Comprehensive assessment of geographic atrophy - general concepts and autofluorescence imaging findings

This post was written by Dr Aaron Yap, Ophthalmology Fellow and Dr Leo Sheck. You can find part 2 and part 3 here. Information on consultation with Dr Sheck can be found here.

Geographic atrophy (GA) is the late manifestation of age-related macular degeneration (AMD) characterised by progressive loss of retinal pigment epithelium and photoreceptors. Until recently, it was a slowly progressive untreatable disease that led to vision loss. There is now potential treatment for geographic atrophy by targeting the complement pathway to slow the progression of GA. 

Here, we will summarise the recent trial of using Pegcetacoplan for the treatment of GA. Furthermore, we will look at the assessment of GA using different imaging modalities to help inform the risk of vision loss and to identify patients who maybe suitable for treatment when it becomes available.

Pegcetacoplan Randomised Control Trial (Liao et. al.)

The complement system is part of our innate immune system. Pegcetacoplan is a complement C3 inhibitor.. Dysregulation of the complement system is strongly linked to the development and progression of AMD with the evidence coming both from genome wide association studies and individual case series with rare complement factor H (CFH) gene variants. (De Breuk et.al, Taylor et.al) As the point of convergence for all 3 complement pathways, C3 complement inhibition is the ideal target for drug therapy.

Eligible patients were at least 50 years of age, had best-corrected visual acuity (BCVA) of 6/95 or better, confirmed diagnosis of GA secondary to AMD using fundus autofluorescence imaging with GA area between 2.5 mm2 - 17.5 mm2. Patients with current or previous neovascular AMD are excluded from the study.

There were then randomised into four groups and followed up for 12 months

• 15 mg pegcetacoplan monthly
• 15 mg pegcetacoplan every other month
• Sham injection monthly
• Sham injection every other month

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The primary outcome measure was a mean change in square root GA lesion area from baseline to month 12. In patients receiving pegcetacoplan monthly or every other month, the GA growth rate was reduced by 29% and 20% compared with the sham treatment group. The effect was more pronounced in the second 6 months of treatment, with observed reductions of 45% and 33% for pegcetacoplan monthly and every other month, respectively.

The incidence of endopthalmitis was 1-2% in the pegcetacoplan treatment group. New onset exudative AMD was reported more frequently in pegcetacoplan-treated eyes (20.9% and 8.9% in monthly and every other month groups) than in sham-treated eyes (1.2%).

Disappointingly, Pegcetacoplan had no effect on changes in foveal encroachment or visual acuity measures at month 12 compared with sham treatment. All groups exhibited a gradual decline in visual acuity measures with no significant difference between groups.

Vogl et. al. used artificial intelligence on the same dataset to identify OCT biomarkers that are associated with faster progressing lesions, in which pegcetacoplan treatment would be particularly beneficial. Local progression rate was higher for areas with low eccentricity to the fovea, thinner photoreceptor layer thickness, or higher hyperreflective foci concentration in the GA junctional zone. From this modelling, the authors were able to demonstrate a significant lowering of the local progression rate by 28.0% in monthly pegcetacoplan treated eyes compared with sham.

Phase 3 trials are near completion. Preliminary results demonstrate sustained benefits of pegcetacoplan therapy at reducing GA progression rates up to 24 months with no serious safety concerns.

Assessing GA

General statements on rate of growth

Are there any features that can be used to predict which patients will progress faster? The location of atrophy development, rate and direction of progression will determine the imminent threat to foveal involvement and central vision loss. 

To date, studies have been consistently reporting the following

• Smaller baseline lesion sizes progress slower. (Fleckenstein et. al.)
• Extrafoveal and multifocal lesions enlarge faster than foveal (<300mm fovea diameter) or unifocal lesions. (Fleckenstein et. al.)
• Progression toward the periphery appears faster than progression toward the fovea. (Lindner et. al.)
• Growth is faster when the fellow eye has GA or in regions of reticular pseudodrusen. (Marsiglia et. al.)

Autofluorescence features that influence GA growth rate

Fundus autofluorescence (FAF) is an imaging modality that highlights the lipofuscin within the retinal pigment epithelium to create an image of the retina. In established areas of GA, retinal pigment cells are absent and these areas will be dark on FAF. However, different patterns observed at the junctional zone of GA can give information about the growth rate. One hypothesis is that increased autofluorescence may represent excessive accumulation of lipofuscin load, which is toxic to retinal pigment epithelial cells and a harbinger to further GA progression.

Previously, Holtz et. al. identified six patterns of FAF surrounding GA : “None,” “Focal,” “Banded,” “Patchy,” “Diffuse Trickling,” and “Diffuse Nontrickling”. Shen et. al. conducted a systematic review into the reclassification of these patterns. He coalesced the six patterns into four groups based on rates of progression.

In stepwise fashion, group 1 with no surrounding FAF had the lowest rate of progression (0.061mm/year), while group 4 had the highest rate (0.245mm/year). The GA radius growth rates of the Banded, Patchy, and Diffuse Nontrickling patterns were not statistically different, hence they were classified into group 3.

Fleckenstein et. al. conducted a study looking into the characteristics of patients with diffuse tricking FAF phenotype. Patients with diffuse trickling, in comparison to those with diffuse non-tricking, were younger at first presentation (68.2 vs 75.4) and had higher rates of cardiovascular comorbidities, including high blood pressure, angina and heart attacks. Torczynski et. al. described the choriocapillaris as a multiple lobules with each lobule having its own blood supply. The corresponding lobulated appearance of GA lesions in the diffuse trickling phenotype, thinned choroid and association with cardiovascular risk factors elude to vascular insufficiency to the choriocapillaris bed as an inciting factor.

Clinical implications

GA is now becoming a disease that may be treatable. It is important to identify patients that are most likely to benefit using multimodal imaging given the somewhat disappointing trial result. Here, we summarise the recent findings on autofluorescence imaging in assessing GA growth rate. 

The next article in this series will look at OCT features of GA and biomarkers for progression.

About Dr Leo Sheck

Dr Sheck is a RANZCO-qualified, internationally trained ophthalmologist. He combined his initial training in New Zealand with a two-year advanced fellowship in Moorfield Eye Hospital, London. He also holds a Doctorate in Ocular Genetics from the University of Auckland and a Master of Business Administration from the University of Cambridge. He specialises in medical retina diseases (injection therapy), cataract surgery, ocular genetics, uveitis and electrodiagnostics.