Increasing the knowledge base of GA is key to individualizing patient therapy

The more information amassed about geographic atrophy (GA), the better the chances of clinicians individualizing patient treatment to provide the best management options.

To get closer to that goal, a recent review¹ described the typical phenotypes of patients with GA and the clinical and imaging features that may lead to rapid progression of GA in various phenotypes. With the recent FDA approval of new GA treatments that reduce lesion growth, “…understanding the risk of progression to GA and factors contributing to GA growth may aid in patient selection and guide patient-level management and treatment,” according to first author Rishi P. Singh, MD, who at the time of publication was vice president and chief medical officer, Cleveland Clinic Martin North and South Hospitals, and professor of ophthalmology at Cleveland Clinic Lerner College of Medicine in Cleveland, Ohio.

GA is the late, relentlessly progressive form of non-neovascular age-related macular degeneration (nAMD) in older patients in which the retinal pigment epithelium (RPE) cells, photoreceptors, and choriocapillaris are permanently lost.²

GA negatively affects the quality of life of older individuals by interfering with reading, writing, and facial recognition.³ It also impairs mobility and the ability to drive, resulting in loss of independence.⁴ The investigators noted that patients became ineligible to drive in a period as short as a median of 1.6 years from baseline.⁵

According to the authors, these facts emphasize the importance of understanding the risk factors for GA development from intermediate AMD. Further, understanding GA growth is vital for providing patients with accurate prognoses, directing treatment, and designing clinical trials.^2,6

The investigators searched PubMed during July 2023 to identify key characteristics such as rapid lesion growth, imaging approaches, and GA location of the selected patient phenotypes.

Contributions of various imaging techniques for GA diagnosis and monitoring

The available imaging technologies vary in their abilities to visualize the GA lesion characteristics. The authors enumerated the benefits of several of these technologies.

Although GA lesions are not well demarcated from the adjacent retinal tissue on color fundus photographs,⁷ fundus autofluorescence (FAF) is approved for assessing and measuring GA lesion growth.⁷ “Abnormal FAF patterns in the junctional zone may predict progression of GA, as the varied FAF patterns display different rates of disease progression,”⁸ the investigators said.

Fluorescein angiography and optical coherence tomography (OCT) angiography are preferred for identifying and assessing choroidal neovascularization or exudation that may be a feature in nAMD.⁷

Microperimetry has been shown to be useful in correlating retinal function with GA lesion features.⁹

OCT can define areas of GA and identify early RPE and photoreceptor atrophy in AMD and GA lesions. Both OCT B-scans and en face OCT can identify hypertransmission defects in GA.^10,11

“OCT may shorten clinical trials through earlier identification of end points related to the development and progression of AMD or GA and allow for earlier intervention with complement inhibitor treatment if warranted.^11,12 The benefits of OCT include its wide availability, fast and noninvasive scanning, ease of use, repeatability, and comfort for patients.⁷ Near infrared reflectance imaging or en-face OCT is performed simultaneously on most commercial OCT devices to detect reticular pseudodrusen (RPD) in the macula or around the optic nerve, which is a risk factor for GA progression.^7,13,14

Consensus terminology developed by retina and imaging specialists^11,15 was based on OCT findings. However, the complete RPE and outer retinal atrophy (cRORA) measurements by FAF and spectral-domain OCT correlated well.¹⁶“Incomplete RPE and outer retinal atrophy (iRORA) are the precursors to cRORA and describe characteristic OCT findings in the presence of AMD and drusen.¹⁵ As an indicator of GA progression, the risk of progression from iRORA to cRORA may be useful because it evaluates possible treatment outcomes earlier in the natural history of GA lesion progression,¹⁵ Singh and colleagues said.

Data from the FILLY study (NCT02503332) showed that monthly and every-other-month pegcetacoplan (Syfovre; Apellis Pharmaceuticals, Inc) treatments reduced the progression risk from iRORA to cRORA by 48% and 24%, respectively, compared with sham treatment at 6 months.¹⁷ Findings from a post hoc analysis of the 18-month GATHER1 study (NCT02686658) showed that a smaller proportion of patients treated with avacincaptad pegol (Izervay; Astellas Pharma US, Inc) progressed from iRORA to cRORA than sham-treated patients (20% vs 42%, respectively).¹⁸

Risk factors for GA development and progression

Intermediate or large GA lesions, multifocal or irregular GA lesions, GA not located centrally, GA in the fellow eye, and specific genetic factors^19,20 were all associated with faster growth of GA lesions.

FAF images demonstrated faster GA progression; specifically, eyes with banded and especially diffuse trickling, hyperautofluorescent patterns have faster GA progression than eyes without those patterns.⁸

“Reticular pseudodrusen (RPD) was reported to be a risk factor for the development and progression of GA and associated with faster GA growth and progression toward the central macula.^2,21 Although RPD was more common in individuals with ARMS2/HTRA1 risk alleles in the Age-Related Eye Disease Study (AREDS) 2 study, the presence of RPD conferred increased risk of GA progression, independent of ARMS2/HTRA1 status,” the investigators reported.

