With the recent approval in Australia of two drugs for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD), the Australian clinical community can now actively manage – rather than simply monitor – the disease in their patients. In this article, Professor Robyn Guymer and Associate Professor Zhichao Wu discuss how clinicians can best identify those patients who will benefit most from GA treatments.

Patients with GA secondary to AMD have historically faced an inevitable course of progressive vision loss. Indeed, GA remains a common cause of irreversible vision loss in people over 50 in our community. Estimates suggest that 1–2% of the Australian population over 50 years of age have late-stage AMD, or 100–200,000 people, with half having geographic atrophy (GA). first treatments for GA starting to be used in clinical care in Australia, we are on the cusp of a transformative era for the management of GA. Pivotal trials of pegcetacoplan (OAKS and DERBY ) and avacincaptad pegol (GATHER2) were able to show a slowing in the growth rate of GA lesions in treated eyes compared to sham-treated eyes, thus meeting their primary efficacy outcome. Following on from their approval in the United States, the Therapeutic Goods Administration (TGA) in Australia recently approved these two treatments, Syfovre (pegcetacoplan) and Izervay (avacincaptad pegol).

As a clinical community, we now have an opportunity to move from a monitoring paradigm to more active management of patients with GA. To do this, we need to ensure that we can (1) optimise the certainty that the diagnosis of atrophy is secondary to AMD, and not another disease; (2) be able to identify lesion characteristics that have been associated with a faster rate of growth, as this will help with individualised patient counselling; (3) understand the trial outcomes in terms of visual benefit, and the trial limitations in being able to capture any visual benefit. These skills will help clinicians contextualise their patients within the broad GA landscape, to help identify who, among all the patients with GA, will likely benefit most from treatment.

1. Optimise the certainty of the diagnosis of atrophy being secondary to age- related macular degeneration,

2. Identify lesion characteristics that have been associated with a faster rate of geographic growth, and

images was the approved primary endpoint in the pivotal clinical trials and used to test the efficacy of new treatments.

FAF can also be used to identify the background hyper-autofluorescence (hyperAF), surrounding the GA lesion, which occurs as a result of the accumulation of fluorophores. Distinctly different patterns of hyperAF are seen and help predict growth characteristics, where a diffuse background hyperAF signals the likelihood of faster growth. characteristic FAF patterns can be seen in many inherited retinal diseases (IRD), which adds significantly to our ability to differentiate

Figure 5. FAF images of a case of extensive macular atrophy with pseudodrusen-like appearance (EMAP) – a sub-phenotype of GA. Note the vertical direction of growth, the trickling background fluorescence pattern, and the lesser degree of decrease in autofluorescence of the atrophic lesion.

may be necessary. Using MMI, characteristics that are currently thought to be associated with an increased risk of faster GA growth are related to the number, size, and location of the GA lesions, the background autofluorescence pattern, and the presence of reticular pseudodrusen (RPD).

Slower GA growth rates are seen when baseline lesions are small, unifocal (compared to multifocal), and are located at the fovea (compared to extrafoveally). OAKS and DERBY trials found that as the distance from the foveal centre increased, so too did the rate of the lesion growth. Similarly, data from these trials found that the smaller the circularity index (a measure of the regularity of the GA lesions), the faster the rate of growth. The status of both eyes is also important, with growth rates appearing to be faster when the fellow eye also has GA.

OCT allows for other relevant biomarkers to be identified, such as the presence of RPD, which are deposits located above the RPE, and are distinct from conventional drusen, which are located below the RPE. AMD eyes with GA and RPD have been found to have more rapid GA growth than those without RPD, and GA lesions appear to grow faster in the actual region that has RPD. On OCT B-scans, disruption of the photoreceptor ellipsoid zone (EZ) has also been reported as a possible biomarker for predicting the location of future GA progression. Now with AI algorithms, the difference or ratio between the extent of EZ and RPE loss can be calculated, with a larger difference or ratio (i.e., greater EZ compared to RPE loss) potentially indicative of faster growth. Regulatory-approved AI algorithms can now be accessed via payment – where scans can be uploaded to portals, and a report received on parameters such as the EZ-RPE difference or EZ/RPE ratio. These parameters are now being used as inclusion criteria for some current trials in GA. OCT imaging can also more definitely identify how close the atrophic lesion is to the foveal centre point, which is not so precise with FAF imaging,

GA trials in various phases of development are currently being, or will soon be, undertaken in Australia. Some of these novel interventions are being given by other forms of administration apart from intravitreal injections, such as orally and subcutaneously. Thus, while we have our first treatments available, they will not be the last to be developed. Support for clinical trials and allowing our own patients with GA to access potentially efficacious novel treatments, often years before they become widely available, is not only critical for new drug developments, but gives our patients a unique opportunity to contribute, and possibly benefit, from this access.

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This article was sponsored by iCare Australia.

Robyn Guymer AM MBBS PhD FRANZCO FAHMS is Professor of Ophthalmology at Melbourne University and a deputy director of the Centre for Eye Research Australia. She is a senior retinal specialist at the Royal Victorian Eye and Ear Hospital, and a clinician scientist who leads a team of researchers primarily investigating age-related macular degeneration. Prof Guymer has co-authored over 450 peer-reviewed papers. She is currently investigating new strategies for treating early stages of AMD and is working to identify novel imaging, functional biomarkers, and surrogate endpoints to improve the feasibility of conducting early intervention trials. She has been a principal investigator in many industry- sponsored trials, serves on several pharmaceutical advisory boards, and is a member of several international working groups on macular diseases.

Associate Professor Zhichao Wu BOptom PhD is a clinician- scientist and leads Centre for Eye Research Australia’s clinical biomarkers research. His work focuses on expediting the discovery of new treatments and ways to prevent irreversible vision loss from conditions such as AMD and glaucoma.