Pegcetacoplan Treatment and Consensus Features of Geographic Atrophy Over 24 Months

Abstract

Importance: Despite widespread availability and consensus on its advantages for detailed imaging of geographic atrophy (GA), spectral-domain optical coherence tomography (SD-OCT) might benefit from automated quantitative OCT analyses in GA diagnosis, monitoring, and reporting of its landmark clinical trials.

Objective: To analyze the association between pegcetacoplan and consensus GA SD-OCT end points.

Design, setting, and participants: This was a post hoc analysis of 11 614 SD-OCT volumes from 936 of the 1258 participants in 2 parallel phase 3 studies, the Study to Compare the Efficacy and Safety of Intravitreal APL-2 Therapy With Sham Injections in Patients With Geographic Atrophy (GA) Secondary to Age-Related Macular Degeneration (OAKS) and Study to Compare the Efficacy and Safety of Intravitreal APL-2 Therapy With Sham Injections in Patients With Geographic Atrophy (GA) Secondary to Age-Related Macular Degeneration (DERBY). OAKS and DERBY were 24-month, multicenter, randomized, double-masked, sham-controlled studies conducted from August 2018 to July 2020 among adults with GA with total area 2.5 to 17.5 mm2 on fundus autofluorescence imaging (if multifocal, at least 1 lesion ≥1.25 mm2). This analysis was conducted from September to December 2023.

Interventions: Study participants received pegcetacoplan, 15 mg per 0.1-mL intravitreal injection, monthly or every other month, or sham injection monthly or every other month.

Main outcomes and measures: The primary end point was the least squares mean change from baseline in area of retinal pigment epithelium and outer retinal atrophy in each of the 3 treatment arms (pegcetacoplan monthly, pegcetacoplan every other month, and pooled sham [sham monthly and sham every other month]) at 24 months. Feature-specific area analysis was conducted by Early Treatment Diabetic Retinopathy Study (ETDRS) regions of interest (ie, foveal, parafoveal, and perifoveal).

Results: Among 936 participants, the mean (SD) age was 78.5 (7.22) years, and 570 participants (60.9%) were female. Pegcetacoplan, but not sham treatment, was associated with reduced growth rates of SD-OCT biomarkers for GA for up to 24 months. Reductions vs sham in least squares mean (SE) change from baseline of retinal pigment epithelium and outer retinal atrophy area were detectable at every time point from 3 through 24 months (least squares mean difference vs pooled sham at month 24, pegcetacoplan monthly: -0.86 mm2; 95% CI, -1.15 to -0.57; P < .001; pegcetacoplan every other month: -0.69 mm2; 95% CI, -0.98 to -0.39; P < .001). This association was more pronounced with more frequent dosing (pegcetacoplan monthly vs pegcetacoplan every other month at month 24: -0.17 mm2; 95% CI, -0.43 to 0.08; P = .17). Stronger associations were observed in the parafoveal and perifoveal regions for both pegcetacoplan monthly and pegcetacoplan every other month.

Conclusions and relevance: These findings offer additional insight into the potential effects of pegcetacoplan on the development of GA, including potential effects on the retinal pigment epithelium and photoreceptors.

Trial registration: ClinicalTrials.gov Identifiers: NCT03525600 and NCT03525613.

Figure 1.. Segmentation of Geographic Atrophy (GA) Features From Spectral-Domain Optical Coherence Tomography (SD-OCT) Imaging

For each SD-OCT volume, all B-scans were segmented for photoreceptor degeneration (PRD), retinal pigment epithelium (RPE) loss, hypertransmission (HTR), and RPE and outer retinal atrophy (RORA). RORA was taken to be overlapping regions of the 3 former features—that is, co-occurrence as per A-scan. Exemplar segmentation of a single B-scan and its axis along en face fundus photograph shown. Resultant feature probability maps from total volume segmentations collectively presented by projection onto en face fundus photograph. AI indicates artificial intelligence.

Figure 2.. Association Between Pegcetacoplan and Geographic Atrophy (GA) Features at the Spectral-Domain Optical Coherence Tomography (SD-OCT) Level

The figure shows differences between treatment groups in least square mean (LSM) mean change in area of GA features from baseline. SD-OCT GA features considered were retinal pigment epithelium (RPE) loss and outer retinal atrophy (RORA), RPE loss, hypertransmission, photoreceptor degeneration (PRD), and PRD in isolation in study eyes. Changes within total Early Treatment Diabetic Retinopathy Study regions were considered. Graphs show LSMs and SEs (error bars) by treatment group and time postbaseline, which were estimated from a mixed-effects model with a random intercept at the level of the participant that included the following as cross-level interactions: treatment, presence of choroidal neovascularization in the fellow eye (yes or no), baseline GA lesion area (<7.5 mm² or ≥7.5 mm²), baseline SD-OCT GA feature, analysis visit, treatment × analysis visit, and baseline SD-OCT GA feature × analysis visit. EOM indicates every other month.

Figure 3.. Least-Squares Mean (LSM) Change in Normal-Luminance Best-Corrected Visual Acuity (NL-BCVA) Score

The figure shows differences between treatment groups in LSM change in NL-BCVA in Early Treatment Diabetic Retinopathy Study letter score from baseline. The graph shows LSMs and SEs (error bars) by treatment group and time postbaseline, which were estimated from a mixed-effects model with a random intercept at the level of the participant that included the following as cross-level interactions: treatment, baseline geographic atrophy lesion area (<7.5 mm² or ≥7.5 mm²); baseline BCVA score; analysis visit; baseline presence of choroidal neovascularization in the fellow eye (yes or no); analysis visit × treatment; baseline BCVA score × analysis visit. EOM indicates every other month.