Age-related macular degeneration in 2025- opportunities and challenges

The efficacy of anti-VEGF therapy for nAMD is undisputed. Nonetheless, maintenance of vision in the long-term remains a challenge due to the need for timely retreatment to avoid disease activity recurrence. The treat-and-extent regimen was developed to mitigate the risk of recurrence at the same time as increasing retreatment interval, and has been widely adopted since. Teo et al.‘s comprehensive review summarized published evidence on treatment regimens [9]. With newer agents offering increased durability and advances in imaging technology, treatment regimens continue to evolve and enable further personalization. An example is the use of an automated OCT analyser algorithm in the TRUCKEE study using real world imaging data. The authors demonstrated the feasibility of automating retinal fluid assessment, which may further streamline the care pathway of nAMD treatment in future [10].

While fluid features highly in decision making for nAMD treatment, findings from new imaging studies suggest there are several mechanisms leading to exudation, some neovascular and some non-neovascular. The reviews on type 3 macular neovascularization [11] and pachychoroid neovasculopathy [12] both highlighted new understanding in the pathogenesis of these subtypes of MNV. This knowledge is important to further personalize therapy and is crucial to developing novel therapeutic strategies beyond anti-VEGF. The potential role of choroidal alterations was highlighted in both cases, which is in keeping with findings from basic science studies evaluating the effect of retinal pigment epithelial hypoxia. Digsby et al. demonstrated in their cell culture system that retinal pigment epithelial hypoxia may alter the ratio of apical to basal secretion of apoE, which in turn leads to SDD-promoting secretion profile [13, 14].

More recently, attention has been turned to the treatment of another form of AMD, specifically geographic atrophy (GA). While two agents targeting the complement system have received FDA approval for the treatment of GA, the lack of functional improvement have limited their global penetrance. What is the future of GA therapy?

One key challenge in implementing therapies for GA is the diverse spectrum of GA phenotypes and variability in progression pattern. Of particular significance in relation to treatment, the limited correlation between structural and functional measures have been increasingly recognized. Compared to nAMD, the functional impact of GA onset and progression is much more variable and tend to occur later in course of disease. These differences partly explain the FDA’s acceptance of GA lesion growth as a surrogate endpoint. However, these anatomical outcomes have not been correlated with functional changes, at least within the timeframe of pivotal clinical trials to-date. Broadbent et al. summarized current evidence on the natural history of GA and highlighted the influence of baseline features such as size, perimeter, focality, location and autofluorescence pattern on GA lesion progression [15]. Incorporating the learnings from these studies into future clinical trials are crucial. Similarly, understanding of these features are vital in the appropriate selection of patients for treatment in clinical settings.

A rich and exciting pipeline exploring novel mode of action and delivery route is currently being evaluated for both nAMD and GA. These approaches are fitting in view of the complexity of pathogenesis in AMD. The reviews by Shirian et al. and Jamil et al. will provide the readers with an understanding of the mode of action and potential side effect profile of the leading pharmaceutical and gene therapies being evaluated [16, 17]. Additional opportunities lie in the huge potential of imaging data for biomarker discovery. Non-exudative OCT findings, ellipsoid zone assessment, fibrosis biomarkers and OCT angiography findings offer new opportunities to correlate functional outcomes more precisely than simple fluid status assessment. However, efforts in harmonizing nomenclature, image acquisition protocol, and standardization of grading approaches are required. Unlike nAMD, the natural history of intermediate AMD and GA are less well understood. Efforts such as the MACUSTAR and PINNACLE studies are expected to provide additional clarify and develop endpoints for future clinical trials. Artificial intelligence offers the potential to overcome some of these challenges but additional concerns such as black box and data privacy need to be addressed before prime time deployment [18].

In this special issue of Eye on AMD, we have curated a great selection of articles and reviews from leaders in the field to discuss the current status, future opportunities and challenges. While technological advances and automation may present new opportunities, the importance in understanding the complex basic science mechanism driving AMD cannot be over-emphasized. Imaging studies reflecting the effect on different cell and tissue types and their impact on visual function are essential in developing the next wave of clinical trials and corresponding endpoints.