Geographic Atrophy in Age-Related Macular Degeneration

Background: Age-related macular degeneration (AMD), a condition of multifactorial origin, is a major cause of irreversible vision loss in industrialized countries. The dry late stage of the disease, known as geographic atrophy (GA), is characterized by progressive loss of photoreceptor cells and retinal pigment epithelial cells in the central retina. An estimated 300 000 to 550 000 people in Germany suffer from GA.

Methods: This review is based on pertinent literature retrieved by a selective search in the PubMed and Web of Science databases.

Results: In 2023, the complement inhibitors pegcetacoplan and avacincaptad pegol were approved in the USA for repeated intravitreal injections and thereby became the first drugs ever approved for the treatment of GA. In Europe, the marketing authorization application for both drugs was withdrawn by the manufacturers after a negative judgment was expressed by the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP). The EMA stated that the significant slowing of atrophy progression that had been achieved in the approval trials did not lead to any clinically relevant functional benefit for the patients. Further treatment approaches, including gene therapy, are now being studied in clinical trials. There is evidence that micronutrients may slow the progression of atrophy.

Conclusion: In Europe at present, there is no approved treatment for GA due to AMD. There is thus a continuing need for preventive and rehabilitative measures such as smoking cessation, a balanced diet, and magnifying visual aids for patients in the advanced stages of the disease.

Cite this as: Liakopoulos S, von der Emde L, Biller ML, Ach T, Holz FG: Geographic atrophy in age-related macular degeneration. Dtsch Arztebl Int 2025; 122: 82–8. DOI: 10.3238/arztebl.m2025.0003

For many people, sight is the most important sense. In a representative survey of the German population, 67% of respondents said that blindness was the type of sensory loss that they feared most, and one in ten considered blindness to be the worst possible health problem, even compared to cancer, dementia, or stroke (1). In industrialized countries, the late form of age-related macular degeneration (AMD) is the main cause of irreversible vision loss and legal blindness in industrialized countries in people over the age of 60 (2, 3). Blindness is legally defined as a visual acuity of ≤ 0.02 (20/1000) even with optimal visual aids on the better eye, or any other equivalent permanent impairment of vision. The prevalence of AMD in Europe is 12.3% in persons over the age of 45, in persons over age the age of 55 the prevalence of late-stage AMD is 0.5% (3). Due to demographic changes, it is estimated that the absolute number of patients with AMD will nearly double by 2050 (4).

In the early stages of AMD, patients often notice gradual worsening vision and difficulty in adjusting to suboptimal light conditions (5). In the late stage, there may be marked visual loss leading to inability to read and, possibly, legal blindness. The late stage is characterized either by secondary formation of pathological, hyperpermeable blood vessels in or beneath the retina (neovascular AMD), or by geographic atrophy (GA) with progressive loss of the choriocapillaris, retinal pigment epithelium (RPE), and photoreceptors (6).

Repeated intravitreal injections of VEGF inhibitors have been available since 2006 as a treatment for neovascular AMD. This can often improve vision and has lowered the incidence of blindness in persons over age 50 by approximately half since the treatment was approved, from 52.2 to 25.7 cases per 100 000 persons worldwide between 2000 and 2010 (7).

An estimated 300 000–550 000 people in Germany suffer from GA (8). In a cohort analysis of 1901 British patients with bilateral GA, two-thirds were unable to drive on their initial presentation, 7% were classified as blind, and a further 16% became blind after a median interval of 6 years (9). No treatment for GA has yet been approved in Europe. Two agents, pegcetacoplan and avacincaptad pegol, were approved for the first time in the USA in 2023. In phase III trials, continuous monthly or bi-monthly intravitreal injections of these complement inhibitors led to significantly less enlargement of the area of atrophy than in the control groups (10, 11). However, the achievement of this primary endpoint was not accompanied by a significant benefit in secondary functional endpoints, such as best-corrected visual acuity.

In Europe, the marketing authorization application for both drugs was withdrawn by the manufacturers after a negative judgment from the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP). Other therapeutic approaches are under investigation in clinical trials, including neuroprotection, visual cycle inhibitors, stem cell therapies, gene therapy, and subretinal implants (12). Modern high-resolution imaging, sometimes combined with analyses by artificial intelligence, are being used to study the course of this phenotypically highly variable disease, as well as the efficacy of new treatments and potential variations across individuals in responsiveness to treatment (13, 14, 15).

