Over the last several issues, we have discussed potential pharmacologic targets to combat nonexudative AMD, and specifically geographic atrophy (GA) progression. While early data suggest that some of these targets may slow GA progression, the ultimate goal is to stop GA progression. But how should this be assessed, and at what stage in the disease process should we intervene? Current studies, including the phase 2 FILLY study looking at intravitreal APL-2 to slow the rate of GA, used area of GA as measured by fundus autofluorescence (FAF). Patients had to already have GA at the start of the study to participate.

With the new Classification of Atrophy Meetings (CAM) classification recently published,¹ we realize that macular atrophy may be more complex and multifaceted than just GA alone. This raises the question as to whether we should start clinical trials at early stages. For instance, should we start clinical trials at the level where the RPE and outer retina are incompletely disrupted (iRORA) or should we wait for complete retinal pigment epithelium and outer retinal atrophy (cRORA)? When designing future clinical trials in dry AMD, should we continue to use FAF evaluation or should we consider a more specific and micron-level outcome that is afforded by SD-OCT and the corresponding near infrared image? To help us shed light on the consensus meetings, we have asked 2 incredible thinkers and experts in our field, Dr. Glenn Jaffe and Dr. SriniVas Sadda, to opine.

DEFINING ATROPHY

Glenn Jaffe, MD, and SriniVas Sadda, MD

The CAM are a series of consensus conferences with goals to define imaging protocols, definitions, and features of atrophy associated with retinal diseases that can be used in the clinic and in clinical trials. The CAM participants include imaging experts, basic scientists, clinician scientists, and clinical trialists. The CAM group has developed criteria based on optical coherence tomography criteria that define atrophy in neovascular and advanced non-neovascular age-related macular degeneration. Macular atrophy is the general term, and geographic atrophy is the specific term for tissue loss that causes loss of visual function. Complete RPE and outer retinal atrophy is the CAM term for macular atrophy on OCT that requires loss of the outer retinal tissue, corresponding RPE loss ≥250 µm and choroidal hypertransmission ≥250 µm. Incomplete RPE and outer retinal atrophy is the term used to describe outer retinal and RPE atrophy and hypertransmission, that is of lesser magnitude than that needed for cRORA, and usually proceeds cRORA.

There is an unmet need for effective treatments that prevent progression from intermediate AMD to advanced AMD, and treatments that limit progression of atrophy in eyes with neovascular AMD and GA.

This unmet need has been reflected by an increasing number of intermediate AMD and observational and interventional GA clinical trials. CAM cRORA criteria have been used by reading centers to assess eligibility and to assist measurement of GA area at baseline and at study endpoints in GA trials, and to identify macular atrophy in neovascular AMD trials. Furthermore, studies that assess progression of intermediate AMD to iRORA will soon be initiated. If successful, data from these trials will be useful to validate and further refine the CAM criteria. Once treatments are available, clinicians will then be able to apply these criteria, perhaps facilitated by artificial intelligence tools, to identify patients likely to benefit from these interventions. RP

REFERENCE

1. Wu Z, Pfau M, Blodi BA, et al. OCT signs of early atrophy in age-related macular degeneration: interreader agreement: Classification of Atrophy Meetings report 6 [published online ahead of print, 2021 Mar 23]. Ophthalmol Retina. 2021;S2468-6530(21)00093-2. doi:10.1016/j.oret.2021.03.008