Impact of Baseline “Ellipsoid Zone At-Risk” Burden on Geographic Atrophy Natural History Growth Rate in the ReCLAIM-2 Clinical Trial

Abstract

Purpose : To evaluate automated baseline assessment of ellipsoid zone (EZ) At-Risk burden and assess the impact of this biomarker on the natural history geographic atrophy (GA) growth in the ReCLAIM-2 clinical trial.

Methods : ReCLAIM-2 is a Phase 2 prospective, randomized clinical trial of elamipretide, a mitochondrial protective agent, compared to placebo in advanced dry age-related macular degeneration (AMD) with GA at week 48. All baseline scans that were of sufficient quality for analysis and segmentation from patients in the placebo arm that completed the week 48 visit were included.
The EZ At-Risk feature assessment tool is an automated deep learning (DL)-enabled image feature extraction system that was trained to identify areas of EZ abnormality and areas that may be at greatest risk for progressive loss. The DL model was previously trained and validated based on areas of EZ degradation consisting of areas where the EZ-RPE thickness was < 10 um while excluding areas of EZ loss with GA, in order to focus feature extraction on areas that were still “at-risk” rather than already atrophic.
SD-OCT scans from the ReCLAIM-2 were analyzed by the EZ At-Risk analysis tool and evaluated with a DL-enhanced multi-layer segmentation platform that provided compartmental quantitative assessment, including OCT-based GA area. The subset of patients in 25th and 75th percentile groups of EZ At-Risk burden were the compared for change in GA area.

Results : Thirty-eight eyes from the study placebo group were included. The 25th percentile group had a mean baseline EZ At-Risk burden of 7.6% and the 75th percentile group had a mean baseline EZ At-Risk burden of 20.8%. The 48-week change in GA area was over 3-fold higher in the high burden group compared to the low burden group (4.5% absolute increase in macular coverage vs 1.4%, p = 0.03).

Conclusions : Higher baseline burden of the novel biomarker – EZ At-Risk is associated with higher growth rates GA area in eyes in the placebo arm of the ReCLAIM-2 clinical trial. This suggests that EZ degradation represents a potential critical biomarker for AMD progression and GA growth risk. Utilization of such a fully automatic biomarker in clinical trial enrollment could facilitate identification of subjects at high risk for progression and may also provide a novel biomarker for progressive photoreceptor loss.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.