Imaging features like ellipsoid zone (EZ) attenuation may hold the key to identifying the patients who would benefit most from newly approved treatments for late stage dry age-related macular degeneration (AMD), as they can predict disease progression over time, said Justis P. Ehlers, MD, at the 2024 American Academy of Ophthalmology meeting in Chicago.

Dr. Ehlers, the director of the Tony and Leona Campane Center for Excellence in Image-guided Surgery and Advanced Imaging Research at the Cole Eye Institute of Cleveland Clinic, noted that there are several retinal biomarkers that could be potential OCT-based endpoints for clinical trials. These include drusen volume, ellipsoid zone loss, hyperreflective foci, hypertransmission defects, and incomplete retinal pigment epithelial and outer retinal atrophy (iRORA). He focused his presentation on EZ integrity, explaining that the US Food and Drug Administration (FDA) has already specified that this as an approvable endpoint for clinical trials investigating treatment for dry AMD.

“There are multiple ways to potentially characterize EZ integrity. The approach that we have taken is to measure the distance between the ellipsoid zone and the RPE. And when it's completely absent from visualization, we call this total ellipsoid zone loss or total attenuation. This is what’s now considered FDA approvable,” said Dr. Ehlers. “Interestingly, this allows us to look at potential earlier damage, such as EZ to RPE thinning or partial ellipsoid zone degradation or attenuation, representing damage to the outer segment. Additional areas that have been looked at by multiple groups include the actual reflectivity or brightness of the ellipsoid zone, and this has also been found to be linked to disease progression.”

Elements of a Useful Endpoint

Dr. Ehlers explained that a useful OCT-based endpoint must be functionally relevant, linked to disease pathogenesis, minimally disruptive to trial sites, and scalable for large trials, both at a site and at a reading center. There also needs to be a way to interpret the results and validate their accuracy, he said.

“How do we get to feasibility and reproducibility at a reading center level?” he asked. “Part of that includes being able to surmount  the challenges that the disease poses. With dry macular degeneration, there’s multiple potential challenges and confounders, including the complexity of the anatomy, and potentially concerns around directionality that can occur related to drusen that might affect ellipsoid zone visualization.”

To use ellipsoid zone integrity as an endpoint, it’s necessary to develop an efficient and reliable way to accurately measure this retinal feature, said Dr. Ehlers. The platform must be able to work with multiple OCT devices, and certified readers must be able to review the information and correct or validate it as needed, he said. The approach he described involved a machine learning segmentation platform to analyze patient OCT scans with a multi-model approach with multiple logic checkpoints. Data indicates the tool can effectively identify the EZ regions as a biomarker for predicting GA progression in intermediate dry AMD.

Methodology of Assessment

The key method Dr. Ehlers described to assess EZ integrity involves evaluating the thickness of photoreceptor outer segments by measuring the distance between the ellipsoid zone and the retinal pigment epithelium (RPE). When this space is completely absent from visualization, it represents total EZ loss, or total attenuation. “This is what’s now considered to be FDA approvable,” said Dr. Ehlers. This measurement also allows researchers to look at potential earlier damage, such as EZ to RPE thinning. EZ-RPE thickness ≤20 µm represents partial EZ attenuation, he said.

Another potential approach, which has been explored by other groups,^1,2 is to measure EZ intensity, which measures the reflectivity or brightness of the ellipsoid zone. “This has been found to be linked to things like visual function as well as disease progression and should be looked at as well,” said Dr. Ehlers. In this approach, reflectivity is measured on a scale from 0 (black, which denotes atrophy) to 256 (white, which represents healthy photoreceptors).

Dr. Ehlers and other researchers recently conducted a study to assess the feasibility, accuracy, and consistency of manual and semi-automated segmentation methods for outer retinal layers, focusing on EZ integrity.³ They found that a semi-automated method, enhanced by machine learning and validated by expert readers, showed consistency comparable to manual segmentation by human readers.

Other recently published data shows the link between EZ changes and visual function, said Dr. Ehlers.^4-7 “When we looked at this in a retrospective data set, what we found was that visual acuity was clearly linked to ellipsoid zone degradation,” he said. “When we want to look for future vision loss, which may be important in terms of clinical trial inclusion, we found that those eyes that had more degradation of the ellipsoid zone at baseline had much greater risk of 2-line vision loss or more over the course of 5 years.”

