For nearly two decades ophthalmologists have successfully used intravitreal antivascular endothelial growth factor (antiVEGF) injections for nAMD to restore sight for millions of patients worldwide.2-5

Thanks to recent regulatory approval by the FDA in 2023, patients in the United States are now receiving intravitreal anti-complement factor inhibition for management of GA. This is following the results of important randomised control trials comparing two different anti-complement drugs to sham for the treatment of GA.

The OAKS and DERBY studies examined monthly, or every other month, pegacetacoplan (Syfovre)6,7 compared to sham for patients with both subfoveal and extra-foveal GA. Conversely, the GATHER1/ GATHER2 studies examined the use of monthly avacincaptad pegol (Izervay) compared to sham for patients with extrafoveal GA only.8,9

Both studies showed favourable slowing of disease progression via fundus autofluorescence (FAF) in the treatment arms compared to sham. However, the key difference between anti-VEGF injections and anti-complement injections is the immediate effect on vision following treatment.

Anti-VEGF injections can restore lost vision due to the resorption of macular fluid, the prevention of further leakage, and the development of subretinal fibrosis. Anticomplement injections, conversely, aim only to slow disease progression and do not improve visual acuity in the peri-injection period.

This makes regulatory approval much more difficult as best corrected visual acuity (BCVA) is the most common metric by which treatment success is gauged in eye disease. There has, therefore, been a concerted effort by scientists and clinicians to explore alternative end points to BCVA, and to argue for the success of these agents in management of GA.

NATURAL HISTORY OF GA AND EFFECT ON VISION

Despite a common final clinical picture of irreversible loss of photoreceptors, retinal pigment epithelium (RPE), and choriocapillaris, the development of GA is highly variable both within the same patient and within populations.10 In general, lesions initially appear in the peri-foveal region and can thus preserve BCVA until late in the disease process.11

Despite the disease heterogeneity, a definition of GA was formulated in the Wisconsin age-related maculopathy grading system on the basis of stereoscopic colour fundus photography (CFP) images as a sharply defined area of “drop out of the RPE, exposing choroidal blood vessels”.12 This was then revised for the Age-related Eye Disease Study (AREDS) system for classifying age-related macular degeneration (AREDS report No. 6), which defined GA on CFP as a “sharply demarcated, usually circular zone of partial or complete depigmentation of the retinal pigment epithelium, typically with exposure of underlying large choroidal blood vessels that must be as large as the circle I1 (1/8 disc diameter)”.13 More recently, the widespread use of multimodal imaging (MMI) to diagnose and manage retinal disease has led to further definitional changes. Both optical coherence tomography (OCT) and FAF are now routinely used in natural history and interventional studies to monitor GA progression. The Classification of Atrophy (CAM) group has established spectral domain OCT (SD-OCT) definitions of GA for research and clinical purposes.14 Similarly, the Fundus Autofluorescence Imaging in Agerelated Macular Degeneration Study (FAM) and the Natural History of Geographic Atrophy Study (GAP) identified different FAF patterns that were predictive of rapid GA progression.11,15

The rate of GA lesion growth varies in the literature from 0.5316 to 2.6 mm2 /year17 (median 1.78 mm2 /year).10 There are certain FAF patterns that predict faster lesion expansion. For example, extra-foveal disease progresses faster than sub-foveal disease.15 Multifocal disease also progresses faster than unifocal lesions.15 There are also FAF patterns that are predictive of more rapid growth. FAF GA changes are classified into four patterns: focal, banded, patchy, and diffuse (further subdivided into reticular, branching, fine granular, and fine granular with peripheral punctate spots).18 More rapid progression of GA is seen in eyes with banded or diffuse patterns at the junctional zone.19 Conversely, eyes without FAF alterations at the junctional zone have slower disease progression.18

FDA ACCEPTANCE OF ANATOMICAL ENDPOINTS

Identifying clinically appropriate end points for GA studies has long been challenging. Due to relative foveal sparing in some patients until late in the disease, BCVA can often be preserved. In addition, the rate of vison loss in GA can be unpredictable. The GAP study reporting a 12 month BCVA decrease of 6.2 letters with a wide standard deviation of ± 15.6 letters.15 However, despite good BCVA, dense scotomas do occur over the areas of GA which are readily measurable with perimetry.20,21 Thus, using BCVA as the primary endpoint in GA trials would render them unfeasibly long.22,23 This led to a joint symposium in 2006 between the FDA and the National Eye Institute (NEI) to discuss, in part, how best to judge success in treatment for new therapies in AMD.24 After extensive deliberation, it was determined that an acceptable clinical end point for GA trials could be the rate of progression in treated versus placebo groups. Therefore, in both the OAKS/DERBY and GATHER1/2 studies, the primary end point was the change from baseline to the end of the study period, in the total area of GA lesions based on FAF images. It is recognised that areas of GA appear as a dark area on FAF due to a reduction in the normal autofluorescence signal following the death of photoreceptors and retinal pigment epithelial cells, and the subsequent loss of the normal fluorophores such as lipofuscin.11 The rationale is that GA lesion growth is a proxy for photoreceptor cell death – which inevitably leads to irreversible visual function loss. Preserving retinal structure is thought to be crucial for maintaining visual function, and therefore the goal of complement inhibition therapy is to slow disease progression.

