6% for the active treatment arms in GATHER1 and GATHER2, respectively; they were 2.7% and 9.0% for the sham arms in both studies, respectively.

In DERBY and OAKS, there were two cases of endophthalmitis (0.5%) in the monthly arm and three cases (0.7%) in the EOM arm, compared with no cases (0.0%) in the pooled sham arms. There were three cases of ION (0.7%) in the monthly arm and no cases (0.0%) in the EOM and pooled sham arms. Note that there were more patients enrolled in pegcetacoplan studies than in avacincaptad pegol studies, and a comparison of safety data should rely on percentages and not absolute numbers of events.

A total of 14 eyes in 13 patients in the postmarketing period have reported IOI and retinal vasculitis following pegcetacoplan treatment.¹⁴ All instances arose after the first injection. More than half (57%) of eyes experienced a vision decrease of 3 lines, 43% experienced a loss of at least 6 lines, and two eyes were enucleated. In all, approximately 210,000 vials of pegcetacoplan have been distributed in real-world and clinical trial settings, which means that one case of IOI has been reported for approximately every 15,000 injections. 

1. Syfovre prescribing information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217171s000lbl.pdf.

2. Singh R. Efficacy and Safety of Intravitreal Pegcetacoplan in GA: Results From the Phase 3 DERBY and OAKS Trials. Paper presented at: 2021 American Academy of Ophthalmology Annual Meeting; November 12-15, 2021; New Orleans, LA.

3. Izervay prescribing information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217225s000lbl.pdf.

4. 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.

5. Khanani AM, Patel SS, Staurenghi G, et al. Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial. Lancet. 2023;402(10411):1449-1458.

6. Astellas Pharma. https://www.prnewswire.com/news-releases/iveric-bio-announces-positive-24-month-topline-results-from-phase-3-study-of-izervay-avacincaptad-pegol-intravitreal-solution-for-geographic-atrophy-301931191.html. Sep 2023. Accessed Sep 19, 2023

7. Khanani AM. Presented at: Angiogenesis, Exudation, and Degeneration 2024; Feb. 3, 2024.

8. Danzig C, et al. Presented at: ARVO 2023. April 23-27, 2023; New Orleans, LA.

9. Wykoff C, et al. Presented at: AAO 2023. Nov 3-6, 2023; San Francisco, CA.

10. Chiang A, et al. Presented at: ARVO 2023; April 23-27, 2023; New Orleans, LA

11. Suner IJ, et al. Responsiveness of NEI VFQ-25 to Changes in visual acuity in neovascular AMD: validation studies from two phase 3 clinical trials. Invest Ophthalmol Vis Sci. 2009;50(8):3629-3635.

12. Chakravarthy U, et al. Presented at: 23rd EURETINA Congress. October 5-8, 2023; Amsterdam, Netherlands.

13. Lally DR. Presented at: Angiogenesis, Exudation, and Degeneration 2024; Feb. 3, 2024.

14. ASRS ReST Committee. ReST Committee Update on Intraocular Inflammation (IOI). Paper presented at: American Society of Retina Specialists Annual Meeting; July 28-August 1, 2023; Seattle, WA.

Patient Education

Anat Loewenstein, MD, MHA

Many retina specialists are adept at educating patients about their disease and treatment options when it comes to conditions for which we have treatments, such as neovascular age-related macular degeneration (AMD) and diabetic macular edema. Because no regulatory body had approved a treatment for geographic atrophy (GA) prior to 2023, we rarely had in-depth discussions with patients about GA. As we anticipate the possible approval of one or more options for GA in Europe, we should consider how to best educate patients about the nuances of GA and its management.

Personalizing Your Education

As was mentioned earlier, GA has many different prognoses, patterns, and unique manifestations. As such, we should customize our education about GA to the specifics of that patient. Clear, jargon-free explanations of what may have caused GA and how it will affect vision are necessary.^1,2 Some providers may wish to rely on visual aids or diagrams during this part of patient education. Anatomic explanations may be useful for some patients, and providers should be willing to answer questions about anatomic changes occurring in the presence of GA.

Educating patients about the stages of AMD is key to educating them that GA is an advanced form of AMD. We must emphasize that disease is sometimes present irrespective of subjective visual function and, if appropriate, show patients results of imaging tests that illustrate extrafoveal disease that has not yet advanced to the fovea. Patients who have already lost vision in one eye due to GA should be particularly well educated on this topic.