Learning objectives

This article is intended to give readers knowledge of the following:

• recent developments in the diagnosis and treatment of geographic atrophy,
• the frequency and significance of geographic atrophy in age-related macular degeneration,
• the uses of multimodal imaging in the diagnostic evaluation of geographic atrophy, and
• current approaches to the prevention and treatment of the disease.

Methods

This review is based on pertinent publications retrieved by a selective search in the PubMed and Web of Science databases employing the search terms “geographic atrophy” and “multimodal imaging.”

Pathogenesis

AMD is of multifactorial origin. Among its risk factors, age, sex, and ethnicity are non-modifiable, while diet and lifestyle are modifiable. Large-scale population studies (the Blue Mountains Eye Study, the Age-Related Eye Disease Study, and the Beaver Dam Eye Study) identified smoking as a major independent risk factor for both the onset and progression of AMD (OR 2 to 4) (16, 17, 18, 19). The incidence and prevalence of GA rise with age (hazard ratio 1.14–1.18 per year, corresponding to an approximately 40-fold increased risk at age 85 compared to age 60) (3, 20). The risk of onset and progression of AMD is higher in women than in men, both for early-onset AMD (OR 2.2) and late-onset AMD (OR 1.6–2.6). Moreover, all manifestations of AMD are more common in the European population than in the Asian population (12.3% vs. 7.4%; Bayes factor 4.3 [moderate evidence]) (3).

Genome-wide association studies have so far identified 52 genetic variants at 34 different loci that are independently associated with AMD and that affect, in particular, lipid metabolism, the extracellular matrix, and the complement system (21). The two loci most frequently associated with AMD are the age-related maculopathy susceptibility 2/high-temperature requirement factor A1 (ARMS2/HTRA1) and the extended region of complement factor H (CFH) (22).

Among clinical findings, soft drusen in the center of the macula and pigmentary changes are considered to be the main risk factors for progression to late-stage AMD. Eyes with AMD show a wide range of structural abnormalities, including not only soft drusen, but also subretinal drusenoid deposits (so-called reticular pseudodrusen), basal laminar deposits, and vitelliform deposits (23) (Figure 1). These deposits often gradually worsen over the years; the dry late form of the disease is characterized by progressive atrophy of the RPE and outer retina. Within the area of atrophy, retinal function is markedly impaired. The disease often begins outside the center of the macula and then slowly expands. In a large-scale study, the mean interval from the initial diagnosis of non-central GA to foveal involvement was 3.2 ± 1.5 years (24). Once the fovea is affected, best-corrected central visual acuity decreases. This renders the patient unable to drive and impairs reading ability as well as face recognition (Figure 2).

Figure 1

Eye with geogrphic atrophy

Figure 2

The progression of geographic atrophy over 5 years (left: baseline, center: year 3, right: year 5).

Diagnostic evaluation

For many years, the standard diagnostic technique for AMD was clinical examination with funduscopy or color fundus photography. Large-scale epidemiological studies on the prevalence and progression of the disease are, therefore, based on the use of these methods to detect drusen and pigment changes. The Age-Related Eye Disease Study (AREDS) revealed that the risk of developing late-stage AMD within five years rises from 0.4% in eyes without large drusen (≥125 µm) and pigmentary changes to nearly 50% when both are found in both eyes (25).

Technological advances in retinal imaging have led to the development of newer multimodal imaging methods (Figure 3) that should enable the identification of new biomarkers, the evaluation of their prognostic relevance, and thus a better understanding of the pathogenesis of AMD (26). The Classification of Atrophy Meeting (CAM) Group, an international expert panel, has issued recommendations for the use of the various imaging techniques, as well as definitions to enable the standardized analysis and interpretation of study data (27, 28, 29, 30). One important noninvasive imaging technique is optical coherence tomography (OCT; spectral domain OCT [SD-OCT] or swept source OCT [SS-OCT]), which is now widely used and can generate high-resolution, cross-sectional images of the retina with near-histological detail within seconds. OCT can detect risk factors for GA even in the early stages of AMD (24). GA is seen in OCT as thinning of the outer retinal layers, loss of reflectivity of the RPE, and associated increased transmission of light into the choroid (complete RPE and outer retinal atrophy, cRORA) (29).