The AREDS natural history data also showed that the rate of decrease of the central residual effective radius was approximately 53% higher in patients with GA who had advanced AMD (central GA or nAMD) in their fellow eye than in patients with GA without AMD in the fellow eye.²² Data from several studies demonstrated that greater GA area was correlated with faster lesion progression^23,24; others disagreed with that finding when a square-root transformation was applied.^22,25 However, evidence from a recent meta-analysis showed that the baseline lesion area was correlated with the lesion growth rate regardless of whether square-root transformation was applied.²⁶ Data from another GA natural history study showed faster progression toward the periphery than the fovea.²⁷

Rapid GA progression on OCT

Several retinal morphologic changes have been associated with faster increases in GA growth. These include the following:

Intraretinal hyper-reflective foci are a risk factor for faster progression of preexisting GA, especially if numerous and distributed across the retina.^10,28

OCT-reflective drusen substructures are associated with faster growth of preexisting GA.²⁹

Increased distance between the RPE and Bruch membrane at the margins of GA lesions and thinner outer retinal layer measurements immediately around the GA are associated with faster growth.^30,31

GA progressed more slowly when photoreceptor density was thicker in the junctional zone, faster with a higher concentration of hyper-reflective foci in the junctional zone, and generally decreased with increasing retinal eccentricity.³²

The peak progression rate was about 1 mm from the fovea for lesions progressing toward the fovea; slower rates were seen both closer and farther away.

For lesions progressing away from the fovea, this peak was not observed, and the progression rate decreased with increasing retinal eccentricity.³²

The application of artificial intelligence to large OCT data sets showed, for example, reductions in photoreceptor and RPE loss of up to 46% and 28%, respectively, after pegcetacoplan treatment in the phase 3 OAKS (NCT03525613) and DERBY (NCT03525600) studies.³³ The ratio of photoreceptor degeneration to RPE loss at baseline was correlated with the GA growth rate over 12 months in the phase 2 FILLY study.³⁴

Phenotype selection and management considerations

Singh and colleagues also described commonly encountered patient phenotypes to illustrate key clinical and imaging characteristics of GA used to monitor and manage the condition.

They recommended that features that may confer increased risk of GA progression should be assessed when evaluating candidates for treatment with complement inhibitors. There are currently no accepted guidelines regarding the recommended amount of time to monitor patients before starting treatment with complement inhibitors. This time period may vary in slow vs fast GA progressors. However, initiating treatment early, particularly before foveal involvement, may slow GA progression and preserve visual function over time.^2,35-37

They also noted that the period of time to determine progression should be considered when determining patient inclusion in clinical trials. “Given the variability in progression rates between phenotypes, such decisions should be individualized, and clinical trials should aim to stratify for different baseline morphological characteristics,”^2,36 they said.

The authors also suggested the following:

1. All patients with AMD should stop smoking.²⁰
2. AREDS2 supplementation should be considered to lower the risk of developing advanced AMD in patients with intermediate AMD in the fellow eye.³⁸
3. Determining the status of the fellow eye is critical, as it may be receiving intravitreal injections for nAMD or bilateral GA.
4. Age and nonocular medical conditions should be taken into consideration.
5. The patient’s ability to return for follow-up is key when considering anticomplement treatment options, as intervals between intravitreal injections varied across the clinical trials.

The investigators discussed the management approaches in the following scenarios: subfoveal GA in 1 eye and intermediate AMD in the fellow eye, fovea-involving atrophic scar with good vision, older patients with bilateral subfoveal GA, subfoveal GA in 1 eye and nAMD in the fellow eye, and nonsubfoveal GA consisting of multiple large multifocal GA lesions.

“In 2023, FDA approvals of pegcetacoplan followed by avacincaptad pegol for GA secondary to AMD offered new treatment options that slowed GA growth.^39-42 In-depth knowledge of the imaging features, risk factors for development and progression of GA, and details of the phase 3 trials of complement inhibitors is critical for clinicians caring for patients with GA, as it may help them recognize and stratify patients to maximize treatment effect. Treatment for GA should be individualized to the patient’s specific needs and preferences, taking into consideration individual patients’ ocular characteristics such as GA location, lesion progression, and morphologic changes in the retina,” Singh and colleagues concluded.

Rishi P. Singh, MD

E: [email protected]

Singh is vice president and chief medical officer, Cleveland Clinic Martin North and South Hospitals, and professor of ophthalmology at Cleveland Clinic Lerner College of Medicine in Cleveland, Ohio. Singh was recently named chair of the Department of Ophthalmology at Mass General Brigham in Boston, Massachusetts, effective November 10, 2025. He reports receiving personal fees from Alcon, Apellis Pharmaceuticals, Astellas Pharma, Bausch + Lomb, EyePoint Pharmaceuticals, Genentech, Regeneron, Regenxbio, and Zeiss; and research grants from Janssen.

Singh was joined in this study by Christina Y. Weng, MD, MBA, Department of Ophthalmology, Baylor College of Medicine, Houston, Texas; John W. Kitchens, MD, Retina Associates of Kentucky, Lexington; Jaclyn Quilantan, PhD, MBA, CMD, Apellis Pharmaceuticals, Inc, Waltham, Massachusetts; Roy Schwartz, MD, PhD, Apellis UK Limited, London, UK; Caroline R. Baumal, MD, Apellis Pharmaceuticals, Inc, and New England Eye Center, Boston, Massachusetts; and Roger A. Goldberg, MD, MBA, Bay Area Retina Associates, Walnut Creek, California.

Weng reports receiving consulting fees from Alcon, Alimera Sciences, Allergan/AbbVie, Apellis Pharmaceuticals, Astellas Pharma, EyePoint Pharmaceuticals, Genentech, Novartis, Regeneron, Regenxbio, and Zeiss/DORC; research funds from AGTC, Alimera Sciences, and DRCR Retina Network; and royalties from Springer Publishing.

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