In eyes with intermediate AMD, the total volume of drusen is not as important as whether the drusen has a significant encroachment on the EZ, he said. “We know, based on studies that have been done, that not all drusen are created equal,” said Dr. Ehlers. “When we evaluate which factors drive most progression risk, ellipsoid zone quantitative assessment really drives models in terms of classifying eyes at greater risk.”

Results in Past Trials

The first phase 2 trial to prespecify changes in ellipsoid zone attenuation as a secondary endpoint was ReCLAIM-2 (NCT03891875), which evaluated elamipretide (Stealth BioTherapeutics) in subjects with non-central GA secondary to AMD. “What this trial showed was that there was a 43% reduction in total EZ loss and 47% reduction in partial EZ loss over the course of the first year with elamipretide treatment,” said Dr. Ehlers. In the phase 3 trial program for elamipretide, change in slope for total EZ loss has been designated as a primary endpoint, he said.⁸

Post hoc analyses of several other recent trials in GA show the potential of total and/or partial EZ loss as a future endpoint, he said. Analysis of ARCHER (NCT04656561) found that treatment with a complement C1q inhibitor (ANX007; Annexon Biosciences) showed a 29% reduction in total EZ loss compared to sham (P=.017), and a 27% reduction in partial EZ loss (P=.021) compared to sham at 12 months. “Interestingly, this study showed preservation of visual acuity in its primary analysis,” Dr. Ehlers commented. Analyses of data from the phase 3 trials for DERBY (NCT03525600) and OAKS (NCT03525613) evaluating pegcetacoplan (Syfovre; Apellis) and the GATHER1 (NCT04435366) and GATHER2 (NCT05536297) trials for avacincaptad pegol (Izervay; Astellas) also demonstrated EZ preservation, he said.

Dr. Ehlers noted that more research will help scientists better understand the relationship between the EZ structure and visual function, as well as the cadence of EZ progression. “Ellipsoid zone integrity appears to be a promising biomarker and clinical trial endpoint for dry macular degeneration that could be used for risk prognostication, precision clinical trial design, and for study population stratification/enrichment,” he concluded.

References

1. Ha A, Sun S, Kim YK, Jeoung JW, Kim HC, Park KH. Automated quantification of macular ellipsoid zone intensity in glaucoma patients: the method and its comparison with manual quantification. Sci Rep. 2019;9(1):19771. doi:10.1038/s41598-019-56337-7

2. Thiele S, Isselmann B, Pfau M, et al. Validation of an automated quantification of relative ellipsoid zone reflectivity on spectral domain-optical coherence tomography images. Transl Vis Sci Technol. 2020;9(11):17. doi:10.1167/tvst.9.11.17

3. Bell J, Whitney J, Cetin H, et al. Validation of inter-reader agreement/consistency for quantification of ellipsoid zone integrity and sub-RPE compartmental features across retinal diseases. Diagnostics. 2024;14(21):2395. https://doi.org/10.3390/diagnostics14212395

4. Litts KM, Zhang Y, Freund KB, Curcio CA. Optical coherence tomography and histology of age-related macular degeneration support mitochondria as reflectivity sources. Retina. 2018;38(3):445-461. doi:10.1097/IAE.0000000000001946

5. Sarici K, Abraham JR, Sevgi DD, et al. Risk classification for progression to subfoveal geographic atrophy in dry age-related macular degeneration using machine learning-enabled outer retinal feature extraction. Ophthalmic Surg Lasers Imaging Retina. 2022;53(1):31-39. doi:10.3928/23258160-20211210-01

6. Cassels NK, Wild JM, Margrain TH, Chong V, Acton JH. The use of microperimetry in assessing visual function in age-related macular degeneration. Surv Ophthalmol. 2018;63(1):40-55. doi:10.1016/j.survophthal.2017.05.007

7. Yordi S, Cakir Y, Kalra G, et al. Ellipsoid zone integrity and visual function in dry age-related macular degeneration. J Pers Med. 2024;14(5):543. doi:10.3390/jpm14050543

8. Ehlers JP, Hu A, Boyer D, et al. ReCLAIM-2: a randomized phase 2 clinical trial evaluating elamipretide in age-related macular degeneration, geographic atrophy growth, visual function, and ellipsoid zone preservation. Ophthalmol Sci. 2024;5(1):100628. doi:10.1016/j.xops.2024.100628