Association of complement C3 inhibitor pegcetacoplan with reduced photoreceptor degeneration beyond areas of geographic atrophy

Abstract

Preservation of photoreceptors beyond areas of retinal pigment epithelium atrophy is a critical treatment goal in eyes with geographic atrophy (GA) to prevent vision loss. Thus, we assessed the association of treatment with the complement C3 inhibitor pegcetacoplan with optical coherence tomography (OCT)-based photoreceptor laminae thicknesses in this post hoc analysis of the FILLY trial (NCT02503332). Retinal layers in OCT were segmented using a deep-learning-based pipeline and extracted along evenly spaced contour-lines surrounding areas of GA. The primary outcome measure was change from baseline in (standardized) outer nuclear layer (ONL) thickness at the 5.16°-contour-line at month 12. Participants treated with pegcetacoplan monthly had a thicker ONL along the 5.16° contour-line compared to the pooled sham arm (mean difference [95% CI] + 0.29 z-score units [0.16, 0.42], P < 0.001). The same was evident for eyes treated with pegcetacoplan every other month (+ 0.26 z-score units [0.13, 0.4], P < 0.001). Additionally, eyes treated with pegcetacoplan exhibited a thicker photoreceptor inner segment layer along the 5.16°-contour-line at month 12. These findings suggest that pegcetacoplan could slow GA progression and lead to reduced thinning of photoreceptor layers beyond the GA boundary. Future trials in earlier disease stages, i.e., intermediate AMD, aiming to slow photoreceptor degeneration warrant consideration.

Multimodal imaging and deep learning in geographic atrophy secondary to age‐related macular degeneration

“…Interestingly, independent groups demonstrated that AI‐based OCT quantification of retinal layers can reveal progressive photoreceptor degeneration outside areas of GA (Figure 2) (Pfau, Möller, Künzel, et al., 2020; Pfau, von der Emde, de Sisternes, et al., 2020; Pfau, von der Emde, Dysli, et al., 2020; Reiter et al., 2020). Even therapeutic effects at the level of photoreceptors outside of GA areas could be demonstrated by two independent groups for pegcetacoplan (Pfau et al., 2022; Riedl et al., 2022).…”

“…However, many of the more refined analyses (e.g. degree of retina‐wide photoreceptor degeneration) (Pfau et al., 2022; Pfau, Möller, Künzel, et al., 2020; Pfau, von der Emde, de Sisternes, et al., 2020; Pfau, von der Emde, Dysli, et al., 2020; Riedl et al., 2022), necessitate algorithms that are currently only available in a reading centre setting. Furthermore, assessment of larger GA lesions may be impaired by the limited OCT scan field, at least with some of the current OCT devices.…”

The roadmap to geographic atrophy treatment: A journey of trials and promise

“…Pegcetacoplan demonstrated its efficacy in preserving photoreceptors beyond the regions of retinal pigment epithelium (RPE) atrophy, a pivotal goal in managing eyes with geographic atrophy (GA) to mitigate vision deterioration. Post hoc analysis, on both monthly and bi‐monthly regimens, exhibited a pronounced thickness in the outer nuclear layer (ONL) relative to the control group as well as a thicker photoreceptor inner segment layer was observed in pegcetacoplan‐treated eyes by Month 12 (Pfau et al., 2022).…”

Phase 2 Trial Evaluating Minocycline for Geographic Atrophy in Age-Related Macular Degeneration

“…Therefore, additional therapeutic approaches are desirable. GA progression is typically assessed by manual reading center grading of fundus autofluorescence (FAF) images, although automated segmentation of FAF and optical coherence tomography (OCT) images has been described …”

“…GA progression is typically assessed by manual reading center grading of fundus autofluorescence (FAF) images, although automated segmentation of FAF and optical coherence tomography (OCT) images has been described. 6,7 The innate immune system is centrally involved in GA pathogenesis. [8][9][10][11] AMD is characterized by the accumulation of activated cells of the innate immune system in the subretinal space, at the hallmark lesions of large drusen and GA. 8,11,12 In GA, they are found in both atrophic areas and surrounding transition zones.…”