Figure 3

Multimodal imaging of an eye with geographic atrophy and surrounding soft drusen

Another imaging technique used in the diagnostic evaluation of GA, especially in larger hospitals and clinical trials, is fundus autofluorescence (FAF). Autofluorescence images capture the intrinsic fluorescence of molecules at the fundus when illuminated with light of a specific wavelength. The autofluorescence signal is decreased in the area of RPE atrophy because it contains lower amounts of lipofuscin, so this method can be used to detect GA objectively and reproducibly. Quantitative measurements of the GA area on FAF images are strongly correlated with measurements on color fundus images (intra-class correlation coefficient 0.9) (31). The change in the area of GA in the FAF has been accepted by the US Food and Drug Administration (FDA) as a morphological endpoint of clinical trials (13). Software programs from the manufacturers of imaging devices enable the quantitative assessment of various parameters with automatic segmentation (13). The quality of evaluation is continually improving through refinements in technology (32). Many biomarkers can now be quantitatively measured and displayed for easy visual interpretation (Figure 2) (33). These analyses are helpful in clinical practice for patient counseling and follow-up examinations,, as well as for evaluations in the setting of clinical trials.

Therapeutic approaches

General measures such as a balanced Mediterranean diet, protection from sunlight, and not smoking can beneficially affect the progression of AMD. The ARED study showed in 2001 that dietary supplements can lower the risk of conversion of intermediate AMD to late AMD (34). The ARED2 study examined various modifications to the composition of these dietary supplements and showed that replacing beta-carotene with lutein and zeaxanthin was helpful, because beta-carotene was associated with an increased risk of lung cancer in smokers (35). The formulation found to be effective in the ARED2 study contains 500 mg vitamin C, 400 IU vitamin E, 2 mg copper oxide, 10 mg lutein, 2 mg zeaxanthin, and 80 mg zinc oxide. In 2020, the same research group showed that a Mediterranean diet can also significantly lower the risk of conversion to a late-stage form of AMD, particularly to GA (36). A recent retrospective analysis of AREDS2 study data further revealed that a Mediterranean diet can be beneficial to persons who already have GA by slowing the growth of the atrophic area (24). Among these patients, there were also indications that the use of dietary supplements (especially antioxidants including lutein/zeaxanthin) might slow the progression of GA towards the fovea (37); these findings must now be confirmed in a prospective trial in order to prove the benefit of taking these supplements in patients with extrafoveal GA.

No drug for GA has yet been approved in Europe. In 2023, the FDA approved two complement inhibitors for intravitreal administration for the treatment of GA. Pegcetacoplan and avacincaptad pegol are injected intravitreally once a month or once every two months (10, 11). The goal of treatment is to slow the growth of GA. In contrast to anti-VEGF therapy for neovascular AMD, an improvement in visual acuity is not expected. The OAKS and DERBY trials (two multicenter, randomized, double-blind, sham-controlled phase III trials evaluating the C3 complement inhibitor pegcetacoplan, NCT03525613 and NCT03525600) and the GATHER 2 trial (a multicenter, randomized, double-blinded, sham-controlled phase III trial to evaluate the C5 complement inhibitor avacincaptad pegol, NCT04435366) yielded positive findings with respect to their primary endpoint, with a significant reduction by about 20% in the enlargement of the area of GA, compared to a control group with sham injections (10, 11). This morphological parameter is used as a surrogate marker for disease progression and reflects the structural effect of the intervention. The best-corrected central visual acuity may remain unchanged despite the progression of atrophy, as long as GA has not yet reached the fovea. It had been hoped that slowing the enlargement of GA would preserve foveal integrity longer and delay the worsening of central vision, but none of the above trials yielded a significant difference between the treatment and control groups in the change in visual acuity over the period of observation. The reasons for this are not well understood and require further study (38).

In all of these trials, a larger amount of exudative macular neovascularization was observed as an adverse event in the treatment arms (5% in the monthly treatment arm with avacincaptad pegol versus 3% in the control group in the first year in the GATHER-2 study; 11–13% in the monthly treatment arms with pegcetacoplan versus 2–4% in the control groups of the OAKS and DERBY studies within 24 months) and required additional treatment with intravitreal VEGF inhibitors (10, 11). Moreover, isolated cases of intraocular inflammation, some with occlusive vasculitis, and isolated cases of visual worsening and even blindness were described in the USA after the approval of pegcetacoplan (39). The effects of treatment on retinal structure and function as well as possible adverse events over a further three years are now being studied in GALE, an open-label extension trial (NCT04770545).

