Treating patients with geographic atrophy: are we there yet?

Abstract

Geographic atrophy (GA) is a progressive degenerative disease that significantly contributes to visual impairment in individuals aged 50 years and older. The development of GA is influenced by various modifiable and non-modifiable risk factors, including age, smoking, and specific genetic variants, particularly those related to the complement system regulators. Given the multifactorial and complex nature of GA, several treatment approaches have been explored, such as complement inhibition, gene therapy, and cell therapy. The recent approval by the Food and Drug Administration of pegcetacoplan, a complement C3 inhibitor, marks a significant breakthrough as the first approved treatment for GA. Furthermore, numerous interventions are currently in phase II or III trials, alongside this groundbreaking development. In light of these advancements, this review provides a comprehensive overview of GA, encompassing risk factors, prevalence, genetic associations, and imaging characteristics. Additionally, it delves into the current landscape of GA treatment, emphasizing the latest progress and future considerations. The goal of starting this discussion is to ultimately identify the most suitable candidates for each therapy, highlight the importance of tailoring treatments to individual cases, and continue monitoring the long-term implications of these emerging interventions.

Keywords: Age-related macular degeneration; Avacincaptad pegol; Complement cascade inhibitors; Multimodal imaging; Pegcetacoplan.

Fig. 1

Optical Coherence Tomography (OCT) Illustration of Drusen and Reticular Pseudodrusen (RPD), A Color Fundus Photography depicts conventional drusen in the macular region and RPD positioned near the arcades. The OCT images correspond to the dashed lines on the fundus photography, with the third column displaying magnified views of the second column. B “Ribbon” RPD, hyperreflective material positioned above the retinal pigmented epithelium (RPE), leading to a modification in the contour of the ellipsoid zone (EZ). C Magnified view of area delineated by white dashed box, arrows indicate "Ribbon" RPD. D Conventional Drusen, located between the RPE and Bruch’s membrane. E Magnified view of area delineated by white dashed box, arrows indicate conventional Drusen. F “Dot” RPD, hyperreflective material penetrates through the EZ. G Magnified view of area delineated by white dashed box, arrows indicate "Dot" RPD. (Reprinted from Wu Z, Fletcher EL, Kumar H, Greferath U, Guymer RH. Reticular pseudodrusen: A critical phenotype in age-related macular degeneration. Progress in Retinal and Eye Research. 2022;88:101017, with permission from Elsevier)

Fig. 2

Optical Coherence Tomography Classification of Geographic Atrophy. The Classification of Atrophy Meeting (CAM) group has recommended the adoption of standardized terms such as incomplete retinal pigmented epithelium (RPE) and outer retinal atrophy (iRORA) and complete RPE and outer retinal atrophy (cRORA) in age-related macular degeneration classification. cRORA corresponds to an area of at least 250 μm on a single horizontal B-scan (Reprinted from Corradetti G, Corvi F, Nittala MG, Nassisi M, Alagorie AR, Scharf J, et al. Natural history of incomplete retinal pigment epithelial and outer retinal atrophy in age-related macular degeneration. Canadian Journal of Ophthalmology. 2021;56(5):325–34, with permission from Elsevier)

Fig. 3

Fundus Autofluorescence Patterns of Geographic Atrophy Patterns. The Fundus Autofluorescence in Age-related Macular Degeneration (FAM) study categorized geographic atrophy eyes into five distinct phenotypes: none, focal increased, banded, patchy, and diffuse. The pattern is presented in pairs, with the baseline FAF image on the left and the follow-up FAF image on the right (follow-up ranged from 12 to 25 months). Diffuse pattern is further divided into reticular, branching, fine granular, fine granular with peripheral punctate spots and trickling. (Reprinted from Holz FG, Bindewald-Wittich A, Fleckenstein M, Dreyhaupt J, Scholl HPN, Schmitz-Valckenberg S. Progression of Geographic Atrophy and Impact of Fundus Autofluorescence Patterns in Age-related Macular Degeneration. American Journal of Ophthalmology. 2007;143(3):463–72.e2, with permission from Elsevier)

Fig. 4

Overview and Pathways of the Complement System. The complement cascade involves a multitude of protein interactions occurring within the plasma, within the cells, and membranes. This process is initiated through the classical, lectin, and alternative pathways. These three pathways ultimately converge at C3, a pivotal mediator with diverse functions. The accompanying image highlights points of therapeutic intervention indicated by C3 (in red) and C5 (in blue) inhibition (Reprinted from Kim BJ, Mastellos DC, Li Y, Dunaief JL, Lambris JD. Targeting complement components C3 and C5 for the retina: Key concepts and lingering questions. Prog Retin Eye Res. 2021;83:100936, with permission from Elsevier)