Complement inhibition, as a potential intervention for GA, gained popularity after genome-wide association studies (GWAS) consistently showed polymorphisms in the complement factor H (CFH) gene in AMD.25 Other polymorphisms in the alternative complement pathway have been shown to be associated with AMD, albeit less strongly.26 Interestingly, while these polymorphisms have been shown to be associated with the onset of GA, there is less support for their association with GA progression.27,28

OTHER TOOLS FOR ASSESSING VISUAL FUNCTION IN GA

It is recognised that there needs to be some measurement of a patient’s visual function in GA in trial settings. Most clinical tests in these patients demonstrate poor anatomicalfunctional correlation. Conversely, imaging alone does not provide information regarding visual deficits. Tests of visual function include BCVA, low luminance visual acuity, reading speed, and patient reported outcomes; all of which have been reported to be reduced in GA.22 Microperimetry maps retinal sensitivity spatially and correlates anatomic features with visual function,29 and has been shown to correlate retinal function with GA lesion characteristics.30,31 However, these tests are a time consuming exercise for both patient and doctor alike, and are therefore often used only in the context of trials rather than clinical practice. Indeed, these tests were used in the OAKS/DERBY and GATHER 1/2 trials. Unfortunately, the mean threshold sensitivity using microperimetry assessment in GA was not greater in patients treated with pegcetacoplan compared with sham in the OAKS trial.

Other tests of visual function, like reading speed, have been shown to be reduced in patients with GA.32 Interestingly, the OAKS and DERBY studies did not show a benefit in slowing the decline in patients treated with pegcetacoplan over sham.33 The extension study GALE, with results due in September 2025, will further elaborate on the effect of complement inhibition on both microperimetry and reading speed. Similarly, there was also a lack of secondary functional outcomes in the GATHER1/2 studies, including standard and low luminance BCVA.9,34

However, the apparent discrepancy between reduction in GA growth demonstrated by these complement inhibitors, and the lack of visual function benefit, is being explored. There are some studies that highlight the location of the GA may be more influential when determining reading speed than the size of the scotoma.21,35 When considering English readers, scotomas above fixation (the fovea) correspond to faster reading speeds compared to scotomas to the left of fixation. Prior to the current OAKS, DERBY and GATHER trials, other complement inhibitors have been studied. Retrospective analysis of these trials showed that the correlation between GA and functional outcomes was driven by different disease manifestations, including location of the atrophy.36 Chakravarthy et al. have shown that the most significant correlation between GA expansion rates (measured on FAF) and loss of BCVA was in eyes with subfoveal, unifocal lesions. Importantly a subfoveal, unifocal GA lesion with a growth rate of 1.7 mm2 /year resulted in a 15-letter loss at 96 weeks, whereas the same lesion with a GA growth rate of 1.2 mm2 /year resulted in a three-letter loss at 96 weeks.36 These insights from post-hoc analyses will be important to guide ophthalmologists in choosing the patients who will benefit the most from anticomplement therapy.

Other novel experimental biomarkers, as a predictor of GA progression, include the ratio between photoreceptor (PR) loss and RPE loss. Schmidt-Erfurth and coworkers investigated the PR loss / RPE loss in GA patients and analysed the effect of pegcetacoplan treatment in patients enrolled in the Phase 2 FILLY study.37 Using two AI algorithms, the authors found that eyes with higher baseline PR loss / RPE loss ratios had higher rates of GA expansion than eyes with lower ratios.37 Such baseline characteristics will be useful in refining selection criteria in future studies, such that the patients with the most potential for success with these therapies can be recruited.

CONCLUSION

We are in an exciting moment when it comes to the management of GA. Not only are there two FDA approved therapies currently in use, but there are also several other drugs in the pipeline nearing the end of their trial periods. In addition, as real-world evidence and Phase 4 studies are reported, ophthalmologists will have greater insights into who will benefit the most from these therapies. Patients stand to benefit greatly from these advances, and we need to understand more comprehensively how best to identify, image, and follow them up to maximise their outcomes.

To earn your CPD hours from this article visit mieducation.com/geographic-atrophy-understanding-current-therapies.

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