In Europe, the marketing authorization application for both drugs was withdrawn by the manufacturers after a negative judgment was expressed by the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP). Although the EMA recognized the unmet medical need for an effective treatment, it justified its rejection on the ground that the significant slowing of atrophy progression that had been achieved in the approval trials did not lead to a clinically relevant functional benefit for the patients and thus does not outweigh the risks, including intraocular inflammation (40). Post-hoc analyses showed that the rate of persistent loss of 15 letters within 12 months was lowered by the treatment (7.8% in the control group versus 3.4% with avacincaptad pegol) (e1), but this finding did not persuade the EMA. Further studies are needed to elucidate the cause of the seeming contradiction between the structural and functional results, and to study these patients’ long-term course. The identification of predictive biomarkers with multimodal imaging may help identify subgroups in which a clear functional benefit can be demonstrated.

Aside from intravitreal complement inhibitors, other therapeutic approaches are now being studied in clinical trials, including intravitreally injected neuroprotective drugs, subretinally injected RPE cells grown from embryonic stem cells, subretinal implantation of a bionic retinal chip, and gene therapy (12) (Figure 4, eFigure). The last three approaches might yield a permanent effect with a single intervention. Approaches to gene therapy for GA are based on the applied active substances that enable the cellular transduction of plasmids via viral vectors, thereby inducing the secretion of inhibitory proteins of the complement system (e2). In the fall of 2023, a phase II study of gene therapy for complement inhibition was terminated early on the advice of the Data Monitoring Committee after an evaluation of the risk-benefit ratio (e3, e4). The subretinal application of patches consisting of pluripotent stem cells has already been investigated in phase I/II trials, but its clinical application is not yet within reach. The situation is different with the subretinal implantation of microchips that, with the aid of special eyeglasses with a built-in microcamera, receive image signals and energy via infrared projection and then transmit electrical impulses to the optic nerve. This treatment even carries the prospect of a certain degree of visual improvement. The results of the multicenter PRIMAvera intervention trial (NCT04676854) are expected to become available this year (e5, e6).

Figure 4

Routes of administration of new therapeutic approaches for geographic atrophy

eFigure

Signaling pathways of the complement cascade and targets of new therapeutic approaches

Perspectives

Blindness due to neovascular AMD has become much less common since the introduction of anti-VEGF therapy in 2006 (7), but GA remains one of the more common causes of irreversible loss of vision. While no treatment for GA has been approved to date in Europe, intravitreal complement inhibitors were approved and has been available in the United States since 2023 that can significantly slow the progression of the GA area. This treatment, however, cannot stop the disease or improve vision. Moreover, the need for repeated treatments over the long term is burdensome for patients and their families and poses a challenge for physicians and the healthcare system. In the future, it is hoped that preventive treatments will become available that can prevent the development of AMD or slow the progression of early AMD to a more advanced stage. In the meantime, it remains important to advise patients in detail about lifestyle changes that can promote their visual health and about rehabilitative measures, such as magnifying visual aids, that can help them meet the demands of everyday life.

Conflict of interest statement

SL has served as a paid consultant for Apellis, Astellas, Bayer, Janssen, and Novartis. She has received payment for presentations at continuing medical education events from Apellis, Astellas, Bayer, Heidelberg Engineering, Janssen, Novartis, AbbVie, Biogen, Roche, and Zeiss.
Her institution received research funding from Novartis and Roche.

LvdE has served as a paid consultant for Boehringer Ingelheim and has received lecture honoraria from Heidelberg Engineering.

TA has served as a paid consultant for Apellis. He has received lecture honoraria from Apellis, Heidelberg Engineering, Bayer, Novartis, and Roche. He has received support for travel expenses from Apellis. He holds two patents: German patent application 10 2022 132 717.5 and US patent APP 18/532, 270, 2024.

FGH has served as a paid consultant for Acucela, Alcon, Alexion, Alzheon, Apellis, Bayer, Boehringer-Ingelheim, Genentech/Roche, Grayburg Vision, Heidelberg Engineering, ivericBio/Astellas, Lin Bioscience, Janssen, Novartis, Oculis, Opthea, Oxurion, PixiumScience, Stealth Biotherapeutics, and Zeiss.

His institution has received research funding from Acucela, Allergan, Apellis, Bayer, Belite Bio, Bioeq, Centervue, Geuder, Roche/Genentech, Heidelberg Engineering, ivericBio/Astellas, NightStarx, Novartis, Optos, and Zeiss.

MLB states that he has no conflict of interest.

Manuscript submitted on 23 September 2024, revised version accepted on 8 January 2025.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
Prof. Dr. med. Sandra Liakopoulos

Klinik für Augenheilkunde,
Universitätsklinikum der Goethe-Universität

Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany

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