For some patients, a discussion about how GA may affect quality of life clearly illustrates the real-world consequences of vision loss. We already know that patients with GA experience difficulty with activities of daily living, and will see reductions in the quality of their social lives, mental health, and driving confidence.^3,4 Reduced driving ability is linked clearly to GA, with a majority (52%) of patients with GA reporting that they do not feel comfortable driving with GA and a vast majority (88%) reporting no confidence driving at night.³

Providers must educate patients with AMD and GA about common symptoms, such as blurry vision, distorted vision, difficulty reading, and changes to color perception. Tell your patients that they should report to your clinic any new or changing symptoms. Patients with intermediate AMD but no GA may be good candidates for home-based monitoring systems that detect conversion to wet AMD; unfortunately, there are no home monitoring devices for conversation from intermediate AMD to GA.

Upon diagnosis of GA, providers outside of the United States may wish to engage in conversation about possible forthcoming therapeutic options. Some providers may wish to limit this conversation to patients with GA that is conducive to treatment (ie, progressing disease). Discuss the risks, benefits, and limitations of possible future treatment options with your patients so that, if one or more treatments are approved for use, they are aware of the possible treatments when they become available. 

1. Bhattad PB, Pacifico L. Empowering patients: promoting patient education and health literacy. Cureus. 2022;14(7):e27336.

2. Dahlin-Ivanoff S, Klepp KI, Sjostrand J. Development of a health education programme for elderly with age-related macular degeneration: a focus group study. Patient Educ Couns. 1998;34(1):63-73.

3. 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.

4. Kim A, Device B, Campbell J, et al. Healthcare resource utilization and costs in patients with geographic atrophy secondary to age-related macular degeneration. Clin Ophthamol. 2021:12;2643-2651.

Real-World Cases | Panel Discussion

Case 1: GA in a Patient With Only One Functional Eye

Anat Loewenstein, MD, MHA: A 78-year-old woman with a history of scarring OS, which left her with 20/200 BCVA, presented to the clinic with complaints of vision loss OD. BCVA OD was 20/25. Multimodal imaging showed evidence of extensive extrafoveal geographic atrophy (GA) lesions (Figure 1). Optical coherence tomography (OCT) B-scan imaging shows areas of hypertransmission consistent with complete retinal pigment epithelium and outer retinal atrophy (cRORA) (Figure 2).

Jordi Monés, MD, PhD: This patient will likely progress quickly given the presence of reticular pseudodrusen (RPD). She still has foveal integrity, so treatment that slows the rate of progression—and possibly slows the rate of foveal encroachment—has high value. If I had a treatment available, I would initiate therapy as quickly as possible.

Dr. Loewenstein: This patient is symptomatic, but when they presented 1 year prior, they were asymptomatic (Figure 3). Would your decision to treat be different if the patient reported no symptoms?

Dr. Mones: No. The presence of RPD indicates a high risk of progression to me. In this case, the patient’s subjective vision has little effect on my decision-making.

Baruch D. Kuppermann, MD, PhD: I, too, would initiate a conversation about therapy with this patient irrespective of her symptoms. We must remember that this is the only eye with functional vision, given the scarring OS. If the patient, after weighing risks and benefits, opts for treatment, I would first administer a dose OS to assess the risk of vasculitis or another complication. If no signals occur, then I would suggest every-other-month (EOM) treatment with anticomplement therapy.

Dr. Loewenstein: Would you initiate treatment 2 years prior the presentation that started this discussion (Figure 4)? At that point, the patient had 20/20 BCVA OD.

Dr. Mones: Yes, I would still initiate treatment in this case. I can confidently estimate that given the patient’s phenotypic presentation, foveal encroachment is inevitable. Treating this eye early may slow extrafoveal GA lesion growth significantly.

Dr. Loewenstein: Dr. Kuppermann, you have the most challenging scenario to face: would you treat this patient given their presentation 3 years ago (Figure 4)?

Dr. Kuppermann: I would observe this patient for signs of lesion growth and increase the frequency with which I see them for clinical examination. I would also begin having the conversation about treatments so that, if the patient decides that treatment is right for them in the future, they are already familiar with their treatment options.

Case 2: Central GA in a Patient with Contralateral Intermediate AMD

Dr. Loewenstein: An 82-year-old man presented to the clinic with central GA OD as seen on OCT imaging (Figure 5A). BCVA OD was 20/100. In his fellow eye, noncentral intermediate age-related macular degeneration (AMD) is observed with BCVA OS 20/20, but a double layer sign can be detected on B-scan imaging (Figure 5B). How would you approach management of this patient’s disease?

Dr. Kuppermann: We have to remember that the drugs that have been approved in the United States do not return functional vision to patients, but rather slow the rate of progression. Even with frequent treatment OD, this patient is likely to lose vision in the coming years, and I’m not sure that the burden and risks of treatment are worth potential benefits of therapy.

The left presents a more challenging question. Given that function has declined in the contralateral eye, I may be inclined to treat the left eye earlier than I normally would if it ever progresses from intermediate AMD to GA. 

Cases are courtesy of Omer Trivizki, MD, MBA, Tel Aviv Medical Center and Bascom Palmer Eye Institute.